Javelin DLBCL: Avelumab In Combination Regimens That Include An Immune Agonist, Epigenetic Modulator, CD20 Antagonist and/or Conventional Chemotherapy in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL)
Sponsor
Pfizer (Industry)
Overall Status
Terminated
CT.gov ID
NCT02951156
Collaborator
EMD Serono (Industry)
29
30
5
35.5
1
0
Study Details
Study Description
Brief Summary
Study B9991011 is a multi-center, international, randomized, open label, 2 component (Phase 1b followed by Phase 3), parallel-arm study of avelumab in combination with various agents for the treatment of Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
The target study population of this Phase 1b/3 registrational study is patients with R/R DLBCL who have completed at least 2 (but not more than 4) lines of prior rituximab-containing multi-agent chemotherapy, and/or in whom autologous stem cell transplant (ASCT) has failed, or who are not candidates for ASCT or who are not eligible for intensive chemotherapy. Patients who are ineligible for intensive second line chemotherapy must have received at least one prior rituximab-containing combination chemotherapy regimen. The study will assess the safety, efficacy, pharmacokinetics (PK), immunogenicity of the 3 avelumab-based combination regimens tested, and collect patient reported outcome (PRO) data.
Study Design
Study Type:
Interventional
Actual Enrollment
:
29 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
PHASE 1B/PHASE 3 MULTICENTER STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION REGIMENS THAT INCLUDE AN IMMUNE AGONIST, EPIGENETIC MODULATOR, CD20 ANTAGONIST AND/OR CONVENTIONAL CHEMOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) JAVELIN DLBCL
Actual Study Start Date
:
Dec 16, 2016
Actual Primary Completion Date
:
Dec 2, 2019
Actual Study Completion Date
:
Dec 2, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1b Arm A avelumab/utomilumab/rituximab |
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
Biological: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist
Other Names:
Biological: Rituximab
CD20-directed cytolytic antibody
Other Names:
|
| Experimental: Phase 1b Arm B avelumab/utomilumab/azacitidine |
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
Biological: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist
Other Names:
Other: Azacitidine
Antimetabolite antineoplastic agent and demethylation agent.
Other Names:
|
| Experimental: Phase 1b Arm C avelumab/rituximab/bendamustine |
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
Biological: Rituximab
CD20-directed cytolytic antibody
Other Names:
Drug: Bendamustine
Alkylating drug
Other Names:
|
| Experimental: Phase 3 Arm D (selected from Phase 1b) Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine |
Biological: Avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
Biological: Utomilumab
Investigational, fully human IgG2 CD 137/4-1BB agonist
Other Names:
Biological: Rituximab
CD20-directed cytolytic antibody
Other Names:
Other: Azacitidine
Antimetabolite antineoplastic agent and demethylation agent.
Other Names:
Drug: Bendamustine
Alkylating drug
Other Names:
|
| Active Comparator: Phase 3 Arm E Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin |
Biological: Rituximab
CD20-directed cytolytic antibody
Other Names:
Drug: Bendamustine
Alkylating drug
Other Names:
Drug: Gemcitabine
Nucleoside analogue
Other Names:
Drug: Oxaliplatin
Platinum-based drug
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose Limiting Toxicities (DLT) [Day 1 Cycle 1 up to 4 Weeks]
AEs occurring in first 4 weeks of treatment,attributable to 1 of study drugs. Hematology:1)Grade 4 neutropenia,2)Grade >=3 febrile neutropenia with single temperature of >38.3 degrees Celsius (C)/sustained temperature of >=38.0 degrees C for more than 1 hour with/without associated sepsis,3)Grade >=3 neutropenic infection,4)Grade 4 thrombocytopenia/Grade 3 thrombocytopenia with clinically significant bleeding,5)Grade 4 anemia 6)Any grade >=3 non-hematology toxicity except:transient Grade 3 flu like symptoms/fever controlled with standard medical management;transient Grade 3 fatigue,localized skin reactions/headache that resolves to Grade <=1;Grade 3 nausea,vomiting/diarrhea resolved to Grade <=1 in ˂72 hours after initiation of adequate medical management;Grade 3 skin toxicity resolved to Grade <=1 in ˂7 days;tumor flare;Single laboratory values that are out of normal range,that have no clinical correlate and resolve to Grade <=1 within 7 days with adequate medical management.
- Objective Response Rate (ORR) as Assessed by Investigator Per Lugano Response Classification Criteria [Randomization until date of PD, start of new anticancer therapy, discontinuation from study or death due to any cause, whichever occurred first (maximum up to 36 months)]
ORR was defined as percentage of participants with complete response (CR) or partial response (PR), as assessed by investigator per lugano response classification criteria. CR was defined as a score of 1 (no uptake above background), 2 (uptake less than or equal to [<=] mediastinum), or 3 (uptake less than [<] mediastinum but <=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. PR was defined as >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in sum of products of diameters (SPD) of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease.
Secondary Outcome Measures
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Greater Than or Equal to (>=) Grade 3, As Per National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE), Version 4.03 [From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)]
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,severity was graded as Grade 1:asymptomatic/mild symptoms,clinical/diagnostic observations only, intervention not indicated; Grade 2:moderate, minimal, local/noninvasive intervention indicated,limiting age-appropriate instrumental activities of daily life (ADL); Grade 3:severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to AE. TEAE was defined as events which occurred during on-treatment period beginning with first dose of study treatment through minimum (30 days + last dose of study treatment or start of new anti-cancer drug therapy). In this outcome measure participant with any TEAE of Grade 3 or above are reported.
- Number of Participants With Laboratory Abnormalities As Per National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03 [From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)]
Laboratory parameters included hematological and biochemistry: Hematological parameters included: anemia, haemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cells decreased. Biochemistry parameters included alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, creatine kinase(cpk) increased, creatinine increased, gamma glutamyl transferase(ggt) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased,serum amylase increased.Test abnormalities were graded by NCI CTCAE version 4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening. Number of participants with abnormalities of any grade were reported.
- Number of Participants With Electrocardiogram (ECG) Abnormalities [From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months)]
ECG abnormalities included: 1) QT interval, QT interval corrected using Bazett's formula (QTcB) and QT interval corrected using Fridericia's formula (QTcF): increase from baseline greater than (>) 30 millisecond (ms) or 60 ms; absolute value >450 ms, >480 ms and >500 ms; 2) heart rate (HR): absolute value <=50 beats per minute (bpm) and decrease from baseline >=20 bpm; absolute value >=120 bpm and increase from baseline >=20 bpm; 3) PR interval: absolute value >=220 ms and increase from baseline >=20 ms; 4) QRS interval: absolute value >=120 ms.
- Duration of Response (DOR) as Assessed by Investigator Per Lugano Response Classification Criteria [First response (CR or PR) to date of PD, start of new anti-cancer therapy, discontinuation from the study, censoring date or death due to any cause, whichever occurred first (maximum up to 36 months)]
Investigator assessed DOR: was defined for participants with OR as time from first documentation of OR to time of first documentation of disease progression/death due to any cause, whichever occurred first. CR: score of 1(no uptake above background),2(uptake <=mediastinum),or 3(uptake <mediastinum but <=liver) with or without a residual mass on PET 5-PS,for lymph nodes extralymphatic sites;no new lesions;no evidence of FDG-avid disease in bone marrow. PR: >=50% decrease in SPD of up to 6 of largest dominant lymph nodes,no increase in size of other nodes,liver,spleen volume,>=50% decrease in SPD of hepatic splenic nodules,absence of other organ involvement,no new sites of disease. PD: appearance of new lesion more than 1.5 cm in any axis,at least a 50% increase from nadir in SPD/longest diameter of previous lesion/node. Data was censored on date of last adequate tumor assessment in participants with no event,started new anti-cancer therapy/had 2 or more missing assessments.
- Time to Tumor Response (TTR) as Assessed by Investigator Per Lugano Response Classification Criteria [From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to 36 months)]
TTR was defined for participants who achieved objective response as time from randomization to first documentation of objective tumor response (CR or PR) that was subsequently confirmed. CR was defined as a score of 1 (no uptake above background), 2 (uptake <= mediastinum), or 3 (uptake <mediastinum but <=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR was defined as >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease.
- Disease Control Rate as Assessed by the Investigator Per Lugano Response Classification Criteria [From the date of randomization to the first documentation of PD, study discontinuation, start of new anti-cancer therapy or death due to any cause, whichever occurred first (maximum up to 36 months)]
Disease control rate was defined as percentage of participants with disease control. Disease Control (DC) was defined as the best overall response of CR, PR, or stable disease (SD). CR: score of 1 (no uptake above background), 2 (uptake <= mediastinum), or 3 (uptake less than <mediastinum but <=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR: >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. SD: <50% decrease in SDP of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease met. 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.
- Progression-Free Survival (PFS) as Assessed by the Investigator Per Lugano Response Classification Criteria [From the date of randomization to progression of disease, study discontinuation, censoring date or death due to any cause, whichever occurred first (up to 36 months)]
Investigator assessed 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. PFS data was censored on the date of the last adequate tumor assessment for participants who had no an event (PD or death), for participants who start a new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing or inadequate post-baseline tumor assessment. Participants without an adequate baseline or post-baseline tumor assessment were censored on the date of randomization unless death occurred on or before the time of the second planned tumor assessment in which case the death was considered as an event.
- Overall Survival [From the date of randomization to discontinuation from the study or death, whichever occurred first (maximum up to 36 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.
- Concentration Verses Time Summary of Avelumab [1 hour Post dose Day 2 Cycle 1, 144 hour Post dose Day 8 of Cycle 1, 0 hour Post dose Day 16 of Cycle 1, Day 1 of Cycle 4 and Cycle 6]
- Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status [Baseline: 2 hours pre-dose of first dose of avelumab, Post baseline: post first dose up to up to 30 Days after the end of treatment (maximum up to 36 months)]
ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point.
- Number of Participants With Anti-Drug Antibodies (ADA) Against Rituximab by Never and Ever Positive Status [From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)]
ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point.
- Number of Participants With Anti-Drug Antibodies (ADA) Against Utomilumab by Never and Ever Positive Status [From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)]
ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point.
- Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status [From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)]
nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point.
- Number of Participants With Neutralizing Antibodies (nAb) Against Rituximab by Never and Ever Positive Status [From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)]
nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point.
- Number of Participants With Neutralizing Antibodies (nAb) Against Utomilumab by Never and Ever Positive Status [From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months)]
nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point.
- Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline [Screening (prior to first dose of study treatment)]
Percentage of Tumor and Immune Cells as Assessed by Immunohistochemistry at Baseline.
- Number of Participants With Minimal Residual Disease Burden (MRD) Positive, Negative and Not Evaluable (NE) Status [Baseline, Day 1 of Cycle 3, 6, 9, 12 and 18]
Number of participants with MRD positive, negative and not evaluable status were reported in this outcome measure.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Key Inclusion Criteria:
-Any of the following as defined by the WHO, 2016 lymphoid neoplasm classifications and histologically confirmed:
-
Diffuse large B-cell lymphoma (DLBCL), Not Otherwise Specified (NOS): Germinal center B-cell type (GCB), Activated B-cell type (ABC)
-
High-grade B-cell lymphoma (HGBCL) NOS
-
HGBCL with MYC and BCL2 and/or BCL6 rearrangements
-
T-cell histocyte-rich large B-cell lymphoma
-
EBV+ DLBCL, NOS
-
HHV8+ DLBCL, NOS
Relapsed or refractory disease following at least 2 lines (and a maximum of 4 lines) of prior rituximab containing multi-agent chemotherapy which may include an autologous stem cell transplantation unless patients are not considered suitable for intensive second-line chemotherapy or autologous stem cell transplantation. Patients who are ineligible for intensive second line chemotherapy,must have received at least one prior rituximab-containing combination chemotherapy regimen. Patients who are ineligible for intensive second line chemotherapy, must have received at least one prior rituximab-containing combination chemotherapy regimen.
-
Baseline measurable disease with at least 1 bi dimensional lesion with longest diameter (LDi) >1.5cm on CT scan which is FDG avid on PET scan.
-
A biopsy (archived or Screening/recent) will be collected at Screening.
-
At least 18years of age (or ≥20 years in Japan).
-
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
Key Exclusion Criteria:
-
Active central nervous system (CNS) lymphoma.
-
Prior organ transplantation including prior allogeneic SCT.
-
Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody, or drug specifically targeting T cell co stimulatory or immune checkpoint pathways).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope | Duarte | California | United States | 91010 |
| 2 | Norton Cancer Institute | Louisville | Kentucky | United States | 40207 |
| 3 | Norton Diagnostic Center - Dupont | Louisville | Kentucky | United States | 40207 |
| 4 | Norton Women's and Children's Hospital | Louisville | Kentucky | United States | 40207 |
| 5 | Tulane Medical Center | New Orleans | Louisiana | United States | 70112 |
| 6 | Parexel International | Billerica | Massachusetts | United States | 01821 |
| 7 | University of Michigan Health System | Ann Arbor | Michigan | United States | 48109 |
| 8 | Mayo Clinic | Rochester | Minnesota | United States | 55905 |
| 9 | North Shore Hematology Oncology Associates | East Setauket | New York | United States | 11733 |
| 10 | St. George Hospital | Kogarah | New South Wales | Australia | 2217 |
| 11 | Monash Health | Clayton | Victoria | Australia | 3168 |
| 12 | Cancer Clinical Trials Centre, Austin Health, Level 4 | Heidelberg | Victoria | Australia | 3084 |
| 13 | Genesis Care | Heidelberg | Victoria | Australia | 3084 |
| 14 | UZ Gent | Gent | Belgium | 9000 | |
| 15 | UZ Leuven | Leuven | Belgium | 3000 | |
| 16 | Farmacia Studi Clinici | Rozzano | MI | Italy | 20089 |
| 17 | Istituto Clinico Humanitas | Rozzano | MI | Italy | 20089 |
| 18 | Samsung Medical Center Clinical Trial Pharmacy | Seoul | Korea, Republic of | 06351 | |
| 19 | Samsung Medical Center | Seoul | Korea, Republic of | 06351 | |
| 20 | Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli | Lublin | Lubelskie | Poland | 20-090 |
| 21 | Malopolskie Centrum Medyczne S.C. | Krakow | Malopolskie | Poland | 30-510 |
| 22 | Nzoz McD Voxel Osrodek Pet-Tk-Nmr | Krakow | Poland | 30-006 | |
| 23 | Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli Oddzial Hematologiczny | Lublin | Poland | 20-090 | |
| 24 | NU-MED Centrum Diagnostyki i Terapii Onkologicznej Zamosc Sp. z o.o. | Zamosc | Poland | 22-400 | |
| 25 | Hospital San Pedro de Alcantara | Caceres | Spain | 10003 | |
| 26 | Hospital San Pedro de Alcantara | Cáceres | Spain | 10003 | |
| 27 | Centro de Investigación Medicina Especializada Sanitaria (CIMES) | Málaga | Spain | 29010 | |
| 28 | Hospital Universitario Virgen de la Victoria | Málaga | Spain | 29010 | |
| 29 | The Christie NHS Foundation Trust | Manchester | United Kingdom | M20 4BX | |
| 30 | The Christie Pathology Partnership | Manchester | United Kingdom | M20 4BX |
Sponsors and Collaborators
- Pfizer
- EMD Serono
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02951156
Other Study ID Numbers:
- B9991011
- 2016-002904-15
First Posted:
Nov 1, 2016
Last Update Posted:
Dec 17, 2020
Last Verified:
Nov 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This study included participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after completion of at least 2 and not more than 4 lines of rituximab-containing multi-agent chemotherapy (prior to this study), and/or in whom autologous stem cell transplant (ASCT) has failed, or who were not candidates for ASCT or who were not eligible for intensive chemotherapy. |
|---|---|
| Pre-assignment Detail | This study was planned to be conducted into two phases: Phase 1b and Phase 3. Phase 3 of the study was never conducted due to early termination of study because of Phase 1b enrollment closure. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 milligram per meter square (mg/m^2) IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 subcutaneous (SC) dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Period Title: Overall Study | |||
| STARTED | 9 | 9 | 11 |
| COMPLETED | 0 | 0 | 1 |
| NOT COMPLETED | 9 | 9 | 10 |
Baseline Characteristics
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab | Total |
|---|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. | Total of all reporting groups |
| Overall Participants | 9 | 9 | 11 | 29 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
2
22.2%
|
3
33.3%
|
5
45.5%
|
10
34.5%
|
| >=65 years |
7
77.8%
|
6
66.7%
|
6
54.5%
|
19
65.5%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
0
0%
|
3
33.3%
|
2
18.2%
|
5
17.2%
|
| Male |
9
100%
|
6
66.7%
|
9
81.8%
|
24
82.8%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
1
11.1%
|
0
0%
|
1
3.4%
|
| Not Hispanic or Latino |
7
77.8%
|
8
88.9%
|
11
100%
|
26
89.7%
|
| Unknown or Not Reported |
2
22.2%
|
0
0%
|
0
0%
|
2
6.9%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| Race: White |
8
88.9%
|
8
88.9%
|
11
100%
|
27
93.1%
|
| Race: Other |
1
11.1%
|
1
11.1%
|
0
0%
|
2
6.9%
|
Outcome Measures
| Title | Number of Participants With Dose Limiting Toxicities (DLT) |
|---|---|
| Description | AEs occurring in first 4 weeks of treatment,attributable to 1 of study drugs. Hematology:1)Grade 4 neutropenia,2)Grade >=3 febrile neutropenia with single temperature of >38.3 degrees Celsius (C)/sustained temperature of >=38.0 degrees C for more than 1 hour with/without associated sepsis,3)Grade >=3 neutropenic infection,4)Grade 4 thrombocytopenia/Grade 3 thrombocytopenia with clinically significant bleeding,5)Grade 4 anemia 6)Any grade >=3 non-hematology toxicity except:transient Grade 3 flu like symptoms/fever controlled with standard medical management;transient Grade 3 fatigue,localized skin reactions/headache that resolves to Grade <=1;Grade 3 nausea,vomiting/diarrhea resolved to Grade <=1 in ˂72 hours after initiation of adequate medical management;Grade 3 skin toxicity resolved to Grade <=1 in ˂7 days;tumor flare;Single laboratory values that are out of normal range,that have no clinical correlate and resolve to Grade <=1 within 7 days with adequate medical management. |
| Time Frame | Day 1 Cycle 1 up to 4 Weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| DLT evaluable set included all participants who were randomized in the study and received at least 1 dose of study medication and either experienced DLT during the first cycle, or completed the primary DLT observation period of 4 weeks. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 7 | 5 | 10 |
| Count of Participants [Participants] |
1
11.1%
|
0
0%
|
0
0%
|
| Title | Objective Response Rate (ORR) as Assessed by Investigator Per Lugano Response Classification Criteria |
|---|---|
| Description | ORR was defined as percentage of participants with complete response (CR) or partial response (PR), as assessed by investigator per lugano response classification criteria. CR was defined as a score of 1 (no uptake above background), 2 (uptake less than or equal to [<=] mediastinum), or 3 (uptake less than [<] mediastinum but <=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. PR was defined as >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in sum of products of diameters (SPD) of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. |
| Time Frame | Randomization until date of PD, start of new anticancer therapy, discontinuation from study or death due to any cause, whichever occurred first (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set population included all participants who were randomized in the study. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 9 | 9 | 11 |
| Number (95% Confidence Interval) [Percentage of participants] |
11.1
123.3%
|
0
0%
|
27.3
248.2%
|
| Title | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Greater Than or Equal to (>=) Grade 3, As Per National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE), Version 4.03 |
|---|---|
| Description | 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,severity was graded as Grade 1:asymptomatic/mild symptoms,clinical/diagnostic observations only, intervention not indicated; Grade 2:moderate, minimal, local/noninvasive intervention indicated,limiting age-appropriate instrumental activities of daily life (ADL); Grade 3:severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to AE. TEAE was defined as events which occurred during on-treatment period beginning with first dose of study treatment through minimum (30 days + last dose of study treatment or start of new anti-cancer drug therapy). In this outcome measure participant with any TEAE of Grade 3 or above are reported. |
| Time Frame | From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set population included all participants who received at least 1 dose of study drug. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 | 11 |
| Count of Participants [Participants] |
4
44.4%
|
7
77.8%
|
10
90.9%
|
| Title | Number of Participants With Laboratory Abnormalities As Per National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03 |
|---|---|
| Description | Laboratory parameters included hematological and biochemistry: Hematological parameters included: anemia, haemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cells decreased. Biochemistry parameters included alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, creatine kinase(cpk) increased, creatinine increased, gamma glutamyl transferase(ggt) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased,serum amylase increased.Test abnormalities were graded by NCI CTCAE version 4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening. Number of participants with abnormalities of any grade were reported. |
| Time Frame | From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set population included all participants who received at least 1 dose of study drug. Here, "Number Analyzed" signifies number of participants evaluable for specified rows. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 | 11 |
| Anemia |
6
66.7%
|
8
88.9%
|
10
90.9%
|
| Hemoglobin increased |
0
0%
|
0
0%
|
0
0%
|
| Lymphocyte count decreased |
4
44.4%
|
7
77.8%
|
9
81.8%
|
| Lymphocyte count increased |
0
0%
|
0
0%
|
0
0%
|
| Neutrophil count decreased |
2
22.2%
|
2
22.2%
|
9
81.8%
|
| Platelet count decreased |
4
44.4%
|
3
33.3%
|
8
72.7%
|
| White blood cell decreased |
1
11.1%
|
4
44.4%
|
8
72.7%
|
| Alanine aminotransferase increased |
2
22.2%
|
5
55.6%
|
2
18.2%
|
| Alkaline phosphatase increased |
3
33.3%
|
4
44.4%
|
6
54.5%
|
| Aspartate aminotransferase increased |
3
33.3%
|
6
66.7%
|
3
27.3%
|
| Blood bilirubin increased |
0
0%
|
3
33.3%
|
3
27.3%
|
| Cholesterol high |
2
22.2%
|
3
33.3%
|
3
27.3%
|
| Cpk increased |
2
22.2%
|
1
11.1%
|
2
18.2%
|
| Creatinine increased |
6
66.7%
|
6
66.7%
|
10
90.9%
|
| GGT increased |
3
33.3%
|
4
44.4%
|
6
54.5%
|
| Hypercalcemia |
0
0%
|
3
33.3%
|
2
18.2%
|
| Hyperglycemia |
3
33.3%
|
1
11.1%
|
2
18.2%
|
| Hyperkalemia |
0
0%
|
0
0%
|
2
18.2%
|
| Hypermagnesemia |
1
11.1%
|
1
11.1%
|
1
9.1%
|
| Hypernatremia |
0
0%
|
0
0%
|
1
9.1%
|
| Hypertriglyceridemia |
3
33.3%
|
3
33.3%
|
7
63.6%
|
| Hypoalbuminemia |
3
33.3%
|
4
44.4%
|
6
54.5%
|
| Hypocalcemia |
1
11.1%
|
0
0%
|
2
18.2%
|
| Hypoglycemia |
0
0%
|
0
0%
|
1
9.1%
|
| Hypokalemia |
1
11.1%
|
1
11.1%
|
4
36.4%
|
| Hypomagnesemia |
0
0%
|
0
0%
|
4
36.4%
|
| Hyponatremia |
0
0%
|
1
11.1%
|
3
27.3%
|
| Hypophosphatemia |
1
11.1%
|
0
0%
|
5
45.5%
|
| Lipase increased |
1
11.1%
|
2
22.2%
|
3
27.3%
|
| Serum amylase increased |
2
22.2%
|
1
11.1%
|
3
27.3%
|
| Title | Number of Participants With Electrocardiogram (ECG) Abnormalities |
|---|---|
| Description | ECG abnormalities included: 1) QT interval, QT interval corrected using Bazett's formula (QTcB) and QT interval corrected using Fridericia's formula (QTcF): increase from baseline greater than (>) 30 millisecond (ms) or 60 ms; absolute value >450 ms, >480 ms and >500 ms; 2) heart rate (HR): absolute value <=50 beats per minute (bpm) and decrease from baseline >=20 bpm; absolute value >=120 bpm and increase from baseline >=20 bpm; 3) PR interval: absolute value >=220 ms and increase from baseline >=20 ms; 4) QRS interval: absolute value >=120 ms. |
| Time Frame | From first dose of study treatment up to at least 30 days after the last dose of study treatment or initiation of new anti-cancer therapy (up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set population included all participants who received at least 1 dose of study drug. Here, "Number Analyzed" signifies number of participants evaluable for specified rows. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 | 11 |
| QT: Increase from baseline >30 ms |
4
44.4%
|
4
44.4%
|
4
36.4%
|
| QT: Increase from baseline >60 ms |
1
11.1%
|
3
33.3%
|
2
18.2%
|
| QT: >450 ms |
2
22.2%
|
2
22.2%
|
2
18.2%
|
| QT: >480 ms |
0
0%
|
1
11.1%
|
1
9.1%
|
| QT: >500 ms |
0
0%
|
0
0%
|
0
0%
|
| QTcB: Increase from baseline >30 ms |
1
11.1%
|
3
33.3%
|
4
36.4%
|
| QTcB: Increase from baseline >60 ms |
1
11.1%
|
1
11.1%
|
0
0%
|
| QTcB: >450 ms |
4
44.4%
|
5
55.6%
|
9
81.8%
|
| QTcB: >480 ms |
2
22.2%
|
3
33.3%
|
4
36.4%
|
| QTcB: >500 ms |
1
11.1%
|
2
22.2%
|
1
9.1%
|
| QTcF: Increase from baseline >30 ms |
1
11.1%
|
3
33.3%
|
3
27.3%
|
| QTcF: Increase from baseline >60 ms |
0
0%
|
2
22.2%
|
0
0%
|
| QTcF: >450 ms |
4
44.4%
|
3
33.3%
|
6
54.5%
|
| QTcF: >480 ms |
0
0%
|
2
22.2%
|
0
0%
|
| QTcF: >500 ms |
0
0%
|
2
22.2%
|
0
0%
|
| Heart rate: <=50 bpm and decrease from baseline >=20 bpm |
0
0%
|
1
11.1%
|
0
0%
|
| Heart rate: >=120 bpm and increase from baseline >=20 bpm |
0
0%
|
0
0%
|
1
9.1%
|
| PR: >=220 ms and increase from baseline >=20 ms |
0
0%
|
0
0%
|
0
0%
|
| QRS: >=120 ms |
1
11.1%
|
1
11.1%
|
2
18.2%
|
| Title | Duration of Response (DOR) as Assessed by Investigator Per Lugano Response Classification Criteria |
|---|---|
| Description | Investigator assessed DOR: was defined for participants with OR as time from first documentation of OR to time of first documentation of disease progression/death due to any cause, whichever occurred first. CR: score of 1(no uptake above background),2(uptake <=mediastinum),or 3(uptake <mediastinum but <=liver) with or without a residual mass on PET 5-PS,for lymph nodes extralymphatic sites;no new lesions;no evidence of FDG-avid disease in bone marrow. PR: >=50% decrease in SPD of up to 6 of largest dominant lymph nodes,no increase in size of other nodes,liver,spleen volume,>=50% decrease in SPD of hepatic splenic nodules,absence of other organ involvement,no new sites of disease. PD: appearance of new lesion more than 1.5 cm in any axis,at least a 50% increase from nadir in SPD/longest diameter of previous lesion/node. Data was censored on date of last adequate tumor assessment in participants with no event,started new anti-cancer therapy/had 2 or more missing assessments. |
| Time Frame | First response (CR or PR) to date of PD, start of new anti-cancer therapy, discontinuation from the study, censoring date or death due to any cause, whichever occurred first (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who were randomized and achieved an objective response. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 1 | 0 | 3 |
| Median (95% Confidence Interval) [Months] |
1.81
|
NA
|
| Title | Time to Tumor Response (TTR) as Assessed by Investigator Per Lugano Response Classification Criteria |
|---|---|
| Description | TTR was defined for participants who achieved objective response as time from randomization to first documentation of objective tumor response (CR or PR) that was subsequently confirmed. CR was defined as a score of 1 (no uptake above background), 2 (uptake <= mediastinum), or 3 (uptake <mediastinum but <=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR was defined as >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. |
| Time Frame | From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who were randomized and achieved an objective response. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 1 | 0 | 3 |
| Median (Full Range) [Months] |
1.8
|
1.9
|
| Title | Disease Control Rate as Assessed by the Investigator Per Lugano Response Classification Criteria |
|---|---|
| Description | Disease control rate was defined as percentage of participants with disease control. Disease Control (DC) was defined as the best overall response of CR, PR, or stable disease (SD). CR: score of 1 (no uptake above background), 2 (uptake <= mediastinum), or 3 (uptake less than <mediastinum but <=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR: >=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a >=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. SD: <50% decrease in SDP of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease met. 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 the date of randomization to the first documentation of PD, study discontinuation, start of new anti-cancer therapy or death due to any cause, whichever occurred first (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set population included all participants who were randomized in the study. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 9 | 9 | 11 |
| Number (95% Confidence Interval) [Percentage of participants] |
22.2
246.7%
|
0
0%
|
36.4
330.9%
|
| Title | Progression-Free Survival (PFS) as Assessed by the Investigator Per Lugano Response Classification Criteria |
|---|---|
| Description | Investigator assessed 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. PFS data was censored on the date of the last adequate tumor assessment for participants who had no an event (PD or death), for participants who start a new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing or inadequate post-baseline tumor assessment. Participants without an adequate baseline or post-baseline tumor assessment were censored on the date of randomization unless death occurred on or before the time of the second planned tumor assessment in which case the death was considered as an event. |
| Time Frame | From the date of randomization to progression of disease, study discontinuation, censoring date or death due to any cause, whichever occurred first (up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set population included all participants who were randomized in the study. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 9 | 9 | 11 |
| Median (95% Confidence Interval) [Months] |
1.8
|
1.5
|
2.7
|
| Title | 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 the date of randomization to discontinuation from the study or death, whichever occurred first (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set population included all participants who were randomized in the study. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 9 | 9 | 11 |
| Median (95% Confidence Interval) [Months] |
14.8
|
4.0
|
5.2
|
| Title | Concentration Verses Time Summary of Avelumab |
|---|---|
| Description | |
| Time Frame | 1 hour Post dose Day 2 Cycle 1, 144 hour Post dose Day 8 of Cycle 1, 0 hour Post dose Day 16 of Cycle 1, Day 1 of Cycle 4 and Cycle 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Avelumab pharmacokinetic concentration analysis set included all participants who received at least 1 dose of study drug and who had at least 1 post-dose concentration measurement above the lower limit of quantitation for avelumab. Here, "Number Analyzed" signifies number of participants evaluable for specified rows. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 | 11 |
| Cycle 1 Day 2 |
183.29
(83.809)
|
198.43
(29.387)
|
193.30
(29.702)
|
| Cycle 1 Day 8 |
75.14
(21.357)
|
68.44
(18.553)
|
65.33
(17.913)
|
| Cycle 1 Day 16 |
25.33
(13.197)
|
26.53
(9.237)
|
19.36
(7.810)
|
| Cycle 4 Day 1 |
25.00
(4.667)
|
62.00
(NA)
|
120.88
(165.187)
|
| Cycle 6 Day 1 |
7.57
(NA)
|
39.43
(18.327)
|
| Title | Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status |
|---|---|
| Description | ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. |
| Time Frame | Baseline: 2 hours pre-dose of first dose of avelumab, Post baseline: post first dose up to up to 30 Days after the end of treatment (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Avelumab immunogenicity analysis set included participants who had at least 1 ADA sample collected for avelumab. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 | 11 |
| Baseline: ADA ever-positive |
0
0%
|
0
0%
|
1
9.1%
|
| Baseline: ADA never-positive |
8
88.9%
|
9
100%
|
10
90.9%
|
| Post Baseline: ADA ever-positive |
0
0%
|
0
0%
|
0
0%
|
| Post Baseline: ADA never-positive |
8
88.9%
|
9
100%
|
11
100%
|
| Title | Number of Participants With Anti-Drug Antibodies (ADA) Against Rituximab by Never and Ever Positive Status |
|---|---|
| Description | ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. |
| Time Frame | From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Rituximab immunogenicity analysis set included participants who had at least 1 ADA sample collected for rituximab. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 11 |
| ADA ever-positive |
0
0%
|
0
0%
|
| ADA never-positive |
8
88.9%
|
11
122.2%
|
| Title | Number of Participants With Anti-Drug Antibodies (ADA) Against Utomilumab by Never and Ever Positive Status |
|---|---|
| Description | ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. |
| Time Frame | From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Utomilumab immunogenicity analysis set included participants who had at least 1 ADA sample collected for utomilumab. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab |
|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 |
| ADA ever-positive |
1
11.1%
|
2
22.2%
|
| ADA never-positive |
7
77.8%
|
7
77.8%
|
| Title | Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status |
|---|---|
| Description | nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point. |
| Time Frame | From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data for this outcome measure was not collected since there was no participants with post-baseline ADA ever positive sample for avelumab. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 0 | 0 | 0 |
| Title | Number of Participants With Neutralizing Antibodies (nAb) Against Rituximab by Never and Ever Positive Status |
|---|---|
| Description | nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point. |
| Time Frame | From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data for this this outcome measure was not collected since there was no participant with rituximab ADA ever positive sample. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 0 | 0 |
| Title | Number of Participants With Neutralizing Antibodies (nAb) Against Utomilumab by Never and Ever Positive Status |
|---|---|
| Description | nAb never-positive was defined as no positive nAb results at any time point and nAb ever-positive was defined as at least one positive nAb result at any time point. |
| Time Frame | From the date of first study treatment up to 30 Days after the end of treatment (maximum up to 36 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Utomilumab immunogenicity analysis set included participants from the safety analysis set who had at least one ADA/nAb sample collected for utomilumab. Here, 'overall number of participants analyzed' signifies number of participants who were ADA positive and whose samples were further analyzed for nAb. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab |
|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. |
| Measure Participants | 1 | 2 |
| nAb ever-positive |
0
0%
|
0
0%
|
| nAb never-positive |
1
11.1%
|
2
22.2%
|
| Title | Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor and Immune Cells as Assessed by Immunohistochemistry (IHC) at Baseline |
|---|---|
| Description | Percentage of Tumor and Immune Cells as Assessed by Immunohistochemistry at Baseline. |
| Time Frame | Screening (prior to first dose of study treatment) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set population included all participants who were randomized in the study. Here 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 6 | 8 | 6 |
| Tumor Cells (membrane) |
0
|
0.5
|
0
|
| Immune Cells |
7.5
|
7.5
|
17.5
|
| Title | Number of Participants With Minimal Residual Disease Burden (MRD) Positive, Negative and Not Evaluable (NE) Status |
|---|---|
| Description | Number of participants with MRD positive, negative and not evaluable status were reported in this outcome measure. |
| Time Frame | Baseline, Day 1 of Cycle 3, 6, 9, 12 and 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set population included all participants who received at least 1 dose of study drug. |
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab |
|---|---|---|---|
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. |
| Measure Participants | 8 | 9 | 11 |
| Baseline: Positive |
3
33.3%
|
1
11.1%
|
3
27.3%
|
| Baseline: Negative |
0
0%
|
0
0%
|
2
18.2%
|
| Baseline: NE |
5
55.6%
|
8
88.9%
|
6
54.5%
|
| Cycle 3 Day 1: Positive |
3
33.3%
|
1
11.1%
|
1
9.1%
|
| Cycle 3 Day 1: Negative |
0
0%
|
0
0%
|
3
27.3%
|
| Cycle 3 Day 1: NE |
2
22.2%
|
1
11.1%
|
1
9.1%
|
| Cycle 6 Day 1: Positive |
0
0%
|
1
11.1%
|
0
0%
|
| Cycle 6 Day 1: Negative |
0
0%
|
0
0%
|
2
18.2%
|
| Cycle 6 Day 1: NE |
0
0%
|
0
0%
|
2
18.2%
|
| Cycle 9 Day 1: Positive |
0
0%
|
0
0%
|
0
0%
|
| Cycle 9 Day 1: Negative |
0
0%
|
0
0%
|
1
9.1%
|
| Cycle 9 Day 1: NE |
0
0%
|
0
0%
|
2
18.2%
|
| Cycle 12 Day 1: Positive |
0
0%
|
0
0%
|
0
0%
|
| Cycle 12 Day 1: Negative |
0
0%
|
0
0%
|
1
9.1%
|
| Cycle 12 Day 1: NE |
0
0%
|
0
0%
|
2
18.2%
|
| Cycle 18 Day 1: Positive |
0
0%
|
0
0%
|
0
0%
|
| Cycle 18 Day 1: Negative |
0
0%
|
0
0%
|
0
0%
|
| Cycle 18 Day 1: NE |
0
0%
|
0
0%
|
1
9.1%
|
Adverse Events
| Time Frame | Baseline up to follow up (36 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. Safety analysis set population included all participants who received at least 1 dose of study drug. | |||||
| Arm/Group Title | Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab | |||
| Arm/Group Description | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Azacitidine 40 mg/m^2 SC dose was administered on Days 1 to 5 of each treatment cycle until the participant no longer received clinical benefit, along with fixed dose of 100 mg IV infusion of utomilumab on Day 2 of each treatment cycle in Cycles 1 and 2. If the dose of utomilumab was well tolerated, then it was administered on Day 1 of Cycle 3 and all subsequent cycles until the participant no longer received clinical benefit. The duration of each treatment cycle was 28 days. | Avelumab 10 mg/kg IV infusion was administered every 2 weeks on Day 2 and Day 16 of Cycles 1 and 2, if well tolerated then continued on Day 1 and Day 15 in Cycle 3 and all subsequent cycles, until the participant no longer received clinical benefit. Rituximab 375 mg/m^2 IV infusion was administered on Day 1 of each treatment cycle (maximum of 8 cycles), along with 90 mg/m^2 IV infusion of bendamustine on Day 2 and Day 3 of each treatment cycle in Cycles 1 and 2. If the dose of bendamustine was well tolerated, then it was administered on Day 1 and Day 2 in Cycle 3 and all subsequent cycles for a maximum of 6 cycles. The duration of each treatment cycle was 28 days. | |||
All Cause Mortality |
||||||
| Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/8 (50%) | 8/9 (88.9%) | 6/11 (54.5%) | |||
Serious Adverse Events |
||||||
| Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/8 (37.5%) | 6/9 (66.7%) | 7/11 (63.6%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Febrile neutropenia | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Thrombocytopenia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Gastrointestinal disorders | ||||||
| Small intestinal obstruction | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Gastrointestinal haemorrhage | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| General disorders | ||||||
| Death | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Disease progression | 0/8 (0%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Fatigue | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Pain | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Pyrexia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Infections and infestations | ||||||
| Bronchitis | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Herpes zoster | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Ophthalmic herpes zoster | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Pneumonia | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Sepsis | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Septic shock | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Urinary tract infection | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Hypercalcaemia | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Non-Hodgkin's lymphoma | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Nervous system disorders | ||||||
| Syncope | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Dyspnoea | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Laryngeal oedema | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Respiratory failure | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Vascular disorders | ||||||
| Superior vena cava syndrome | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Avelumab+Rituximab+Utomilumab | Avelumab+Azacitidine+Utomilumab | Avelumab+Bendamustine+Rituximab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 8/8 (100%) | 9/9 (100%) | 11/11 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 2/8 (25%) | 2/9 (22.2%) | 4/11 (36.4%) | |||
| Leukopenia | 0/8 (0%) | 0/9 (0%) | 2/11 (18.2%) | |||
| Lymph node pain | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Neutropenia | 2/8 (25%) | 1/9 (11.1%) | 5/11 (45.5%) | |||
| Thrombocytopenia | 1/8 (12.5%) | 0/9 (0%) | 3/11 (27.3%) | |||
| Cardiac disorders | ||||||
| Atrial fibrillation | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Sinus bradycardia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Tachycardia | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Endocrine disorders | ||||||
| Primary hypothyroidism | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Eye disorders | ||||||
| Conjunctival haemorrhage | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Dry eye | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Lacrimation increased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal discomfort | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Abdominal distension | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Abdominal pain | 0/8 (0%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Abdominal pain upper | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Constipation | 1/8 (12.5%) | 5/9 (55.6%) | 4/11 (36.4%) | |||
| Diarrhoea | 2/8 (25%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Hiatus hernia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Nausea | 2/8 (25%) | 2/9 (22.2%) | 4/11 (36.4%) | |||
| Oesophageal obstruction | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Stomatitis | 0/8 (0%) | 0/9 (0%) | 2/11 (18.2%) | |||
| Toothache | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Vomiting | 0/8 (0%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| General disorders | ||||||
| Asthenia | 2/8 (25%) | 0/9 (0%) | 0/11 (0%) | |||
| Chest pain | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Chills | 3/8 (37.5%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Fatigue | 1/8 (12.5%) | 1/9 (11.1%) | 4/11 (36.4%) | |||
| Generalised oedema | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Influenza like illness | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Injection site erythema | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Injection site reaction | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Malaise | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Oedema | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Oedema peripheral | 0/8 (0%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Pyrexia | 3/8 (37.5%) | 1/9 (11.1%) | 3/11 (27.3%) | |||
| Infections and infestations | ||||||
| Bronchitis | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Herpes zoster | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Nasopharyngitis | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Ophthalmic herpes zoster | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Pneumonia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Upper respiratory tract infection | 2/8 (25%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Urinary tract infection | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Fall | 0/8 (0%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Infusion related reaction | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Post procedural haemorrhage | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Skin abrasion | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Transfusion reaction | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 0/8 (0%) | 2/9 (22.2%) | 1/11 (9.1%) | |||
| Amylase increased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Aspartate aminotransferase increased | 0/8 (0%) | 2/9 (22.2%) | 1/11 (9.1%) | |||
| Bilirubin conjugated increased | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Blood alkaline phosphatase | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Blood alkaline phosphatase increased | 0/8 (0%) | 2/9 (22.2%) | 2/11 (18.2%) | |||
| Blood bilirubin increased | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Blood calcium | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Blood chloride increased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Blood cholesterol increased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Blood creatine phosphokinase increased | 2/8 (25%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Blood creatinine increased | 0/8 (0%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Blood triglycerides increased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Electrocardiogram QT prolonged | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Gamma-glutamyltransferase increased | 0/8 (0%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Haemoglobin decreased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Lipase decreased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Lymphocyte count decreased | 0/8 (0%) | 1/9 (11.1%) | 3/11 (27.3%) | |||
| Neutrophil count decreased | 0/8 (0%) | 0/9 (0%) | 2/11 (18.2%) | |||
| Platelet count decreased | 0/8 (0%) | 0/9 (0%) | 2/11 (18.2%) | |||
| White blood cell count decreased | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 3/8 (37.5%) | 0/9 (0%) | 3/11 (27.3%) | |||
| Hypercalcaemia | 0/8 (0%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Hypercholesterolaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hyperglycaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hyperkalaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypermagnesaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypernatraemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypertriglyceridaemia | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Hyperuricaemia | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypoalbuminaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypocalcaemia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypokalaemia | 1/8 (12.5%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Hypomagnesaemia | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Hypophosphataemia | 0/8 (0%) | 0/9 (0%) | 2/11 (18.2%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Back pain | 2/8 (25%) | 3/9 (33.3%) | 0/11 (0%) | |||
| Bone pain | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Joint range of motion decreased | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Muscular weakness | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Musculoskeletal pain | 1/8 (12.5%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Myalgia | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Pain in extremity | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Tumour pain | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Nervous system disorders | ||||||
| Dizziness | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Dysgeusia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Head discomfort | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Headache | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Lethargy | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Paraesthesia | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Somnolence | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Syncope | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Taste disorder | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 1/8 (12.5%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Confusional state | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Depression | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Renal and urinary disorders | ||||||
| Acute kidney injury | 1/8 (12.5%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Haematuria | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Microalbuminuria | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Nocturia | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Pollakiuria | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Proteinuria | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Renal failure | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Chronic obstructive pulmonary disease | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Cough | 2/8 (25%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Dyspnoea | 0/8 (0%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Dyspnoea exertional | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Nasal congestion | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Pleural effusion | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Productive cough | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Pulmonary oedema | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Rhinorrhoea | 1/8 (12.5%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Decubitus ulcer | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Hyperhidrosis | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Night sweats | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Pruritus | 1/8 (12.5%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Rash | 1/8 (12.5%) | 1/9 (11.1%) | 2/11 (18.2%) | |||
| Rash erythematous | 0/8 (0%) | 1/9 (11.1%) | 0/11 (0%) | |||
| Rash maculo-papular | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Rash papular | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
| Urticaria | 1/8 (12.5%) | 0/9 (0%) | 0/11 (0%) | |||
| Vascular disorders | ||||||
| Hypertension | 0/8 (0%) | 1/9 (11.1%) | 1/11 (9.1%) | |||
| Hypotension | 0/8 (0%) | 0/9 (0%) | 2/11 (18.2%) | |||
| Superior vena cava syndrome | 0/8 (0%) | 0/9 (0%) | 1/11 (9.1%) | |||
Limitations/Caveats
Data for Phase 3 outcome measures were not collected as study was terminated early and phase 3 was not conducted.
More Information
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.
Results Point of Contact
| Name/Title | Pfizer ClinicalTrials.gov Call Center |
|---|---|
| Organization | Pfizer, Inc. |
| Phone | 1-800-718-1021 |
| ClinicalTrials.gov_Inquiries@pfizer.com |
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02951156
Other Study ID Numbers:
- B9991011
- 2016-002904-15
First Posted:
Nov 1, 2016
Last Update Posted:
Dec 17, 2020
Last Verified:
Nov 1, 2020