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

Phase 2

Completed

Conditions: Small Bowel Cancers
Colorectal Cancers

Interventions: Biological: CV301
Drug: MSB0011359C
Drug: N-803
Drug: NHS-IL12

Registration Number: NCT04491955

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1/Arm 1	MSB0011359C	CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).
2/Arm 2A	MSB0011359C	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.
1/Arm 1	N-803	CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).
3/Arm 2B	CV301	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.
3/Arm 2B	MSB0011359C	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.
3/Arm 2B	N-803	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.
2/Arm 2A	CV301	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.
2/Arm 2A	NHS-IL12	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.
2/Arm 2A	N-803	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.
3/Arm 2B	NHS-IL12	CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.
1/Arm 1	CV301	CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) for Quadruple Therapy	one year	ORR of the combination of (1) Carcinoembryonic antigen (CEA)/Mucin-1 (MUC1) vaccines, (2) N-803 (Anktiva), (3) M7824 (MSB0011359C) and (4) NHS-IL12 (M9241) in participants with advanced small bowel and colorectal cancers was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Objective response is a complete or partial radiographic response as defined by RECIST 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Objective Response Rate (ORR) for Triple Therapy	one year	ORR of the combination of (1) Carcinoembryonic antigen (CEA)/Mucin-1 (MUC1) vaccines, (2) N-803 (Anktiva) and (3) M7824 (MSB0011359C) in participants with advanced small bowel and colorectal cancers was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Objective response is a complete or partial radiographic response as defined by RECIST 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Grade 3, Grade 4, and/or Grade 5 Adverse Events Related to Triple Therapy	Date treatment consent signed to date off study, approximately 29 months and 1 day for Cohort 1, Arm 1.	Safety of the combination of (1) CV301, (2) N-803 (Anktiva) and (3) M7824 (MSB0011359C) in participants with advanced small bowel and colorectal cancers was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Number of Participants With Grade 3, Grade 4, and/or Grade 5 Adverse Events Related to Quadruple Therapy	Date treatment consent signed to date off study, approximately 27 months for Cohort 2, Arm 2a Dose Level 1; 18 months and 29 days for cohort 2, Arm 2a Dose Level 2; and 7 months and 20 days for Cohort 2, Arm 2b, Dose Level 2.	Safety of the combination of (1) CV301, (2) N-803 (Anktiva), (3) M7824 (MSB0011359C) and (4) NHS-IL12 (M9241) in participants with advanced small bowel and colorectal cancers was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Progression Free Survival (PFS)	From time to enrollment up to 35 months	PFS per treatment assignment (three or four drug combination was evaluated using Kaplan-Meier methods and is defined as the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first. Participants who do not have disease progression or have not died at the end of follow up will be censored at the last known date the participant was progression free. Progression was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Overall Survival (OS)	Up to 35 months	OS per treatment assignment (three or four drug combination) evaluated using Kaplan-Meier methods. OS is defined as the time from the date of first treatment to the date of death (any cause). Participants who are alive at the end of follow up will be censored at the last known date alive.
Duration of Response (DOR)	Up to 34 months	DOR per treatment assignment (three or four drug combination) is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is disappearance of all target lesions. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Number of Participants Hospitalized Due to Serious Adverse Events Attributed to Progressive Disease (PD)	time participant is first enrolled to time participant is taken off of study treatment, an average of 2.1 months.	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. A serious adverse event 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, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. And progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.