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

Phase 1

Completed

Conditions: Metastatic Castration-resistant Prostate Cancer
Prostate Cancer
Advanced Solid Tumor
Solid Tumor
Prostate Neoplasm
Non-metastatic Castration-resistant Prostate Cancer

Interventions: Biological: M7824
Drug: N-803
Biological: MVA-BN-Brachyury
Drug: Acetaminophen
Biological: FPV-Brachyury
Drug: Ibuprofen
Drug: Naproxen
Drug: Epacadostat
Other: Benadryl
Diagnostic Test: EKG
Diagnostic Test: Bone scan
Diagnostic Test: CT chest, abdomen and pelvis
Diagnostic Test: MRI

Registration Number: NCT03493945

Lead Sponsor: National Cancer Institute (NCI)

Brief 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 any of the combinations of drugs below have anti-prostate cancer activity and to test if they are safe.

1. Bavarian-Nordic (BN)-brachyury, bintrafusp alfa (M7824).

2. Bavarian-Nordic (BN)-brachyury, bintrafusp alfa (M7824) + Anktiva (N-803).

3. Bavarian-Nordic (BN)-brachyury, bintrafusp alfa (M7824) + Anktiva (N-803) + Epacadostat.

Eligibility:

People ages 18 and older with CRPC or another metastatic cancer

Design:

Participants will be screened with:

* Medical history

* Physical exam

* Computed tomography (CT) or magnetic resonance imaging (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 intravenous (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.

Detailed Description: Background:

* Programmed cell death protein 1 (PD-1)/programmed death ligand 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 natural killer (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.

* Bavarian Nordic (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 (modified vaccinia Ankara (MVA)-BN-Brachyury) and the boost doses (fowlpox virus (FPV)-Brachyury) of the vaccine platform.

* bintrafusp alfa (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.

* Anktiva (N-803) is an interleukin 15 (IL-15)/IL-15R alpha superagonist complex that can enhance NK cell mediated antibody-dependent cell-mediated cytotoxicity (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.

* Indoleamine 2,3-dioxygenase 1 (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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or sustained prostate-specific antigen (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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 59

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Primary Outcome Measures

Name	Time	Method
Clinical Benefit With Any of a Set of 3 Possible Treatments for Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Reported With an 80% Confidence Interval	From enrollment up to 49 weeks	Objective clinical response and/or prostate-specific antigen (PSA) decline of \>=30% sustained for a minimum of 21 days. Any of these is considered 'clinical benefit.' Objective response was assessed by the response evaluation criteria in solid tumors (RECIST) 1.1. Complete response (CR) is disappearance of all non-target lesions and normalization of tumor marker level. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions. Three treatments evaluated are: Phase II Bavarian Nordic (BN) Brachyury + Bintrafusp alfa (M7824), Phase II Bavarian Nordic (BN) Brachyury + Bintrafusp alfa (M7824) + Anktiva (N-803), and Phase II Bavarian Nordic (BN) Brachyury + Bintrafusp alfa (M7824) + Anktiva (N-803) + Epacadostat.
Clinical Benefit(Objective Response if Measurable Disease by Response Evaluation Criteria in Solid Tumors v1.1)With Any of 3 Possible Treatments for Participants With Metastatic Castration-resistant Prostate Cancer Reported With a 95% Confidence Interval	From enrollment up to 49 weeks	Objective response was assessed by the response evaluation criteria in solid tumors (RECIST) 1.1. Complete response (CR) is disappearance of all non-target lesions and normalization of tumor marker level. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions. Three treatments evaluated are: Phase II Bavarian Nordic (BN) Brachyury + Bintrafusp alfa (M7824), Phase II Bavarian Nordic (BN) Brachyury + Bintrafusp alfa (M7824) + Anktiva (N-803), and Phase II Bavarian Nordic (BN) Brachyury + Bintrafusp alfa (M7824) + Anktiva (N-803) + Epacadostat.
Phase I/II: Number of Participants With Grades 3, 4, and/or 5 Serious and/or Non-serious Dose-limiting Toxicities (DLT)	Within 21 days of the start of treatment	A DLT is defined as any of the following adverse events (AE) possibly related to study drugs that occur within 21 days of the start of treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade 3 is moderate. Grade 4 is life-threatening, and Grade 5 is death related to AE. A DLT is any grade ≥ 4 hematologic toxicity or grade 3 thrombocytopenia with associated bleeding; any grade ≥ 3 non-hematologic toxicity, except for any of the following: transient (≤ 48 hour) grade 3 fatigue, local reactions, flu-like symptoms, fever, headache, or nausea, emesis, and diarrhea; or CTCAE Grade 3 skin toxicity lasting less than five days. A non-serious AE is any untoward medical occurrence. A serious AE is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, or congenital anomaly/birth defect.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Grades 3, 4, and/or 5 Serious Adverse Events Related to Treatment Treated With Combinations and Bintrafusp Alfa (M7824) + Anktiva (N-803)	3 weeks dose-limiting toxicity (DLT) period	Number of participants with grades 3 4, and/or 5 serious adverse events related to treatment treated with combinations and Bintrafusp alfa (M7824) + Anktiva (N-803).
6-month Progression Free Survival (PFS) Probability	6-months	6-month progression free survival was measured from the on-study date until progression or death without progression in participants and reported with a 95% confidence interval. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Number of Participants With Grades 1, 2, 3, and 4 Non-serious Adverse Events Related to Treatment Treated With Combinations and Bintrafusp Alfa (M7824) + Anktiva (N-803)	3 weeks dose-limiting toxicity (DLT) period	Number of participants with grades 1, 2, 3, and 4 non-serious adverse events related to treatment treated with combinations and Bintrafusp alfa (M7824) + Anktiva (N-803).

Trial Locations

Locations (1): National Institutes of Health Clinical Center
🇺🇸
Bethesda, Maryland, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States

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