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

Study Overview
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Brief Summary
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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).

Detailed Description
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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

Official Title
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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

Conditions
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Squamous Cell Carcinoma of the Head and Neck (SCCHN), Metastatic Castration Resistant Prostate Cancer (mCRPC)

Intervention / Treatment
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* Drug: avelumab
* Drug: Bempegaldesleukin
* Drug: talazoparib
* Drug: enzalutamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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 mCRPC
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination A<br>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<br>* Investigational fully human anti-PD-L1 monoclonal antibody<br>* Other names: MSB0010718C;Drug: Bempegaldesleukin<br>* Investigational CD122-biased cytokine agonist<br>* Other names: NKTR-214;|
| Experimental: Combination B<br>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<br>* Investigational fully human anti-PD-L1 monoclonal antibody<br>* Other names: MSB0010718C;Drug: Bempegaldesleukin<br>* Investigational CD122-biased cytokine agonist<br>* Other names: NKTR-214;Drug: talazoparib<br>* poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor<br>* Other names: Talzenna;|
| Experimental: Combination C<br>Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC | Drug: avelumab<br>* Investigational fully human anti-PD-L1 monoclonal antibody<br>* Other names: MSB0010718C;Drug: Bempegaldesleukin<br>* Investigational CD122-biased cytokine agonist<br>* Other names: NKTR-214;Drug: enzalutamide<br>* androgen receptor inhibitor<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLT) | 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. | Cycle 1 of the treatment period (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DR) | 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. | Approximately 8 months (246 days). | 
| Time to Tumor Response (TTR) | 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. | Approximately 8 months (246 days). | 
| Progression-Free Survival (PFS) | 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. | Approximately 8 months (246 days). | 
| Overall Survival (OS) | 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. | Approximately 8 months (246 days). | 
| Pharmacokinetic (PK) Parameters - Cmax and Ctrough for Avelumab and 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. | 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. | 
| Number of Participants With Positive Anti-Drug Antibody (ADA) Results | 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. | Day 1 of Cycle 1, 2 and end of treatment (EOT). | 
| Number of Participants With Positive Neutralizing Antibody (nAb) Results | 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. | Day 1 of Cycle 1, 2 and EOT | 
| PD-L1 Expression Level in Baseline and On-treatment Tumor Tissue | 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. | On-treatment biopsy is required to be collected on Cycle 1 between Days 9 and 14 for participants in Combination A. | 
| Number of Participants With Treatment-Emergent Adverse Events(TEAEs), Serious TEAEs, TEAEs Leading to Death and Infusion-Related Reactions (IRRs) During On-treatment Period | 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. | Approximately 6 months (190 days) | 
| Number of Participants With Laboratory Abnormalities With NCI-CTCAE Grade >= 3 - Safety Analysis Set | 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. | Day 1, Day 15 of each treatment cycle |