Avelumab With Bempegaldesleukin With or Without Talazoparib or Enzalutamide in Advanced or Metastatic Solid Tumors

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04052204
• Collaborator: EMD Serono (Industry), Nektar Therapeutics (Industry), Astellas Pharma Inc (Industry)
• Enrollment: 3
• Locations: 5
• Arms: 3
• Actual Duration (Months): 9
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Evaluation of the combination of avelumab + bempegaldesleukin (NKTR-214 ) in locally advanced squamous cell carcinoma of the head and neck ( metastatic SCCHN) and avelumab + bempegaldesleukin (NKTR-214) + talazoparib or enzalutamide in metastatic castration resistant prostate cancer (mCRPC).

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Head and Neck (SCCHN); Metastatic Castration Resistant Prostate Cancer (mCRPC)	Drug: avelumab; Drug: Bempegaldesleukin; Drug: talazoparib; Drug: enzalutamide	Phase 1/Phase 2

Detailed Description

Phase 1b/ Phase 2 Design

Phase 1b will be the sequential dose-finding study.

Once the Phase 1b component is completed, Phase 2 will be initiated to further evaluate the safety and anti-tumor activity across combinations of therapy.

Combination A will enroll participants with SCCHN.

Combination B and C will enroll participants with mCRPC

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Combination A: Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally recurrent (not amendable for treatment with curative intent) or metastatic squamous cell carcinoma of the head and neck Combination B: Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for treatment of metastatic castration-resistant prostate cancer (mCRPC). Phase 2 will enroll participants with DDR defect positive mCRPC. Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPCCombination A: Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally recurrent (not amendable for treatment with curative intent) or metastatic squamous cell carcinoma of the head and neck Combination B: Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for treatment of metastatic castration-resistant prostate cancer (mCRPC). Phase 2 will enroll participants with DDR defect positive mCRPC. Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of Avelumab in Combination With Bempegaldesleukin(NKTR-214) With or Without Talazoparib or Enzalutamide in Participants With Locally Advanced or Metastatic Solid Tumors
• Actual Study Start Date: Dec 30, 2019
• Actual Primary Completion Date: Sep 29, 2020
• Actual Study Completion Date: Sep 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination A Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally recurrent (not amendable for treatment with curative intent) or metastatic squamous cell carcinoma of the head and neck	Drug: avelumab; Investigational fully human anti-PD-L1 monoclonal antibody; Other Names: Bavencio MSB0010718C ; Drug: Bempegaldesleukin; Investigational CD122-biased cytokine agonist; Other Names: NKTR-214
Experimental: Combination B Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for treatment of metastatic castration-resistant prostate cancer (mCRPC). Phase 2 will focus on enrolling participants with DDR defect positive mCRPC.	Drug: avelumab; Investigational fully human anti-PD-L1 monoclonal antibody; Other Names: Bavencio MSB0010718C ; Drug: Bempegaldesleukin; Investigational CD122-biased cytokine agonist; Other Names: NKTR-214 ; Drug: talazoparib; poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor; Other Names: Talzenna
Experimental: Combination C Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC	Drug: avelumab; Investigational fully human anti-PD-L1 monoclonal antibody; Other Names: Bavencio MSB0010718C ; Drug: Bempegaldesleukin; Investigational CD122-biased cytokine agonist; Other Names: NKTR-214 ; Drug: enzalutamide; androgen receptor inhibitor; Other Names: Xtandi

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities (DLT) [Cycle 1 of the treatment period (28 days)]

   DLTs were graded according to NCI- CTCAE version 4.03 and coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) as event category and MedDRA primary system organ class (SOC) body term as Body System category.

Secondary Outcome Measures

1. Duration of Response (DR) [Approximately 8 months (246 days).]

   DR was defined, for participants with a confirmed Objective Response (OR), as the time from the first documentation of OR to the date of first documentation of progressive disease (PD) or death due to any cause. The documentation of PD was defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If a subject had not had an event (PD or death), DR was censored at the date of last adequate tumor assessment. As there were no objective responses in the study, no participant met the definition of analysis population.

2. Time to Tumor Response (TTR) [Approximately 8 months (246 days).]

   TTR was defined, for participants with objective response, as the time from the date of first dose of study treatment to the first documentation of objective response (Complete Response or Partial Response) which was subsequently confirmed. As there were no objective responses in the study, no participant met the definition of analysis population.

3. Progression-Free Survival (PFS) [Approximately 8 months (246 days).]

   Progression-Free Survival (PFS) was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurred first. PFS data were censored on the date of the last adequate tumor assessment for participants who did not have an event (PD or death), for participants who started new anti-cancer therapy prior to an event, or for participants with an event after two or more missing tumor assessments. Participants who did not have an adequate baseline tumor assessment or who did not have any adequate post-baseline tumor assessments were censored on the date of first dose of study treatment unless death occurred on or before the time of the second planned tumor assessment, in which case the death was considered an event. PFS time was summarized using the Kaplan-Meier method.

4. Overall Survival (OS) [Approximately 8 months (246 days).]

   Overall survival (OS) was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. OS time was summarized using the Kaplan-Meier method.

5. Pharmacokinetic (PK) Parameters - Cmax and Ctrough for Avelumab and NKTR-214 [Blood samples were collected on Day 1 and Day 15 in Cycle 1 and Cycle 2 for avelumab. Blood samples were collected on Day 1, Day 3, Day 4 and Day 8 in Cycle 1, Day1 and Day 8 in Cycle 2 for NKTR-214.]

   Cmax was defined as the maximum observed plasma concentration at the end of infusion. Ctrough was defined as the predose concentration at the end of dosing interval.

6. Number of Participants With Positive Anti-Drug Antibody (ADA) Results [Day 1 of Cycle 1, 2 and end of treatment (EOT).]

   ADA against avelumab and NKTR-214 in serum samples was determined and reported separately for ADA never-positive, ADA ever-positive participants, baseline ADA positive, treatment-boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response. For all participants, blood for ADA samples was drawn from the contralateral arm of the avelumab and NKTR-214 infusion.

7. Number of Participants With Positive Neutralizing Antibody (nAb) Results [Day 1 of Cycle 1, 2 and EOT]

   nAb in serum samples was determined and reported separately for nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.

8. PD-L1 Expression Level in Baseline and On-treatment Tumor Tissue [On-treatment biopsy is required to be collected on Cycle 1 between Days 9 and 14 for participants in Combination A.]

   PD-L1 expression level in baseline tumor tissue, and in on-treatment tumor tissue was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and/or inflammatory cells in regions of interest. PD-L1 expression level in baseline tumor tissue and in on-treatment tumor tissue were under pathological analyses, assisted by image analysis. Participants were classified as positive or negative according to scoring algorithms and cut-offs established from internal or external sources.

9. Number of Participants With Treatment-Emergent Adverse Events(TEAEs), Serious TEAEs, TEAEs Leading to Death and Infusion-Related Reactions (IRRs) During On-treatment Period [Approximately 6 months (190 days)]

   Adverse events (AEs) were any untoward medical occurrences in a participant or clinical study participants, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment). A Serious Adverse Event (SAE) was defined as any untoward medical occurrence that, at any dose: a. Results in death, b. Was life-threatening, c. Required inpatient hospitalization or prolongation of existing hospitalization, d. Resulted in persistent disability/incapacity, e. Was a congenital anomaly/birth defect. Causality to study treatment was determined by the investigator.

10. Number of Participants With Laboratory Abnormalities With NCI-CTCAE Grade >= 3 - Safety Analysis Set [Day 1, Day 15 of each treatment cycle]

    Liver Function Tests of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBILI) were used to assess possible drug induced liver toxicity. The number of participants with at least one of the following laboratory results were summarized below: 1. (ALT ≥3 × ULN or AST ≥3 × ULN) post-baseline. 2. TBILI ≥2 × ULN post-baseline. 3. (ALP ≤2 × ULN or missing) post-baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants must be ≥ 18 years old.

• Participants with SCCHN or mCRCP.

• Participants must have histological diagnosis of solid tumors and provide tumor tissue.

• Measurable disease by RECIST v1.1 with at least 1 measurable lesion.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

• Adequate bone marrow, renal and liver function

• Highly effective contraceptive use by men with the ability to father a child or women of childbearing potential.

• A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) at C1D1.

• Signed and dated informed consent.

Exclusion Criteria:

• Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monocolonal antibodies.

• Known history of: immune-mediated colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis.

• Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.

• Prior organ transplantation including allogenic stem cell transplantation.

• Vaccination within 4 weeks prior to C1D1 and while on trial is prohibited except for administration of inactivated vaccines.

• Known symptomatic brain lesions requiring steroids.

• Known history of testing positive for human immunodeficiency virus (HIV or known acquired immunodeficiency syndrome (AIDS).

• Positive HBV surface antigen or HCV test indicating acute or chronic infection..

• Active infection requiring systemic therapy

• Clinically significant (i.e., active) cardiovascular disease including the following: documented left ventricular ejection fraction (LVEF) <50% by ECHO/MUGA; cerebral vascular accident/stroke or transient ischemic attack; myocardial infarction; unstable angina; congestive heart failure or serious cardiac arrhythmia (uncontrolled, clinically significant) requiring medication.

• Diagnosis of any other malignancy within 2 years prior to C1D1, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix and for Combination A only, low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (e.g., surgery, radiation, or castration) or adequately treated prostate cancer.

• Current use of immunosuppressive medication at the time of study enrollment.

• Major surgery within 4 weeks prior to study enrollment.

• Conditions that may impair intake or absorption such as inability to swallow capsules or tablets; known malabsorption syndrome; or baseline diarrhea ≤ Grade 1.

• Participation in other studies involving investigational drug(s) within 2 weeks prior to C1D1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester Medical Center	Rochester	New York	United States	14642
2	GZA Ziekenhuizen campus Sint-Augustinus	Wilrijk	Antwerpen	Belgium	2610
3	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa	Mazowieckie	Poland	02-781
4	Hospital Quirón Barceloma	Barcelona		Spain	08023
5	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035

Sponsors and Collaborators

• Pfizer
• EMD Serono
• Nektar Therapeutics
• Astellas Pharma Inc

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Jun 27, 2019
• Statistical Analysis Plan - Sep 3, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT04052204
• Other Study ID Numbers: B9991040; 2019-001358-24
• First Posted: Aug 9, 2019
• Last Update Posted: Oct 14, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Squamous Cell Carcinoma of Head and Neck; Avelumab; Talazoparib

Study Results

Participant Flow

Pre-assignment Detail	4 participants screened for this study, 1 of the 4 participants was a screen failure, 3 participants were enrolled and received study treatment in Combination A.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)	Avelumab + NKTR-214+ Talazoparib (Combination B)	Avelumab + NKTR- 214 + Enzalutamide (Combination C)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).	The dose level for avelumab was fixed at 800 mg Q2W. The starting dose level for NKTR-214 and talazoparib was determined at the completion of the dose finding for Combination A based on available clinical data. The lowest allowed dose for NKTR-214 was 0.003 mg/kg and the lowest allowed dose for talazoparib was 0.5 mg once daily, in which case participants with moderate renal impairment cannot be enrolled. NKTR-214 was administered prior to avelumab. Talazoparib was taken at the clinic after all procedures/assessments completed, before or after the NKTR-214 and avelumab infusions. Arm was not tested as company terminated this study on 21 May 2021.	The dose level for avelumab was fixed at 800 mg Q2W. The starting dose level for NKTR-214 and enzalutamide was determined at the completion of the dose finding for Combination A based on available clinical data. The approved label dose for enzalutamide was 160 mg once daily (QD) unless unexpected safety issues requiring it lowering according to the Bayesian Logistic Regression Model (BLRM) recommendation. NKTR-214 was administered prior to avelumab. The daily dose of enzalutamide was taken at the clinic after all procedures/assessments completed, and before or after the avelumab and NKTR-214 infusions. Arm was not tested as company terminated this study on 21 May 2021.
Period Title: Overall Study
STARTED	3	0	0
COMPLETED	0	0	0
NOT COMPLETED	3	0	0

Baseline Characteristics

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Overall Participants	3
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64.00
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	3 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLT)
Description	DLTs were graded according to NCI- CTCAE version 4.03 and coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) as event category and MedDRA primary system organ class (SOC) body term as Body System category.
Time Frame	Cycle 1 of the treatment period (28 days)

Outcome Measure Data

Analysis Population Description

The DLT-evaluable analysis set included all enrolled participants in Phase 1b who receive at least one dose of the combination treatment and either experience DLT during the first cycle (28 days) of treatment, or complete the DLT observation period for the first cycle of treatment without a DLT.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Count of Participants [Participants]	1 33.3%

2. Secondary Outcome

Title	Duration of Response (DR)
Description	DR was defined, for participants with a confirmed Objective Response (OR), as the time from the first documentation of OR to the date of first documentation of progressive disease (PD) or death due to any cause. The documentation of PD was defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If a subject had not had an event (PD or death), DR was censored at the date of last adequate tumor assessment. As there were no objective responses in the study, no participant met the definition of analysis population.
Time Frame	Approximately 8 months (246 days).

Outcome Measure Data

Analysis Population Description

All participants treated in combination A who achieved an OR.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	0

3. Secondary Outcome

Title	Time to Tumor Response (TTR)
Description	TTR was defined, for participants with objective response, as the time from the date of first dose of study treatment to the first documentation of objective response (Complete Response or Partial Response) which was subsequently confirmed. As there were no objective responses in the study, no participant met the definition of analysis population.
Time Frame	Approximately 8 months (246 days).

Outcome Measure Data

Analysis Population Description

All participants treated in combination A who achieved an OR.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	0

4. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	Progression-Free Survival (PFS) was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurred first. PFS data were censored on the date of the last adequate tumor assessment for participants who did not have an event (PD or death), for participants who started new anti-cancer therapy prior to an event, or for participants with an event after two or more missing tumor assessments. Participants who did not have an adequate baseline tumor assessment or who did not have any adequate post-baseline tumor assessments were censored on the date of first dose of study treatment unless death occurred on or before the time of the second planned tumor assessment, in which case the death was considered an event. PFS time was summarized using the Kaplan-Meier method.
Time Frame	Approximately 8 months (246 days).

Outcome Measure Data

Analysis Population Description

All participants treated in Combination A.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Median (95% Confidence Interval) [months]	1.69752

5. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. OS time was summarized using the Kaplan-Meier method.
Time Frame	Approximately 8 months (246 days).

Outcome Measure Data

Analysis Population Description

All participants treated in Combination A.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Median (95% Confidence Interval) [months]	2.56293

6. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters - Cmax and Ctrough for Avelumab and NKTR-214
Description	Cmax was defined as the maximum observed plasma concentration at the end of infusion. Ctrough was defined as the predose concentration at the end of dosing interval.
Time Frame	Blood samples were collected on Day 1 and Day 15 in Cycle 1 and Cycle 2 for avelumab. Blood samples were collected on Day 1, Day 3, Day 4 and Day 8 in Cycle 1, Day1 and Day 8 in Cycle 2 for NKTR-214.

Outcome Measure Data

Analysis Population Description

The PK parameter analysis set was a subset of the safety analysis set and included participants who had at least one of the PK parameters of interest for avelumab, NKTR-214, IL-2, talazoparib, enzalutamide, or N-desmethyl-enzalutamide.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Median (95% Confidence Interval) [ug/mL]	NA

7. Secondary Outcome

Title	Number of Participants With Positive Anti-Drug Antibody (ADA) Results
Description	ADA against avelumab and NKTR-214 in serum samples was determined and reported separately for ADA never-positive, ADA ever-positive participants, baseline ADA positive, treatment-boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response. For all participants, blood for ADA samples was drawn from the contralateral arm of the avelumab and NKTR-214 infusion.
Time Frame	Day 1 of Cycle 1, 2 and end of treatment (EOT).

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set was a subset of the safety analysis set and included participants who had at least one ADA/nAb sample collected for avelumab, NKTR-214, or IL-2.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Count of Participants [Participants]	NA NaN

8. Secondary Outcome

Title	Number of Participants With Positive Neutralizing Antibody (nAb) Results
Description	nAb in serum samples was determined and reported separately for nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.
Time Frame	Day 1 of Cycle 1, 2 and EOT

Outcome Measure Data

Analysis Population Description

The immunogenicity analysis set was a subset of the safety analysis set and included participants who had at least one ADA/nAb sample collected for avelumab, NKTR-214, or IL-2.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Count of Participants [Participants]	NA NaN

9. Secondary Outcome

Title	PD-L1 Expression Level in Baseline and On-treatment Tumor Tissue
Description	PD-L1 expression level in baseline tumor tissue, and in on-treatment tumor tissue was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and/or inflammatory cells in regions of interest. PD-L1 expression level in baseline tumor tissue and in on-treatment tumor tissue were under pathological analyses, assisted by image analysis. Participants were classified as positive or negative according to scoring algorithms and cut-offs established from internal or external sources.
Time Frame	On-treatment biopsy is required to be collected on Cycle 1 between Days 9 and 14 for participants in Combination A.

Outcome Measure Data

Analysis Population Description

The biomarker analysis set for biomarkers that were only measured at screening was a subset of the safety analysis set and included participants who had at least one baseline biomarker assessment.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Count of Participants [Participants]	NA NaN

10. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events(TEAEs), Serious TEAEs, TEAEs Leading to Death and Infusion-Related Reactions (IRRs) During On-treatment Period
Description	Adverse events (AEs) were any untoward medical occurrences in a participant or clinical study participants, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment). A Serious Adverse Event (SAE) was defined as any untoward medical occurrence that, at any dose: a. Results in death, b. Was life-threatening, c. Required inpatient hospitalization or prolongation of existing hospitalization, d. Resulted in persistent disability/incapacity, e. Was a congenital anomaly/birth defect. Causality to study treatment was determined by the investigator.
Time Frame	Approximately 6 months (190 days)

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Participants with all-causality TEAEs	3 100%
Participants with grade ≥ 3 all-causality TEAEs	2 66.7%
Participants with treatment-related TEAEs	3 100%
Participants with grade ≥ 3 treatment-related TEAEs	1 33.3%
Participants with serious all-causality TEAEs	1 33.3%
Participants with serious treatment-related TEAEs	1 33.3%
Participants with all-causality TEAEs leading to death	1 33.3%
Participants with treatment-related TEAEs leading to death	1 33.3%
Participants with IRRs	0 0%

11. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities With NCI-CTCAE Grade >= 3 - Safety Analysis Set
Description	Liver Function Tests of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBILI) were used to assess possible drug induced liver toxicity. The number of participants with at least one of the following laboratory results were summarized below: 1. (ALT ≥3 × ULN or AST ≥3 × ULN) post-baseline. 2. TBILI ≥2 × ULN post-baseline. 3. (ALP ≤2 × ULN or missing) post-baseline.
Time Frame	Day 1, Day 15 of each treatment cycle

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least one dose of study drug.

Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
Measure Participants	3
Count of Participants [Participants]	3 100%

Adverse Events

Time Frame	Approximately 8 months (246 days) . For all causality death cases, all death cases were reported regardless if the cases happened during on-treatment period or not. In total, 2 death cases were reported. Only 1 of the 2 death cases was caused by an adverse event , the other participant died due to disease progression. Thus only 1 serious adverse event was reported. All other reported adverse events are treatment-emergent adverse events.
Arm/Group Title	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
Arm/Group Description	NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25).
All Cause Mortality
	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Serious Adverse Events
	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
General disorders
Death	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
General disorders
Asthenia	1/3 (33.3%)	4
Fatigue	1/3 (33.3%)	7
General physical health deterioration	1/3 (33.3%)	1
Influenza like illness	1/3 (33.3%)	1
Injury, poisoning and procedural complications
Fall	1/3 (33.3%)	1
Investigations
Neutrophil count decreased	1/3 (33.3%)	1
Platelet count increased	1/3 (33.3%)	1
Weight decreased	1/3 (33.3%)	1
Metabolism and nutrition disorders
Decreased Appetite	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/3 (66.7%)	5
Musculoskeletal Pain	1/3 (33.3%)	1
Myalgia	1/3 (33.3%)	6
Vascular disorders
Hypotension	1/3 (33.3%)	2

Limitations/Caveats

Phase 1b part of Combination A was conducted but not completed as company terminated this study on 21 May 2021. Termination was not due to a regulatory request or new emerging safety signals. Test for Combination B, Combination C and Phase 2 expansion for Combination A planned in the protocol were 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.