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

Colorectal Cancers Clinical Trial

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

Status Active, not recruiting

Clinical Trial Summary

Background:

Metastatic or refractory/recurrent small bowel and colorectal cancers cannot be cured and are often not helped by standard treatments. Researchers want to find better treatments by testing a combination of drugs.

Objective:

To learn if a new combination of immunotherapy drugs can shrink tumors in people with advanced small bowel and colorectal cancers.

Eligibility:

People ages 18 and older who have advanced metastatic or refractory/recurrent small bowel and/or colorectal cancer.

Design:

Participants will be screened on a separate protocol. They will have a physical exam and medical history. They will have imaging scans. They will have blood and urine tests. Their heart function will be measured. They may have a tumor biopsy.

Participants will repeat some of the screening tests during the study.

Participants will be put into study groups. Each group will get a combination of the following drugs: CV301 vaccine (modified vaccinia Ankara (MVA)-BN-CV301 and Fowlpox (FPV)-CV301), M7824 (MSB0011359C), and N-803 (Anktiva). Some will also get NHS-IL12 (M9241).

Participants will get the CV301 vaccines by injection under the skin. They will get M7824 by intravenous infusion every 2 weeks. They will get N-803 by injection under the skin every 2 or 4 weeks. They may get NHS-IL12 by injection under the skin every 4 weeks. They will take the study drugs for up to 1 year. They will visit the National Institutes of Health (NIH) every 2 weeks.

After treatment ends, participants will go to the clinic for a 28-day follow-up visit or have a telephone call. They will be contacted every 3 months for 1 year, and then every 6 months after that for the rest of their life.

Clinical Trial 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 programmed cell death protein 1 (PD-1) or anti programmed death-ligand 1 (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 (MSB0011359C), and (4) a tumor targeted immunocytokine (NHS-IL12 (M9241).

Objectives:

To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting carcinoembryonic antigen (CEA) and mucin-1 (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 microsatellite stable (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 patient 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.

• Patients 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 patients on arm 1 will be evaluable for dose limiting toxicities (DLTs) and accrual will only continue to 9 patients on that arm if less than 2 out of the first 6 patients experience a DLT.

• In Arm 2B, patients 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 maximum tolerated dose (MTD) or highest safe dose evaluated, the 6 patients at that dose level will be included among the initial 9 patients for the first stage of that arm.

• If two or more out of nine patients have objective responses on a given arm that arm will be expanded to enroll 20 evaluable patients. ;

Related Conditions & MeSH terms

• Colorectal Cancers
• Colorectal Neoplasms
• Small Bowel Cancers

• NCT number: NCT04491955
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 22, 2020
• Completion date: January 31, 2026