Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers

Summary

Participation Requirements

Description

Background: Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and poorly palliated by standard therapies. There is an unmet need for active treatments for these tumors. To date immunotherapies including anti PD-1 or anti PD-L1 inhibitors have proven largely ineffect...

Background: Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and poorly palliated by standard therapies. There is an unmet need for active treatments for these tumors. To date immunotherapies including anti PD-1 or anti PD-L1 inhibitors have proven largely ineffective for the vast majority of these cancers. In microsatellite stable (MSS) colorectal cancer (>95% of these cancers) the response rate to checkpoint inhibitors has been <5%. Preclinical studies suggest that the use of different combinations of multiple immunotherapy agents may improve anti-tumor efficacy. These studies have employed (1) a vaccine targeting a tumor associated antigen, (2) an IL-15 superagonist (N-803, also known as ALT-803), (3) an anti-PD-L1 MAb or a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824), and (4) a tumor targeted immunocytokine (NHS-IL12). Objectives: To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting CEA and MUC1, (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, (3) M7824 and (4) NHS-IL12 (M9241) in subjects with advanced checkpoint naive MSS small bowel and colorectal cancers. Eligibility: Age >= 18 years old Subjects with cytologically or histologically confirmed locally advanced or metastatic small bowel or colorectal adenocarcinomas. Prior first line systemic therapy is required unless the participant declines standard treatment after appropriate counseling has been provided. Subjects must have measurable disease. Design: This is a phase II trial of combination immunotherapy, with a brief dose escalation portion for Arm 2. The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm. Participants will be enrolled on the following arms in sequential order: (1) Arm 1: CV301 + M7824 + N-803, (2) Arm 2A and Arm 2B: CV301 + M7824 + N-803 + NHS-IL12; N-803 dose level will be evaluated in Arm 2A prior to further enrollment in Arm 2B. The first six participants on arm 1 will be evaluable for dose limiting toxicities (DLTs) and accrual will only continue to 9 participants on that arm if less than 2 out of the first 6 participants experience a DLT. In Arm 2B, participants will receive 4 drug treatments (CV301 + M7824 + N-803 + NHSIL12), but the dose level of N-803 will first be determined during a 3-level dose escalation portion, Arm 2A. Following determination of the MTD or highest safe dose evaluated, the 6 participants at that dose level will be included among the initial 9 participants for the first stage of that arm. If two or more out of nine participants have objective responses on a given arm that arm will be expanded to enroll 20 evaluable participants.

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