N-803 Alone or in Combination With BN-Brachyury Vaccine or Bintrafusp Alfa (M7824) for Participants With Castration Resistant Prostate Cancer

BACKGROUND:

• Prostate cancer is poorly recognized by T cells. Lack of an immune response is one explanation for the lower response rates (<15%) observed with anti-PD-1/PD-L1 therapies for prostate cancer.
• BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to induce an enhanced immune response against brachyury, which is overexpressed in many solid tumor types, including prostate adenocarcinoma. BN-Brachyury collectively refers to the priming doses (MVA-BN-Brachyury) and the boost doses (FPV-Brachyury) of the vaccine platform.
• Bintrafusp alfa is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap. Bintrafusp alfa can also mediate antibody-dependent cellular cytotoxicity in vitro.
• N-803 is an IL-15/IL-15Ralpha superagonist complex that can enhance natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and T-cell cytotoxicity.
• Synergistic anti-tumor effects have been observed in vitro when combining bintrafusp alfa and N-803, and in vivo when combining these agents with tumor vaccine in animal models.
• Given the high response rate of 46% seen thus far with the combination of BN-Brachyury, bintrafusp alfa, and N-803 in Arm 2.2A of QuEST1 trial suggests that it is important to determine the relative contribution of each agent in order to determine if a subset of these agents can be used while preserving efficacy and minimizing toxicity. In particular, because the combination of bintrafusp alfa with BN-Brachyury did not produce a significant response rate until N-803 was added, the objective of this Confirmatory QuEST1 trial (ConQuEST) is to investigate the impact of N-803 alone or in an unstudied combination with either BN-Brachyury or bintrafusp alfa.
• This trial offers a means to enhance response rates in castration-resistant prostate cancer (CRPC) on a potentially shorter timeline than with that of traditional trial designs.

OBJECTIVE:

-To determine the clinical efficacy of N-803 alone or in combination with brachyury vaccine or bintrafusp alfa among participants with CRPC

ELIGIBILITY:

• Participants must have castration-resistant prostate cancer. Prior treatment with testosterone lowering therapy for CRPC is required.
• Castrate testosterone level (<50 ng/dl or 1.7nmol /L)
• Age >=18 years
• ECOG performance status <=1

DESIGN:

• This is an open label, non-randomized, Phase II trial with sequential enrollment into Arm 1 followed by Arms 2 or 3 depending on the response to treatment.
• Enrollment will begin with Arm 1 (N-803 + brachyury vaccine), and response will be defined as objective response by response evaluation criteria in solid tumors (RECIST) 1.1 criteria or sustained prostate-specific antigen (PSA) decrease >= 30% for > 21 days.
• If at least 3 responses out of 12 participants are seen in Arm 1 within the first 12 weeks of treatment initiation, enrollment will begin with Arm 2 (N-803 alone); whereas, if fewer than 3 responses out of 12 participants, enrollment will begin in Arm 3 (N-803 + bintrafusp alfa).
• Bintrafusp alfa (1,200 mg) will be given via IV infusion every 2 weeks.
• N-803 (15 mcg/kg) subcutaneous injection will be given every 2 weeks.
• MVA-BN-Brachyury subcutaneous injection will be given as 2 priming doses 2 weeks apart. Each dose will comprise 4 x 0.5 mL subcutaneous injections consisting of a nominal virus titer of 2.0 x 10^8 infectious units (Inf.U).
• FPV-Brachyury subcutaneous injection will follow MVA-BN-Brachyury injection 2 weeks later every month for 6 months total, then every 3 months until reaching 2 years. After 2 years FPV-Brachyury may be continued at 6-month dosing intervals. Each dose will be a 0.5 mL injection consisting of a nominal virus titer of 1 x 10^9 Inf.U.
• Participants who respond or have the stable disease will continue on their assigned treatment regimen with the possibility of switching to triplet therapy (N-803 + brachyury vaccine + bintrafusp alfa) on PSA or radiographic progression if clinically stable should they experience progression beyond 12 weeks. Anyone who progresses clinically at any point during treatment will be taken off treatment, and anyone who progresses radiographically on triplet therapy will be taken off treatment.