Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, N-803 and Epacadostat (QuEST1)

Prostate Cancer Clinical Trial

Official title: A Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, N-803 and Epacadostat (QuEST1)

Status Active, not recruiting

Clinical Trial Summary

Background:

Immunotherapy drugs help the body to fight cancer. Scientists think that combining some of these drugs will make them work better than when used alone. This may be true for many types of cancer, including castration-resistant prostate cancer (CRPC).

Objective:

To test if the combination of the drugs BN-brachyury, M7824, N-803, and Epacadostat is safe and shrinks tumors.

Eligibility:

People ages 18 and older with CRPC or another metastatic cancer

Design:

Participants will be screened with:

• Medical history

• Physical exam

• CT or MRI scans

• Possible bone imaging

• Blood, urine, and heart tests

• Possible tumor biopsy

Participants will be treated with a 2-, 3- or 4-drug combinations of the following study drugs in 2-week cycles:

• Participants will receive M7824 by IV once every 2 weeks.

• Participants will receive N-803 by injection once every 2 weeks. They will record any skin changes at the injection site in a diary.

• Participants will receive BN-brachyury as 4 injections to different limbs. They will get the first 3 doses 2 weeks apart. Then they will get doses every 4 weeks for 6 months, then every 3 months for 2 years, then every 6 months.

• Participants will take Epacadostat orally every 12 hours. They will keep a pill diary.

Participants will have physical exams and blood and urine tests at the start of each cycle. They may have scans every 12 weeks.

Participants will continue treatment until their disease gets worse or they cannot tolerate the side effects.

Participants will have a follow-up visit 4-5 weeks after they stop treatment. They will have a physical exam and blood tests. They may be asked to return for scans every 3 months.

Clinical Trial Description

Background:

• PD-1/PD-L1 signaling appears to be a major inhibitor of activated T cell anti-tumor immune responses. The rapid, deep and durable responses seen in various malignancies with PD-1/PD-L1 targeted agents demonstrate that blockade of this axis is key to facilitating immune responses within the tumor microenvironment (TME).

• 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.

• Increasing response rates will likely require therapeutic nullification of multiple immune deficits by combining immunotherapies that generate tumor-specific T cells (vaccine), dampen the inhibitory milieu of the TME, and enhance T and NK cell activity within the TME.

• A quick efficacy seeking trial, utilizing sequential arms offers a means to identify signals of activity for combinations of immunotherapy, added sequentially, in castration resistant prostate cancer (CRPC) participants.

• 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.

• M7824 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. M7824 can also mediate antibody-dependent cellular cytotoxicity in vitro.

• N-803 is an IL-15/IL-15R alpha superagonist complex that can enhance NK cell mediated ADCC and T-cell cytotoxicity.

• Synergistic anti-tumor effects have been observed in vitro when combining M7824 and N-803, and in vivo when combining these agents with tumor vaccine in animal models.

• IDO1 is overexpressed in many solid tumors and can contribute to immune escape by tumor cells. INCB024360 (Epacadostat) is an IDO1 inhibitor under investigation in combination with different immunotherapies in treatment of various malignancies.

• In treating of CRPC, we hypothesize that these agents and their effects will be complementary. Tumor-specific T cells generated by vaccine may become more functional in a TME following treatment with M7824 and Epacadostat. N-803 can further enhance the activity of antigen-specific T cells as well as NK cells.

Objective:

-To determine if there is clinical benefit to any of a set of 3 possible treatments for participants with CRPC:

• BN-Brachyury + M7824

• BN-Brachyury + M7824 + N-803

• BN-Brachyury + M7824 + N-803 + Epacadostat

Eligibility:

• Adults with histologically proven CRPC, or metastatic solid tumor of any type for which there is no standard treatment or standard treatment has failed.

• Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.

• Participants with acquired immune defects, active systemic autoimmune disease, history of organ transplant, history of chronic infections, or history of active inflammatory bowel disease are excluded.

Design:

Open label Phase I/II trial with following randomization during the expansion.

Phase I: Cohort 1, Arm 1.1

-Up to 18 participants with any solid tumor will be enrolled in dose escalation Cohort 1 for treatment in Arm 1.1 (flat dose of M7824 + different dose levels of N-803).

Phase IIA: expansion with sequential enrollment into Cohort 2A, Arms 2.1A, 2.2A and 2.3 A

• Concurrently with the enrollment to Arm 1.1, 13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.1A (M7824 + BN-Brachyury).

• When safe dosing of N-803 is identified during Phase I, 13 participants have enrolled in arm 2.1A and the first 6 participants, treated in Arm 2.1A, have met safety requirements, 13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.2A (M7824 + BN-Brachyury + N-803).

• When 13 participants have enrolled in Arm 2.2A and the first 6 participants, treated in Arm 2.2A, have met safety requirements, 13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.3A (M7824 + BN-Brachyury + N-803 + Epacadostat).

Phase IIB: expansion with randomized enrollment into Cohorts 2D and 2R, Arms 2.1B, 2.2B. and 2.3B

• Each Arm in Cohorts 2D and 2R: 2.1B, 2.2B and 2.3B will be open for additional enrollment (25 evaluable participants total) when the initial 13 participants have accrued, safety requirements are meet and a positive signal (defined as Objective Response by RECIST 1.1 or sustained PSA decrease >= 30% sustained for > 21 days) in >= 2 participants is shown.

• If only one arm is open for additional enrollment, participants will be directly assigned to this arm. If 2 arms are open for additional enrollment, participants will be randomized between these 2 open arms. If 3 arms are open for additional enrollment, participants will be randomized among these 3 open arms.

If there are >= 6 of 25 participants with a positive signal of activity in any expansion arm, that arm will be considered of interest for future studies. ;

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Metastatic Prostate Cancer
• Prostate Cancer
• Prostate Neoplasm
• Prostatic Neoplasms
• Solid Tumor

• NCT number: NCT03493945
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: May 1, 2018
• Completion date: December 31, 2024