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

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

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

• Drug: avelumab
  Investigational fully human anti-PD-L1 monoclonal antibody
  Other Names:

  • Bavencio
  • MSB0010718C
• Drug: Bempegaldesleukin
  Investigational CD122-biased cytokine agonist
  Other Name: NKTR-214
• Drug: talazoparib
  poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor
  Other Name: Talzenna
• Drug: enzalutamide
  androgen receptor inhibitor
  Other Name: Xtandi

• 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
  Interventions:

  • Drug: avelumab
  • Drug: Bempegaldesleukin
• 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.
  Interventions:

  • Drug: avelumab
  • Drug: Bempegaldesleukin
  • Drug: talazoparib
• Experimental: Combination C
  Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC
  Interventions:

  • Drug: avelumab
  • Drug: Bempegaldesleukin
  • Drug: enzalutamide

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.

• EMD Serono
• Nektar Therapeutics
• Astellas Pharma Inc