N-803 Alone or in Combination With BN-Brachyury Vaccine or Bintrafusp Alfa (M7824) for Participants With Castration Resistant Prostate Cancer
- Conditions
- Castration Resistant Prostate Cancer
- Interventions
- Registration Number
- NCT05445882
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Prostate cancer does not trigger a strong immune response in the body. Hormone therapy, to reduce levels of testosterone in the body, can be helpful to treat some prostate cancers. However, castration-resistant prostate cancer (CRPC) keeps growing even when the testosterone is reduced to a very low level. Men with metastatic CRPC survive an average of only 3 years. More effective treatments are needed.
Objective:
To test whether an immunotherapy drug (N-803), alone or in combination with other drugs, can help treat CRPC.
Eligibility:
Males aged 18 or older with CRPC. Prior treatment with testosterone-lowering therapy is required.
Design:
Participants will be screened. They will have blood and urine tests. They will have a CT scan of the chest, abdomen, and pelvis.
They will continue to receive hormone therapy for prostate cancer.
Participants will come to the NIH clinic once a week for the first 4 weeks. Then they will come once every 2 weeks. Visits will last up to 8 hours. The study will continue up to 3 years.
All participants will receive N-803 once every 2 weeks. The drug is injected just under the skin with a small needle.
Some participants will receive N-803 plus another drug (brachyury vaccine). This drug is also injected under the skin with a small needle.
Some participants will receive N-803 plus a different drug (bintrafusp alfa) once every 2 weeks. This drug is given through a tube attached to a needle placed in a vein in the arm.
Some participants may receive all 3 drugs.
Participants will have imaging scans every 12 weeks.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- Male
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 3 N-803 N-803 + bintrafusp alfa (+ BN-Brachyury if progression beyond 12 weeks) Arm 1 BN-Brachyury N-803 + BN-Brachyury (+ bintrafusp alfa if progression beyond 12 weeks) Arm 1 N-803 N-803 + BN-Brachyury (+ bintrafusp alfa if progression beyond 12 weeks) Arm 2 N-803 N-803 (+ BN-Brachyury + bintrafusp alfa if progression beyond 12 weeks) Arm 3 Bintrafusp alfa N-803 + bintrafusp alfa (+ BN-Brachyury if progression beyond 12 weeks)
- Primary Outcome Measures
Name Time Method Clinical Efficacy of N-803 alone or in combination with brachyury vaccine or bintrafusp alfa 12 weeks In each arm, the fraction who experience a response by 12 weeks will be noted and reported along with a 95% confidence interval.
- Secondary Outcome Measures
Name Time Method Duration of response 3 years the date of response until the date of progression or other determination that the response has ended
Radiographic response 3 years The fraction of participants with a radiographic response will be noted along with a 95% confidence interval, separately for each arm based on imaging
Safety profile of N-803 alone or in combination with brachyury vaccine or bintrafusp alfa 3 years the number of participants with toxicities experienced by grade and type, by arm, as well as overall.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States