Avelumab In Patients With Previously Treated Advanced Stage Classical Hodgkin's Lymphoma (JAVELIN HODGKINS)

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02603419
• Collaborator: (none)
• Enrollment: 34
• Locations: 13
• Arms: 6
• Actual Duration (Months): 37
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an expansion phase. The lead-in phase is a multiple-dose, randomized, parallel-arm, pharmacokinetic and pharmacodynamic study of avelumab as a single agent in adult patients with cHL. Patients enrolled in the lead-in phase of this study are required to have relapsed following a prior autologous or allogeneic HSCT, or to be ineligible for HSCT. Based on the preliminary TO, safety, and efficacy results from the lead-in phase, the expansion phase will evaluate the anti-tumor activity and safety of single-agent avelumab utilizing an intra-patient dose escalation paradigm based on two of the dosing regimens studied in the lead-in phase in 40 cHL patients in whom an allogeneic HSCT has failed.

Condition or Disease	Intervention/Treatment	Phase
Hodgkins Lymphoma	Drug: Avelumab; Drug: Avelumab; Drug: Avelumab; Drug: Avelumab; Drug: Avelumab; Drug: Avelumab	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A PHASE 1 PHARMACOKINETIC-PHARMACODYNAMIC STUDY OF AVELUMAB (MSB0010718C) IN PATIENTS WITH PREVIOUSLY TREATED ADVANCED STAGE CLASSICAL HODGKIN'S LYMPHOMA
• Actual Study Start Date: Mar 10, 2016
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Apr 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lead-in phase-Cohort A X1 mg IV every 2 weeks	Drug: Avelumab; Anti-PD-L1 antibody at X1 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression.
Experimental: Lead-in phase-Cohort B X2 mg IV every 2 weeks	Drug: Avelumab; Anti-PD-L1 antibody at X2 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression.
Experimental: Lead-in phase-Cohort C X3 mg IV every 3 weeks	Drug: Avelumab; Anti-PD-L1 antibody at X3 mg IV every 3 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression
Experimental: Lead-in phase-Cohort D X4 mg IV every 2 weeks	Drug: Avelumab; Anti-PD-L1 antibody at X3 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression
Experimental: Lead-in phase-Cohort E X5 mg IV every 2 weeks	Drug: Avelumab; Anti-PD-L1 antibody at X mg IV every 2 weeks. Treatment with avelumab will continue until disease progression
Experimental: Expansion phase X1 mg IV every 2 weeks followed by X1 or X4 mg every 2 weeks	Drug: Avelumab; Anti-PD-L1 antibody at X1 mg IV every 2 weeks which can be escalated to X4 mg every 2 weeks based on safety and efficacy. Treatment with avelumab will continue until disease progression.

Outcome Measures

Primary Outcome Measures

1. Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1 [Day 2 of Cycle 1]

   Target occupancy on peripheral blood CD14+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

2. Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 1 of Cycle 2 [Day 1 of Cycle 2]

   Target occupancy on peripheral blood CD14+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

3. Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 2 of Cycle 1 [Day 2 of Cycle 1]

   Target occupancy on peripheral blood CD3+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

4. Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 1 of Cycle 2 [Day 1 of Cycle 2]

   Target occupancy on peripheral blood CD3+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.

5. Expansion Phase: Percentage of Participants With Objective Response as Assessed by Blinded Independent Central Review (BICR) [From treatment start in expansion phase until progressive disease or death due to any cause (maximum duration of 14 months)]

   Objective response: complete response (CR) or partial response (PR) according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression (Disease progression: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease) or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in sum of products of greatest diameters. PR was defined >= 50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.

6. Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Single Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1]

   AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to extrapolated infinity AUC(0-inf), after single dose.

7. Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2]

   AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to extrapolated infinity AUC(0-inf), after multiple dose.

8. Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1]

9. Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2]

10. Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab After Single Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1]

    AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after single dose.

11. Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2]

    AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after multiple dose.

12. Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1]

    Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after single dose.

13. Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2]

    Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after multiple dose.

14. Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1]

    Time to reach maximum observed plasma concentration of avelumab, after single dose.

15. Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2]

    Time to reach maximum observed plasma concentration of avelumab, after multiple dose.

16. Lead-in Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2]

17. Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single Dose [pre-dose, 1, 6, 24, 144, 312 and 527 hours post-dose on Day 1 of Cycle 1]

    The last time point of the last quantifiable concentration (Tlast) of avelumab, after single dose.

18. Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Multiple Dose [pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2]

    The last time point of the last quantifiable concentration (tlast) of avelumab, after multiple dose.

Secondary Outcome Measures

1. Lead-in Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related TEAEs and TEAEs Graded >=3 as Per National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)]

   An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03: Grade 3: severe or medically significant but not immediately life-threatening, or prolongation of existing hospitalization indicated; Grade 4: life-threatening consequence; Grade 5: death related to AE. SAE was an AE resulting in any of following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or congenital anomaly. A TEAEs: an event that emerged during treatment period (From first dose of study drug until end of open label phase [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)] that was absent before treatment,or worsened during treatment period relative to pre-treatment state. AE was considered related to study drug if event was assessed by investigator as probably or possibly related.

2. Lead-in Phase: Number of Participants With Laboratory Abnormalities Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [From first dose of study drug up to 90 days after the last administration of the study drug (maximum duration of 32 months)]

   Hematology: Anemia (Grade)G3: Hg <8.0 grams/deciliter (g/dL); lymphocyte count decreased G3: <0.5-0.2*10^9/L, G4: <0.2*10^9/L; neutrophil count decreased: G3: <1.0-0.5*10^9/L, G4: <0.5*10^9/L; platelet count decreased: G3:<50.0-25.0*10^9/L, G4: <25.0*10^9/L; white blood cell (WBC) decreased: G3: <0.2*10^9/L, G4: <1.0*10^9/L. Chemistry: [ALT, ALP increased and AST G3: >5.0-20.0*ULN, G4: >20.0*ULN]. blood bilirubin increased: G3: >3.0-10.0*ULN, G4: >10.0 *ULN. [cholesterol high: G3: >10.34 - 12.92, G4: >12.92; hypokalemia G3: <3.0-2.5, G4: <2.5]mmol/L, creatine phosphokinase (Cpk) increased: G3: >5*ULN-10*ULN, G4: >10*ULN; gamma-glutamyl transferase (Ggt) increased: G3: >5.0-20.0*ULN, G4: >20.0*ULN; [hypertriglyceridemia G3: >500-1000, G4: >1000; hypermagnesemia, G3: >3.0-8.0, G 4: >8.0]mg/dL, Lipase increased: G3: >2.0 - 5.0*ULN, G4: >5.0*ULN, Serum amylase increased: G3: >2.0 - 5.0*ULN, G4: >5.0*ULN. Only those category in which at least one participant had data were reported.

3. Lead-in Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status [Day 1 up to Month 29]

   ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. ADA never-positive participants were those who had no positive (titer less than cutpoint [22.5 percentage (%) inhibition]) ADA results at any time point. ADA ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [22.5% inhibition]) ADA result at any time point.

4. Expansion Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status [Day 1 up to Month 14]

   ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. ADA never-positive participants were those who had no positive (titer less than cutpoint [22.5% inhibition]) ADA results at any time point. ADA ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [22.5% inhibition]) ADA result at any time point.

5. Lead-in Phase: Number of Participants With Neutralizing Antibodies (nAb) Status [Day 1 up to Month 29]

   nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive participants. nAb never-positive participants were those who had no positive (titer less than cutpoint [0.71]) nAb results at any time point. nAb ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [0.71]) nAb result at any time point.

6. Expansion Phase: Number of Participants With Neutralizing Antibodies (nAb) Status [Day 1 up to Month 14]

   nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive participants. nAb never-positive participants were those who had no positive (titer less than cutpoint [0.71]) nAb results at any time point. nAb ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [0.71]) nAb result at any time point.

7. Lead-in Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab [Day 1 up to Month 29]

   Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum ADA titer (180, 4860, 43740 and 131220) are reported.

8. Expansion Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab [Day 1 up to Month 14]

   Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum ADA titer (180, 4860, 43740 and 131220) are reported.

9. Lead-in Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab [Day 1 up to Month 29]

   Serum samples were assayed for nAb using a validated analytical method. Number of nAb ever positive participants for serum nAb titer (1) is reported.

10. Expansion Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab [Day 1 up to Month 14]

    Serum samples were assayed for nAb using a validated analytical method.

11. Lead-in Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy [Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of Cycle 3, 5, 7; and at End of Treatment (EOT) (maximum duration of 29 months)]

12. Lead-in Phase: Number of Participants With Gene Expression of Transcripts Associated With Immune Activation and Regulation [Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of Cycle 3, 5, 7; and at End of Treatment (maximum duration of 29 months)]

13. Lead-in Phase: Number of Participants With T Cell Immunophenotype [Day 1 of Cycles 1, 2, 3, 4, 7, 10 and at End of Treatment (maximum duration of 29 months)]

14. Lead-in Phase: Percentage of Participants With Objective Response as Assessed by Investigator [From randomization until disease progression or death due to any cause (maximum duration of 32 months)]

    Objective response: complete response (CR) or partial response (PR) according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression (Disease progression: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease) or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in sum of products of greatest diameters. PR was defined >= 50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.

15. Lead-in Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator [From randomization to PD, death or start of new anti-cancer therapy (maximum duration of 32 months)]

    DC: best overall response of CR, PR, or stable disease (SD). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75% in sum of the products of greatest diameters. PR was defined >=50% decreased in SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in SPD and SD was defined as < PR but not progressive disease. To qualify as a best overall response of SD, at least one SD assessment must be observed >=6 weeks after start date and before disease progression. (Disease progression: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).

16. Lead-in Phase: Time to Tumor Response (TTR) as Assessed by Investigator [From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of 32 months)]

    TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.

17. Lead-in Phase: Duration of Response (DR) as Assessed by Investigator [From first documentation of objective response to date of first documentation of objective PD or death due to any cause (maximum duration of 32 months)]

    DR is defined, for participants with an objective response, as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective PD or to death due to any cause, whichever occurs first. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.(PD: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).

18. Lead-in Phase: Progression-Free Survival (PFS) as Assessed by Investigator [From randomization to the date of progression of disease or death due to any cause, whichever occurs first (maximum duration of 32 months)]

    PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression as per RECIST 1.1, was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered as progression of disease.

19. Expansion Phase: Percentage of Participants With Objective Response as Assessed by Investigator [From treatment start in expansion phase until disease progression or death due to any cause (maximum duration of 14 months)]

    Objective response was defined as CR or PR according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD. (PD: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).

20. Expansion Phase: Time to Tumor Response (TTR) as Assessed by Investigator and by Blinded Independent Central Review (BICR) [From treatment start in expansion phase to first documentation of objective response (CR or PR) (maximum duration of 14 months)]

    Time to Tumor Response (TTR) was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.

21. Expansion Phase: Duration of Response (DR) as Assessed by Investigator and by Blinded Independent Central Review (BICR) [From first documentation of objective response in expansion phase to date of first documentation of objective PD or death due to any cause (maximum duration of 14 months)]

    Duration of Response (DR) is defined, for participants with an objective response, as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective progression of disease (PD) or to death due to any cause, whichever occurs first. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.

22. Expansion Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator and by Blinded Independent Central Review (BICR) [From treatment start in expansion phase to PD, death or start of new anti-cancer therapy (maximum duration of 14 months)]

    Disease Control (DC) was defined as the best overall response of CR, PR, or SD. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD and Stable Disease was defined as less than a PR but not progressive disease. To qualify as a best overall response of SD, at least one SD assessment must be observed >=6 weeks after start date and before disease progression.

23. Expansion Phase: Progression-Free Survival (PFS) as Assessed by Investigator and by Blinded Independent Central Review (BICR) [From treatment start in expansion phase to date of first documentation of objective Progressive Disease (PD) or death due to any cause, whichever occurs first (maximum duration of 14 months)]

    PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using a Cox's Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.

24. Expansion Phase: Overall Survival [From treatment start in expansion phase until death (maximum duration of 14 months)]

    Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.

25. Expansion Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related TEAEs and TEAEs Graded >=3 Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)]

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03: Grade 3: severe or medically significant but not immediately life-threatening, or prolongation of existing hospitalization indicated; Grade 4: life-threatening consequence; Grade 5: death related to AE. SAE was an AE resulting in any of following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or congenital anomaly. TEAEs: an event that emerged during treatment period (From first dose of study drug until end of expansion phase [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)] that was absent before treatment, or worsened during treatment period relative to pre-treatment state. AE was considered related to study drug if event was assessed by investigator as probably or possibly related.

26. Expansion Phase: Number of Participants With Laboratory Abnormalities of Grade 3 Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)]

    As per NCI-CTCAE v 4.03, Grade >= 3 criteria were; Alanine aminotransferase: 0 LLN, 0.58 ULN microkat/L (microkatal /L); GGT: 0 LLN, 0.63 ULN microkat/L, Glucose: 4.11 LLN, 5.88 ULN mmol/L, LOW Sodium: 136 LLN, 146 ULN mmol/L; Prothrombin intl. normalized ratio: 0.9 LLN, 1.2 ULN; LOW lymphocytes (10^9/L); 1.5 LLN, 4.0 ULN; Platelets (10^9/L): 130 LLN, 400 ULN. Only those category in which at least one participant had data were reported.

27. Expansion Phase: Number of Participants With Acute and Chronic Graft Versus Host Disease (GVHD) [From treatment start in expansion phase up to 90 days after last administration of study drug (maximum duration of 14 months)]

    Acute GvHD is a reaction of donor immune cells against host tissues. The three main tissues that acute GvHD affects are the skin, liver and gastrointestinal tract. Chronic GvHD is a syndrome of variable clinical features resembling autoimmune and other immunologic disorders. Manifestations of chronic GvHD may be restricted to a single organ or site or may be widespread, with profound impact on quality of life.

28. Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf), After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

    AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to infinity AUC(0-inf), after single and multiple dose.

29. Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

30. Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab, After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

    AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after single and multiple dose.

31. Expansion Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

    Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.

32. Expansion Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

33. Expansion Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

34. Expansion Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single and Multiple Dose [pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3]

    The last time point of the last quantifiable concentration (tlast), after single and multiple dose.

35. Expansion Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy [Pre-treatment tumor biopsy for baseline and on-treatment biopsy at Day 7 of Cycle 3]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

KEY INCLUSION CRITERIA

• Histological confirmation of classical Hodgkin's Lymphoma (cHL) with relapsed or refractory disease who, for the lead-in phase, either have had a prior autologous or allogeneic HSCT or are not eligible for HSCT, and , for the expansion phase, have had a prior allogeneic HSCT. In the expansion phase there must be a documented CD3+ donor chimerism of ≥20%.

• Patients must be off previous cHL therapy for at least 28 days prior to randomization in the lead-in phase/first dose of study treatment in the expansion phase.

• At least 1 fluorodeoxyglucose (FDG) PET avid (Deauville 4/5) measurable lesion >1.5 cm on PET-CT scan as defined by the Response Criteria for Malignant Lymphoma (for the lead-in phase) and the Lugano Classification (for the expansion phase) that has not previously been irradiated.

• Expansion phase: Required "de novo" or "archival" tumor biopsy, as well as required on treatment biopsy

• Estern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

KEY EXCLUSION CRITERIA

• Patients with prior allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) who have had:

1. Lead-in phase: allo HSCT performed <12 months prior to randomization. Expansion phase: allo-HSCT performed ≤4 months prior to the first dose of study treatment. NOTE: Patients who have had allo-HSCT performed >4 months prior to the first dose of study treatment must have discontinued all immunosuppressive therapy, and must have no clinical evidence of GVHD; or

2. Immunosuppressive treatment for acute or chronic GVHD within 3 months prior to randomization for the lead-in phase or prior to the first dose of study treatment for the expansion phase (with the exception of those patients who required 15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral prednisone or equivalent must have discontinued it within 7 days prior to first dose of study treatment; or

3. Acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the modified Seattle Glucksberg criteria (Consensus Conference on Acute GVHD Grading Criteria); or

4. Prior chronic GVHD (as defined by the NIH Consensus Development Project) that persisted for >6 months and required systemic immunosuppression (with the exception of those patients who required 15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral prednisone or equivalent must have discontinued it within 7 days prior to the first dose of study treatment; or

5. A donor lymphocyte infusion (DLI) within 3 months prior to randomization for the lead-in phase or first dose of study treatment for the expansion phase.

• Prior therapy with an anti PD 1 or anti PD L1 mAb.

1. Lead-in Phase: May be enrolled if patient stopped prior anti PD1 or anti-PD-L1 therapy more than one year prior to randomization and had a documented prior response.

2. Expansion Phase: Prior therapy with an anti-PD-1 or anti-PD-L1 agent following allo-HSCT is prohibited unless the therapy was stopped more than one year prior to the first dose of study treatment, and the patient had a documented prior response. NOTE: Prior therapy with an anti-PD-1 or anti-PD-L1 agent prior to allo-HSCT is permitted with no time limits and irrespective of a documented response.

3. Patients with a history of ≥Grade 3 anti-PD-1 or anti-PD-L1-related immune toxicity are not eligible.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Az. Ospedaliera-Univers. di Bologna Policlinico S.Orsola-Malpighi	Bologna	BO	Italy	40138
3	Istituto Clinico Humanitas U.O. Oncologia ed Ematologia	Rozzano	Milano	Italy	20089
4	Q2 Solutions	Rosebank	Livingston	United Kingdom	EH54 7EG
5	Oxford University Hospitals NHS Foundation Trust	Headington		United Kingdom	OX3 7LE
6	Leeds Teaching Hospital NHS Trust	Leeds		United Kingdom	LS9 7TF
7	St James's University Hospital	Leeds		United Kingdom	LS97TF
8	University Hospitals of Leicester NHS Trust	Leicester		United Kingdom	LE1 5WW
9	University Hospitals of Leicester NHS Trust	Leicester		United Kingdom	LE2 7LG
10	University College London Hospitals NHS Foundation Trust	London		United Kingdom	N7 9NH
11	UCLH Clinical Research Facility	London		United Kingdom	WIT 7HA
12	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
13	Plymouth Hospitals NHS Trust, Derriford Hospital	Plymouth		United Kingdom	PL6 8DH

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Nov 13, 2017
• Statistical Analysis Plan - Apr 9, 2018

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02603419
• Other Study ID Numbers: B9991007; 2015-002636-41; JAVELIN HODGKINS; JAVELIN HODGKIN'S
• First Posted: Nov 11, 2015
• Last Update Posted: Apr 24, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Pfizer: classical Hodgkins Lymphoma (relapsed/refractory); post-allogeneic HSCT; anti PD-L1; Phase 1; PK; Receptor occupancy; Immunophenotypic biomarkers
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Avelumab; Antibodies, Monoclonal

Study Results

Participant Flow

Pre-assignment Detail	Study was conducted in 2 phases: lead-in and expansion. Expansion phase was terminated by the sponsor on 30 April 2018.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	Participants with relapsed/refractory Classical Hodgkins Lymphoma (cHL) received an intravenous (IV) infusion of 70 milligrams (mg) of avelumab, every two weeks (Q2W) until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, every 3 weeks (Q3W) until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 milligrams/kilogram (mg/kg) of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a complete response (CR) at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a partial response (PR) at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a stable disease (SD) at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Period Title: Lead-in Phase:Maximum Exposure:123Weeks
STARTED	6	7	6	6	6	0
Treated	6	6	6	6	6	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	6	7	6	6	6	0
Period Title: Lead-in Phase:Maximum Exposure:123Weeks
STARTED	0	0	0	0	0	3
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	3

Baseline Characteristics

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W	Expansion Phase: Avelumab 70 mg, 500 mg Q2W	Total
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.	Total of all reporting groups
Overall Participants	6	7	6	6	6	3	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	5 83.3%	5 71.4%	4 66.7%	6 100%	5 83.3%	3 100%	28 82.4%
>=65 years	1 16.7%	2 28.6%	2 33.3%	0 0%	1 16.7%	0 0%	6 17.6%
Sex: Female, Male (Count of Participants)
Female	3 50%	1 14.3%	1 16.7%	1 16.7%	1 16.7%	2 66.7%	9 26.5%
Male	3 50%	6 85.7%	5 83.3%	5 83.3%	5 83.3%	1 33.3%	25 73.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 16.7%	0 0%	1 16.7%	0 0%	1 16.7%	0 0%	3 8.8%
Not Hispanic or Latino	5 83.3%	7 100%	5 83.3%	6 100%	5 83.3%	3 100%	31 91.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 16.7%	1 16.7%	0 0%	0 0%	2 5.9%
Native Hawaiian or Other Pacific Islander	1 16.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.9%
Black or African American	1 16.7%	2 28.6%	0 0%	0 0%	0 0%	0 0%	3 8.8%
White	4 66.7%	5 71.4%	5 83.3%	4 66.7%	5 83.3%	3 100%	26 76.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	1 16.7%	1 16.7%	0 0%	2 5.9%

Outcome Measures

1. Primary Outcome

Title	Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 2 of Cycle 1
Description	Target occupancy on peripheral blood CD14+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.
Time Frame	Day 2 of Cycle 1

Outcome Measure Data

Analysis Population Description

The Target Occupancy (TO) analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	6	5	4	5
Geometric Mean (Geometric Coefficient of Variation) [percentage of occupancy]	99.5 (0.01)	97.7 (0.02)	97.6 (0.03)	99.7 (0.00)	97.8 (0.03)

2. Primary Outcome

Title	Lead-in Phase: Percent Target Occupancy (CD14+ Monocytes) at Day 1 of Cycle 2
Description	Target occupancy on peripheral blood CD14+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.
Time Frame	Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The TO analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	4	6	4	4	4
Geometric Mean (Geometric Coefficient of Variation) [percentage of occupancy]	96.3 (0.04)	96.2 (0.08)	97.0 (0.04)	97.3 (0.05)	98.8 (0.02)

3. Primary Outcome

Title	Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 2 of Cycle 1
Description	Target occupancy on peripheral blood CD3+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.
Time Frame	Day 2 of Cycle 1

Outcome Measure Data

Analysis Population Description

The TO analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	6	5	4	5
Geometric Mean (Geometric Coefficient of Variation) [percentage of occupancy]	99.0 (0.01)	99.0 (0.02)	96.8 (0.05)	99.7 (0.01)	89.8 (0.22)

4. Primary Outcome

Title	Lead-in Phase: Percent Target Occupancy (CD3+ T-Cells) at Day 1 of Cycle 2
Description	Target occupancy on peripheral blood CD3+ T-cells by avelumab was investigated in human blood in vitro by flow cytometry.
Time Frame	Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The TO analysis set included all participants who received at least one dose of study drug and who had at least one receptor occupancy blood sample collected both pre and post Cycle 1 Day 1 dose. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	4	6	4	4	4
Mean (Standard Deviation) [percentage of occupancy]	81.7 (0.37)	91.9 (0.14)	99.1 (0.02)	99.7 (0.01)	98.7 (0.01)

5. Primary Outcome

Title	Expansion Phase: Percentage of Participants With Objective Response as Assessed by Blinded Independent Central Review (BICR)
Description	Objective response: complete response (CR) or partial response (PR) according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression (Disease progression: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease) or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in sum of products of greatest diameters. PR was defined >= 50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.
Time Frame	From treatment start in expansion phase until progressive disease or death due to any cause (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure (OM) was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

6. Primary Outcome

Title	Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Single Dose
Description	AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to extrapolated infinity AUC(0-inf), after single dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	4	6	5	5
Geometric Mean (Geometric Coefficient of Variation) [hour*microgram/mL (hr*mcg/mL)]	2588 (59)	8600 (40)	15887 (29)	17647 (55)	23789 (61)

7. Primary Outcome

Title	Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf) of Avelumab After Multiple Dose
Description	AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to extrapolated infinity AUC(0-inf), after multiple dose.
Time Frame	pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	0	0	0	0

8. Primary Outcome

Title	Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single Dose
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	3	4	4	3
Geometric Mean (Geometric Coefficient of Variation) [micrograms per milliliter (mcg/mL)]	24.0 (35)	68.4 (33)	126 (15)	143 (24)	271 (16)

9. Primary Outcome

Title	Lead-in Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Multiple Dose
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	3	3	4	2
Geometric Mean (Geometric Coefficient of Variation) [mcg/mL]	26.1 (21)	78.7 (19)	135 (8)	195 (46)	273 (22)

10. Primary Outcome

Title	Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab After Single Dose
Description	AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after single dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	4	6	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [hr*mcg/mL]	1933 (64)	8450 (28)	15392 (27)	15436 (38)	23780 (54)

11. Primary Outcome

Title	Lead-in Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab After Multiple Dose
Description	AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after multiple dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	5	5	5	5
Geometric Mean (Geometric Coefficient of Variation) [hr*mcg/mL]	2067 (6)	8789 (39)	19173 (23)	21053 (47)	27196 (59)

12. Primary Outcome

Title	Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single Dose
Description	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after single dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	4	6	5	5
Geometric Mean (Geometric Coefficient of Variation) [days]	3.49 (28)	3.25 (44)	4.04 (23)	4.38 (39)	3.88 (38)

13. Primary Outcome

Title	Lead-in Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Multiple Dose
Description	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half of avelumab, after multiple dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	3	3	4	5
Geometric Mean (Geometric Coefficient of Variation) [days]	2.92 (13)	3.43 (43)	4.62 (17)	4.59 (36)	4.23 (37)

14. Primary Outcome

Title	Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single Dose
Description	Time to reach maximum observed plasma concentration of avelumab, after single dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	3	4	4	3
Median (Full Range) [hours]	1.13	21.60	1.99	1.59	1.50

15. Primary Outcome

Title	Lead-in Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Multiple Dose
Description	Time to reach maximum observed plasma concentration of avelumab, after multiple dose.
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	3	3	3	4	2
Median (Full Range) [hours]	1.18	1.48	1.32	1.53	6.71

16. Primary Outcome

Title	Lead-in Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Multiple Dose
Time Frame	pre-dose, 1, 6, 24, 144, and 312 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	4	6	5	6	6
Geometric Mean (Geometric Coefficient of Variation) [mcg/mL]	1.71 (163)	4.03 (110)	2.54 (125)	12.1 (93)	14.4 (170)

17. Primary Outcome

Title	Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single Dose
Description	The last time point of the last quantifiable concentration (Tlast) of avelumab, after single dose.
Time Frame	pre-dose, 1, 6, 24, 144, 312 and 527 hours post-dose on Day 1 of Cycle 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set included all participants who received at least one dose of study drug and those who had at least one of the PK parameters of interest for avelumab.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	5	6	6	6	6
Median (Full Range) [hours]	168.00	335.00	504.50	334.50	335.50

18. Primary Outcome

Title	Lead-in Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Multiple Dose
Description	The last time point of the last quantifiable concentration (tlast) of avelumab, after multiple dose.
Time Frame	pre-dose, 1, 6, 24, 144, 312, 336 and 504 hours post-dose on Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	0	0	0	0

19. Secondary Outcome

Title	Lead-in Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related TEAEs and TEAEs Graded >=3 as Per National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03: Grade 3: severe or medically significant but not immediately life-threatening, or prolongation of existing hospitalization indicated; Grade 4: life-threatening consequence; Grade 5: death related to AE. SAE was an AE resulting in any of following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or congenital anomaly. A TEAEs: an event that emerged during treatment period (From first dose of study drug until end of open label phase [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)] that was absent before treatment,or worsened during treatment period relative to pre-treatment state. AE was considered related to study drug if event was assessed by investigator as probably or possibly related.
Time Frame	From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who receive at least one dose of study drug.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	6	6	6	6
AEs	6 100%	6 85.7%	6 100%	6 100%	6 100%
SAEs	5 83.3%	2 28.6%	3 50%	2 33.3%	0 0%
Related TEAEs	6 100%	6 85.7%	6 100%	4 66.7%	4 66.7%
TEAEs Graded >=3	6 100%	3 42.9%	2 33.3%	5 83.3%	1 16.7%

20. Secondary Outcome

Title	Lead-in Phase: Number of Participants With Laboratory Abnormalities Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
Description	Hematology: Anemia (Grade)G3: Hg <8.0 grams/deciliter (g/dL); lymphocyte count decreased G3: <0.5-0.2*10^9/L, G4: <0.2*10^9/L; neutrophil count decreased: G3: <1.0-0.5*10^9/L, G4: <0.5*10^9/L; platelet count decreased: G3:<50.0-25.0*10^9/L, G4: <25.0*10^9/L; white blood cell (WBC) decreased: G3: <0.2*10^9/L, G4: <1.0*10^9/L. Chemistry: [ALT, ALP increased and AST G3: >5.0-20.0*ULN, G4: >20.0*ULN]. blood bilirubin increased: G3: >3.0-10.0*ULN, G4: >10.0 *ULN. [cholesterol high: G3: >10.34 - 12.92, G4: >12.92; hypokalemia G3: <3.0-2.5, G4: <2.5]mmol/L, creatine phosphokinase (Cpk) increased: G3: >5*ULN-10*ULN, G4: >10*ULN; gamma-glutamyl transferase (Ggt) increased: G3: >5.0-20.0*ULN, G4: >20.0*ULN; [hypertriglyceridemia G3: >500-1000, G4: >1000; hypermagnesemia, G3: >3.0-8.0, G 4: >8.0]mg/dL, Lipase increased: G3: >2.0 - 5.0*ULN, G4: >5.0*ULN, Serum amylase increased: G3: >2.0 - 5.0*ULN, G4: >5.0*ULN. Only those category in which at least one participant had data were reported.
Time Frame	From first dose of study drug up to 90 days after the last administration of the study drug (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who receive at least one dose of study drug. Here, 'Number analyzed' ('n') = Participants evaluable for this outcome measure for each specified category.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	6	6	6	6
Anemia	0 0%	1 14.3%	0 0%	0 0%	0 0%
Lymphocyte count decreased	2 33.3%	0 0%	0 0%	1 16.7%	1 16.7%
Neutrophil count decreased	1 16.7%	0 0%	0 0%	0 0%	0 0%
Platelet count decreased	0 0%	1 14.3%	2 33.3%	1 16.7%	0 0%
White blood cell decreased	1 16.7%	0 0%	0 0%	0 0%	0 0%
Alanine aminotransferase (ALT)increased	2 33.3%	0 0%	0 0%	1 16.7%	0 0%
Alkaline phosphatase (ALP) increased	2 33.3%	1 14.3%	1 16.7%	0 0%	0 0%
Aspartate aminotransferase (AST) increased	2 33.3%	0 0%	0 0%	0 0%	0 0%
Blood bilirubin increased	1 16.7%	0 0%	1 16.7%	0 0%	0 0%
Cholesterol high	1 16.7%	0 0%	0 0%	0 0%	0 0%
Cpk increased	0 0%	1 14.3%	0 0%	0 0%	0 0%
Ggt increased	2 33.3%	1 14.3%	2 33.3%	0 0%	0 0%
Hypermagnesemia	0 0%	1 14.3%	0 0%	0 0%	0 0%
Hypertriglyceridemia	0 0%	1 14.3%	1 16.7%	0 0%	0 0%
Hypokalemia	0 0%	0 0%	1 16.7%	0 0%	0 0%
Lipase increased	1 16.7%	0 0%	1 16.7%	1 16.7%	0 0%
Serum amylase increased	1 16.7%	0 0%	0 0%	0 0%	0 0%

21. Secondary Outcome

Title	Lead-in Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status
Description	ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. ADA never-positive participants were those who had no positive (titer less than cutpoint [22.5 percentage (%) inhibition]) ADA results at any time point. ADA ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [22.5% inhibition]) ADA result at any time point.
Time Frame	Day 1 up to Month 29

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one ADA sample collected for avelumab.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	5	6	6	6	6
ADA never-positive	5 83.3%	5 71.4%	3 50%	4 66.7%	6 100%
ADA ever-positive	0 0%	1 14.3%	3 50%	2 33.3%	0 0%

22. Secondary Outcome

Title	Expansion Phase: Number of Participants With Anti-Drug Antibodies (ADA) Status
Description	ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. ADA never-positive participants were those who had no positive (titer less than cutpoint [22.5% inhibition]) ADA results at any time point. ADA ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [22.5% inhibition]) ADA result at any time point.
Time Frame	Day 1 up to Month 14

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one ADA sample collected for avelumab.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	3
ADA never-positive	2 33.3%
ADA ever-positive	1 16.7%

23. Secondary Outcome

Title	Lead-in Phase: Number of Participants With Neutralizing Antibodies (nAb) Status
Description	nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive participants. nAb never-positive participants were those who had no positive (titer less than cutpoint [0.71]) nAb results at any time point. nAb ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [0.71]) nAb result at any time point.
Time Frame	Day 1 up to Month 29

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one nAb sample collected for avelumab.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	5	6	6	6	6
nAb never-positive	5 83.3%	5 71.4%	4 66.7%	6 100%	6 100%
nAb ever-positive	0 0%	1 14.3%	2 33.3%	0 0%	0 0%

24. Secondary Outcome

Title	Expansion Phase: Number of Participants With Neutralizing Antibodies (nAb) Status
Description	nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive participants. nAb never-positive participants were those who had no positive (titer less than cutpoint [0.71]) nAb results at any time point. nAb ever-positive participants were defined as those who had at least one positive (titer greater than or equal to cutpoint [0.71]) nAb result at any time point.
Time Frame	Day 1 up to Month 14

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set included all participants who received at least one dose of study drug and who had at least one nAb sample collected for avelumab.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	3
nAb never-positive	3 50%
nAb ever-positive	0 0%

25. Secondary Outcome

Title	Lead-in Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab
Description	Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum ADA titer (180, 4860, 43740 and 131220) are reported.
Time Frame	Day 1 up to Month 29

Outcome Measure Data

Analysis Population Description

Analysis was performed on participants who had received at least one dose of study drug and who had ADA ever-positive results. Here "0" in overall number of participants analyzed signifies that there were no ADA ever-positive participants in that specified group".

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	1	3	2	0
180	0 0%	1 14.3%	1 16.7%
4860	0 0%	1 14.3%	0 0%
43740	0 0%	1 14.3%	1 16.7%
131220	1 16.7%	0 0%	0 0%

26. Secondary Outcome

Title	Expansion Phase: Number of ADA Ever Positive Participants For Each Serum ADA Titers for Avelumab
Description	Serum samples were assayed for ADA using a validated analytical method. Number of ADA ever positive participants for each serum ADA titer (180, 4860, 43740 and 131220) are reported.
Time Frame	Day 1 up to Month 14

Outcome Measure Data

Analysis Population Description

Analysis was performed on participants who had received at least one dose of study drug and who had ADA ever-positive results.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	1
180	1 16.7%
4860	0 0%
43740	0 0%
131220	0 0%

27. Secondary Outcome

Title	Lead-in Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab
Description	Serum samples were assayed for nAb using a validated analytical method. Number of nAb ever positive participants for serum nAb titer (1) is reported.
Time Frame	Day 1 up to Month 29

Outcome Measure Data

Analysis Population Description

Analysis was performed on participants who had received at least one dose of study drug and who had nAb ever-positive results. Here "0" in overall number of participants analyzed signifies that there were no nAb ever-positive participants in that specified group.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	1	2	0	0
Count of Participants [Participants]	0 0%	1 14.3%	2 33.3%	0 0%	0 0%

28. Secondary Outcome

Title	Expansion Phase: Number of nAb Ever Positive Participants For Serum nAb Titer for Avelumab
Description	Serum samples were assayed for nAb using a validated analytical method.
Time Frame	Day 1 up to Month 14

Outcome Measure Data

Analysis Population Description

Analysis was performed on participants who had received at least one dose of study drug and who had nAb ever-positive results. Here "0" in overall number of participants analyzed signifies that there were no nAb ever-positive participants in the specified group.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

29. Secondary Outcome

Title	Lead-in Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy
Time Frame	Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of Cycle 3, 5, 7; and at End of Treatment (EOT) (maximum duration of 29 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected and analyzed due to lack of availability of tumor biopsy tissue for analysis.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	0	0	0	0

30. Secondary Outcome

Title	Lead-in Phase: Number of Participants With Gene Expression of Transcripts Associated With Immune Activation and Regulation
Time Frame	Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of Cycle 3, 5, 7; and at End of Treatment (maximum duration of 29 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected and analyzed due to lack of availability of tumor biopsy tissue for analysis.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	0	0	0	0

31. Secondary Outcome

Title	Lead-in Phase: Number of Participants With T Cell Immunophenotype
Time Frame	Day 1 of Cycles 1, 2, 3, 4, 7, 10 and at End of Treatment (maximum duration of 29 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected and analyzed, as the assay (which was planned for this parameter) could not be used due to quality issues.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	0	0	0	0	0

32. Secondary Outcome

Title	Lead-in Phase: Percentage of Participants With Objective Response as Assessed by Investigator
Description	Objective response: complete response (CR) or partial response (PR) according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression (Disease progression: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease) or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in sum of products of greatest diameters. PR was defined >= 50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.
Time Frame	From randomization until disease progression or death due to any cause (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

The FAS included all randomized participants.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	7	6	6	6
Number (95% Confidence Interval) [percentage of participants]	33.3 555%	0 0%	83.3 1388.3%	33.3 555%	66.7 1111.7%

33. Secondary Outcome

Title	Lead-in Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator
Description	DC: best overall response of CR, PR, or stable disease (SD). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75% in sum of the products of greatest diameters. PR was defined >=50% decreased in SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in SPD and SD was defined as < PR but not progressive disease. To qualify as a best overall response of SD, at least one SD assessment must be observed >=6 weeks after start date and before disease progression. (Disease progression: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).
Time Frame	From randomization to PD, death or start of new anti-cancer therapy (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	7	6	6	6
Number (95% Confidence Interval) [percentage of participants]	50.0 833.3%	57.1 815.7%	100.0 1666.7%	66.7 1111.7%	66.7 1111.7%

34. Secondary Outcome

Title	Lead-in Phase: Time to Tumor Response (TTR) as Assessed by Investigator
Description	TTR was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.
Time Frame	From the date of randomization to the first documentation of objective response (CR or PR) (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

The FAS included all randomized participants. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	2	0	5	2	4
Median (Full Range) [months]	2.6	1.5	1.5	2.1

35. Secondary Outcome

Title	Lead-in Phase: Duration of Response (DR) as Assessed by Investigator
Description	DR is defined, for participants with an objective response, as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective PD or to death due to any cause, whichever occurs first. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.(PD: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).
Time Frame	From first documentation of objective response to date of first documentation of objective PD or death due to any cause (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

The FAS included all randomized participants. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	2	0	5	2	4
Median (95% Confidence Interval) [months]	NA	6.9	6.9	9.4

36. Secondary Outcome

Title	Lead-in Phase: Progression-Free Survival (PFS) as Assessed by Investigator
Description	PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression as per RECIST 1.1, was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered as progression of disease.
Time Frame	From randomization to the date of progression of disease or death due to any cause, whichever occurs first (maximum duration of 32 months)

Outcome Measure Data

Analysis Population Description

The FAS included all randomized participants.

Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W	Lead-in Phase: Avelumab 350 mg Q2W	Lead-in Phase: Avelumab 500 mg Q3W	Lead-in Phase: Avelumab 500 mg Q2W	Lead-in Phase: Avelumab 10 mg/kg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.	Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.
Measure Participants	6	7	6	6	6
Median (95% Confidence Interval) [months]	NA	5.7	8.5	3.1	6.1

37. Secondary Outcome

Title	Expansion Phase: Percentage of Participants With Objective Response as Assessed by Investigator
Description	Objective response was defined as CR or PR according to the Response Criteria for Malignant Lymphoma, from 'start date' until disease progression or death due to any cause. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD. (PD: >= 20% and >= 5-mm increase in sum of target lesion diameters in reference to smallest sum on study and/or substantial worsening in non-target disease).
Time Frame	From treatment start in expansion phase until disease progression or death due to any cause (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

38. Secondary Outcome

Title	Expansion Phase: Time to Tumor Response (TTR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
Description	Time to Tumor Response (TTR) was defined, for participants with an objective response as the time from 'start date' to the first documentation of objective tumor response (CR or PR). CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.
Time Frame	From treatment start in expansion phase to first documentation of objective response (CR or PR) (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

39. Secondary Outcome

Title	Expansion Phase: Duration of Response (DR) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
Description	Duration of Response (DR) is defined, for participants with an objective response, as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective progression of disease (PD) or to death due to any cause, whichever occurs first. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD.
Time Frame	From first documentation of objective response in expansion phase to date of first documentation of objective PD or death due to any cause (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

40. Secondary Outcome

Title	Expansion Phase: Percentage of Participants With Disease Control (DC) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
Description	Disease Control (DC) was defined as the best overall response of CR, PR, or SD. CR was defined as all lymph nodes must have regressed to normal size(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest diameters. PR was defined >=50% decreased in the sum of products of the greatest diameters (SPD) of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >=50% in the SPD and Stable Disease was defined as less than a PR but not progressive disease. To qualify as a best overall response of SD, at least one SD assessment must be observed >=6 weeks after start date and before disease progression.
Time Frame	From treatment start in expansion phase to PD, death or start of new anti-cancer therapy (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

41. Secondary Outcome

Title	Expansion Phase: Progression-Free Survival (PFS) as Assessed by Investigator and by Blinded Independent Central Review (BICR)
Description	PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using a Cox's Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.
Time Frame	From treatment start in expansion phase to date of first documentation of objective Progressive Disease (PD) or death due to any cause, whichever occurs first (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

42. Secondary Outcome

Title	Expansion Phase: Overall Survival
Description	Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Time Frame	From treatment start in expansion phase until death (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

43. Secondary Outcome

Title	Expansion Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Related TEAEs and TEAEs Graded >=3 Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03: Grade 3: severe or medically significant but not immediately life-threatening, or prolongation of existing hospitalization indicated; Grade 4: life-threatening consequence; Grade 5: death related to AE. SAE was an AE resulting in any of following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or congenital anomaly. TEAEs: an event that emerged during treatment period (From first dose of study drug until end of expansion phase [From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)] that was absent before treatment, or worsened during treatment period relative to pre-treatment state. AE was considered related to study drug if event was assessed by investigator as probably or possibly related.
Time Frame	From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who receive at least one dose of study drug.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	3
AEs	2 33.3%
SAEs	2 33.3%
Related TEAEs	0 0%
TEAEs Graded	0 0%

44. Secondary Outcome

Title	Expansion Phase: Number of Participants With Laboratory Abnormalities of Grade 3 Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
Description	As per NCI-CTCAE v 4.03, Grade >= 3 criteria were; Alanine aminotransferase: 0 LLN, 0.58 ULN microkat/L (microkatal /L); GGT: 0 LLN, 0.63 ULN microkat/L, Glucose: 4.11 LLN, 5.88 ULN mmol/L, LOW Sodium: 136 LLN, 146 ULN mmol/L; Prothrombin intl. normalized ratio: 0.9 LLN, 1.2 ULN; LOW lymphocytes (10^9/L); 1.5 LLN, 4.0 ULN; Platelets (10^9/L): 130 LLN, 400 ULN. Only those category in which at least one participant had data were reported.
Time Frame	From first dose of study drug to 90 days after last administration of study drug (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who receive at least one dose of study drug.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	3
Alanine Aminotransferase	1 16.7%
Gamma Glutamyl Transferase	1 16.7%
Glucose	1 16.7%
Low Sodium	1 16.7%
Prothrombin Intl. Normalized Ratio	1 16.7%
Platelets	1 16.7%

45. Secondary Outcome

Title	Expansion Phase: Number of Participants With Acute and Chronic Graft Versus Host Disease (GVHD)
Description	Acute GvHD is a reaction of donor immune cells against host tissues. The three main tissues that acute GvHD affects are the skin, liver and gastrointestinal tract. Chronic GvHD is a syndrome of variable clinical features resembling autoimmune and other immunologic disorders. Manifestations of chronic GvHD may be restricted to a single organ or site or may be widespread, with profound impact on quality of life.
Time Frame	From treatment start in expansion phase up to 90 days after last administration of study drug (maximum duration of 14 months)

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	3
Count of Participants [Participants]	0 0%

46. Secondary Outcome

Title	Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinity (AUC0-inf), After Single and Multiple Dose
Description	AUC(0-inf) was defined as area under the plasma concentration-time profile from time zero to infinity AUC(0-inf), after single and multiple dose.
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

47. Secondary Outcome

Title	Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Avelumab After Single and Multiple Dose
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

48. Secondary Outcome

Title	Expansion Phase: Area Under the Plasma Concentration-Time Profile From Time Zero (Pre-Dose) to the Next Dose (AUC0-tau) of Avelumab, After Single and Multiple Dose
Description	AUCtau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to the next dose (AUC0-tau) of avelumab, after single and multiple dose.
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

49. Secondary Outcome

Title	Expansion Phase: Terminal Elimination Half-Life (t1/2) of Avelumab After Single and Multiple Dose
Description	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

50. Secondary Outcome

Title	Expansion Phase: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Avelumab After Single and Multiple Dose
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

51. Secondary Outcome

Title	Expansion Phase: Pre-Dose Concentration During Multiple Dosing (Ctrough) of Avelumab After Single and Multiple Dose
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

52. Secondary Outcome

Title	Expansion Phase: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Avelumab After Single and Multiple Dose
Description	The last time point of the last quantifiable concentration (tlast), after single and multiple dose.
Time Frame	pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2 and 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

53. Secondary Outcome

Title	Expansion Phase: Number of Participants With Phenotype of Tumor Infiltrating Lymphocytes (TILs) in Tumor Biopsy
Time Frame	Pre-treatment tumor biopsy for baseline and on-treatment biopsy at Day 7 of Cycle 3

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected due to the limited number of participants were enrolled into the expansion phase prior to study termination.

Arm/Group Title	Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
Measure Participants	0

Adverse Events

Time Frame	Lead-in phase: From first dose of study drug to 90 days after last administration of study drug (maximum duration of 32 months), Expansion phase: From first dose of study drug in expansion phase to 90 days after last administration of study drug (maximum duration of 14 months).
Adverse Event Reporting Description	Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non serious in another participant or 1 participant may have experienced both serious and non serious event during study.
Arm/Group Title	Lead-in Phase: Avelumab 70 mg Q2W		Lead-in Phase: Avelumab 350 mg Q2W		Lead-in Phase: Avelumab 500 mg Q3W		Lead-in Phase: Avelumab 500 mg Q2W		Lead-in Phase: Avelumab 10 mg/kg Q2W		Expansion Phase: Avelumab 70 mg, 500 mg Q2W
Arm/Group Description	Participants with relapsed/refractory cHL received an IV infusion of 70 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 47.1 weeks.		Participants with relapsed/refractory cHL received an IV infusion of 350 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 123 weeks.		Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q3W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 51.1 weeks.		Participants with relapsed/refractory cHL received an IV infusion of 500 mg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was of 78 weeks.		Participants with relapsed/refractory cHL received an IV infusion of 10 mg/kg of avelumab, Q2W until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination by the Sponsor, whichever occurred first. Maximum treatment exposure was approximately of 38.1 weeks.		All participants received an initial dose of 70 mg Q2W avelumab for 3 cycles, Each cycle was of 14 days (2 weeks), and were monitored for safety and efficacy. Participants who achieved a CR at the 6-week tumor assessment were continued at the same dose regimen. Participants who achieved a PR at 6 weeks were continued at 70 mg Q2W for an additional 3 cycles, and if the 12-week tumor assessment still showed a PR, participants were dose escalated to 500 mg Q2W. Participants who achieved a SD at the 6-week tumor assessment, dose escalated to 500 mg Q2W. Treatment was continued until disease progression, participant refusal, unacceptable toxicity, lost to follow-up, or until study termination the Sponsor, whichever occurred first. Maximum treatment exposure was of 48 weeks.
All Cause Mortality
	Lead-in Phase: Avelumab 70 mg Q2W		Lead-in Phase: Avelumab 350 mg Q2W		Lead-in Phase: Avelumab 500 mg Q3W		Lead-in Phase: Avelumab 500 mg Q2W		Lead-in Phase: Avelumab 10 mg/kg Q2W		Expansion Phase: Avelumab 70 mg, 500 mg Q2W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		4/6 (66.7%)		1/6 (16.7%)		4/6 (66.7%)		3/6 (50%)		1/3 (33.3%)
Serious Adverse Events
	Lead-in Phase: Avelumab 70 mg Q2W		Lead-in Phase: Avelumab 350 mg Q2W		Lead-in Phase: Avelumab 500 mg Q3W		Lead-in Phase: Avelumab 500 mg Q2W		Lead-in Phase: Avelumab 10 mg/kg Q2W		Expansion Phase: Avelumab 70 mg, 500 mg Q2W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		2/6 (33.3%)		3/6 (50%)		2/6 (33.3%)		0/6 (0%)		2/3 (66.7%)
Blood and lymphatic system disorders
Immune thrombocytopenic purpura	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
General disorders
Pyrexia	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/3 (33.3%)
Condition aggravated	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Disease progression	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Immune system disorders
Graft versus host disease in liver	1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Infections and infestations
Lung infection	0/6 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Encephalitis	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Respiratory syncytial virus infection	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Injury, poisoning and procedural complications
Infusion related reaction	2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Post procedural haemorrhage	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Investigations
Body temperature increased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
C-reactive protein increased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Nervous system disorders
Dysarthria	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Hemiparesis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Dyspnoea	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Vascular disorders
Orthostatic hypotension	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Lead-in Phase: Avelumab 70 mg Q2W		Lead-in Phase: Avelumab 350 mg Q2W		Lead-in Phase: Avelumab 500 mg Q3W		Lead-in Phase: Avelumab 500 mg Q2W		Lead-in Phase: Avelumab 10 mg/kg Q2W		Expansion Phase: Avelumab 70 mg, 500 mg Q2W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		6/6 (100%)		6/6 (100%)		6/6 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Lymph node pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Lymphadenopathy	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Neutropenia	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Thrombocytopenia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Cardiac disorders
Tachycardia	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Ear and labyrinth disorders
Ear pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Vertigo	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Endocrine disorders
Adrenal insufficiency	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Hypopituitarism	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Eye disorders
Iritis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Vision blurred	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Gastrointestinal disorders
Abdominal distension	2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Abdominal pain	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Constipation	2/6 (33.3%)		1/6 (16.7%)		2/6 (33.3%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Diarrhoea	1/6 (16.7%)		1/6 (16.7%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Dry mouth	1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Dysphagia	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Flatulence	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Gingival bleeding	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Gingival pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Lip exfoliation	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Lip swelling	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Nausea	3/6 (50%)		0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		2/6 (33.3%)		0/3 (0%)
Oral pain	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Vomiting	1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
General disorders
Asthenia	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Chest pain	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Chills	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/3 (33.3%)
Discomfort	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Early satiety	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Fatigue	2/6 (33.3%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		0/3 (0%)
Influenza like illness	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		1/3 (33.3%)
Non-cardiac chest pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Oedema peripheral	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Peripheral swelling	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Pyrexia	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		2/3 (66.7%)
Hepatobiliary disorders
Jaundice	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Infections and infestations
Biliary sepsis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Cellulitis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Conjunctivitis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Cystitis	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Folliculitis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Herpes simplex	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Influenza	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Lower respiratory tract infection	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Nasopharyngitis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Oral herpes	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Respiratory syncytial virus bronchitis	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Rhinitis	0/6 (0%)		2/6 (33.3%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Sinusitis	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Upper respiratory tract infection	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Urinary tract infection	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Vascular device infection	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Injury, poisoning and procedural complications
Contusion	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Infusion related reaction	1/6 (16.7%)		2/6 (33.3%)		1/6 (16.7%)		2/6 (33.3%)		2/6 (33.3%)		0/3 (0%)
Muscle strain	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Alanine aminotransferase	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Alanine aminotransferase increased	2/6 (33.3%)		0/6 (0%)		0/6 (0%)		2/6 (33.3%)		1/6 (16.7%)		1/3 (33.3%)
Amylase increased	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Aspartate aminotransferase	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Aspartate aminotransferase increased	2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/3 (33.3%)
Blood alkaline phosphatase	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Blood alkaline phosphatase increased	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		0/3 (0%)
Blood creatine phosphokinase increased	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Blood thyroid stimulating hormone increased	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Blood triglycerides increased	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Blood viscosity increased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Electrocardiogram QT prolonged	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Haemoglobin decreased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Lipase increased	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Transaminases increased	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Weight decreased	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Weight increased	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
White blood cell count decreased	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Blood albumin decreased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Gamma-glutamyltransferase increased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		2/6 (33.3%)		1/6 (16.7%)		0/3 (0%)
Gout	0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Hypokalaemia	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Hypomagnesaemia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Hypophosphataemia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Vitamin D deficiency	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Back pain	0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		3/6 (50%)		0/6 (0%)		0/3 (0%)
Flank pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Groin pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Muscle spasms	0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Muscle tightness	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Muscular weakness	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Musculoskeletal chest pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Musculoskeletal pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Myalgia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Myopathy	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Osteoporosis	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Pain in extremity	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Axillary mass	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Nervous system disorders
Headache	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		2/6 (33.3%)		2/6 (33.3%)		1/3 (33.3%)
Hyperaesthesia	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Hypoaesthesia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Neuropathy peripheral	1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Paraesthesia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Psychiatric disorders
Agitation	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Anxiety	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Depressed mood	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Insomnia	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Renal and urinary disorders
Pollakiuria	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Proteinuria	0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Urinary incontinence	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Urinary retention	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Reproductive system and breast disorders
Breast swelling	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)		2/6 (33.3%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		2/3 (66.7%)
Dyspnoea	0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		1/3 (33.3%)
Epistaxis	0/6 (0%)		0/6 (0%)		2/6 (33.3%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Nasal congestion	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Oropharyngeal pain	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Productive cough	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Respiratory symptom	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Rhinalgia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Rhinorrhoea	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Sneezing	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)
Skin and subcutaneous tissue disorders
Acne	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Decubitus ulcer	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/3 (33.3%)
Dry skin	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Ecchymosis	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Erythema	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		1/3 (33.3%)
Ingrowing nail	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Miliaria	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Night sweats	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		2/6 (33.3%)		0/6 (0%)		0/3 (0%)
Pruritus	0/6 (0%)		0/6 (0%)		0/6 (0%)		2/6 (33.3%)		1/6 (16.7%)		1/3 (33.3%)
Rash	0/6 (0%)		2/6 (33.3%)		1/6 (16.7%)		1/6 (16.7%)		1/6 (16.7%)		0/3 (0%)
Rash erythematous	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Rash maculo-papular	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Rash papular	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Skin exfoliation	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Skin hyperpigmentation	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Skin hypopigmentation	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/3 (0%)
Skin lesion	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Swelling face	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Vascular disorders
Orthostatic hypotension	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/3 (0%)
Thrombosis	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/3 (0%)

Limitations/Caveats

Results for PK parameters(AUC0-inf and Tlast after Multiple Dose) in Lead-in phase and (AUC0-inf, Cmax,AUC0-tau, t1/2, Tmax, Ctrough and Tlast after single and multiple doses) in expansion phase not reported, as data for these OMs were not collected.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.