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NCT number NCT03493945
Study type Interventional
Source National Institutes of Health Clinical Center (CC)
Contact Michell J Manu, R.N.
Phone (240) 760-7117
Email michell.manu@nih.gov
Status Recruiting
Phase Phase 1/Phase 2
Start date April 25, 2018
Completion date December 31, 2021

Clinical Trial Summary

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 metastatic castrate resistant prostate cancer (mCRPC) patients.

- 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.

- ALT-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 ALT-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 mCRPC, 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. ALT-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 patients with mCRPC:

- BN-Brachyury + M7824

- BN-Brachyury + M7824 + ALT-803

- BN-Brachyury + M7824 + ALT-803 + Epacadostat

Eligibility:

- Adults with histologically proven mCRPC, 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.

- Patients 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 patients 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 ALT-803).

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

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

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

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

- Phase IIB: expansion with randomized enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

- Each Arm in Cohort 2: 2.1, 2.2 and 2.3 will be open for additional enrollment (25 evaluable patients total) when the initial 13 patients have accrued, safety requirements are meet and a positive signal (defined as Objective Response by RECIST 1.1 or sustained PSA decrease greater than or equal to 30% sustained for > 21 days) in greater than or equal to 2 patients is shown.

- If only one arm i...


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 metastatic castrate resistant prostate cancer (mCRPC) patients.

- 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.

- ALT-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 ALT-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 mCRPC, 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. ALT-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 patients with mCRPC:

- BN-Brachyury + M7824

- BN-Brachyury + M7824 + ALT-803

- BN-Brachyury + M7824 + ALT-803 + Epacadostat

Eligibility:

- Adults with histologically proven mCRPC, 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.

- Patients 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 patients 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 ALT-803).

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

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

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

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

- Phase IIB: expansion with randomized enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

- Each Arm in Cohort 2: 2.1, 2.2 and 2.3 will be open for additional enrollment (25 evaluable patients total) when the initial 13 patients have accrued, safety requirements are meet and a positive signal (defined as Objective Response by RECIST 1.1 or sustained PSA decrease greater than or equal to 30% sustained for > 21 days) in greater than or equal to 2 patients is shown.

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

- If there are greater than or equal to 6 of 25 patients with a positive signal of activity in any expansion arm, that arm will be considered of interest for future studies.


Study Design


Related Conditions & MeSH terms


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