Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Vaccines

Immunomodulating Agents

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Retifanlimab + TriAdeno Vaccine + N-803 + SX-682

500 mg infused via IV over 30 minutes every 28 days

Retifanlimab

5x10\^11 virus particles per 1 mL administered via subcutaneous injection in the upper arm and anterolateral upper thigh on Day 1 of Cycles 1, 2, 3 and every 3 cycles after that

Therapeutic CEA, Brachyury and MUC1 TriAdeno Vaccine Platform

15 ug/kg administered via subcutaneous injection to the abdomen every 28 days

N-803

100 mg administered orally twice per day on days 6-26 of every cycle

SX-682

NCI Referral Office

NCIMO Referral

National Cancer Institute Referral Office

Jason M Redman, M.D.

Background:

Each year, more than 32,000 people in the United States are diagnosed with colorectal cancer that has returned or progressed after treatment and spread to other organs. This is called metastatic colorectal cancer (mCRC). Most people with mCRC survive only about 2 years.

Objective:

To test the ability of a combination of up to 4 experimental anti-cancer drugs treat mCRC. The names of these drugs are retifanlimab, TriAdeno vaccine, N-803, and SX-682. They are described below.

Eligibility:

Adults aged 18 years or older with mCRC. Participants must have

Design:

Participants will be screened. This includes having a physical exam, blood tests, urine tests, and imaging tests. If signed on to the study, participants will have 2 tumor biopsies. One when starting the study and once about 8 weeks after bring on the study. Participants will receive $500 for each biopsy.

Participants will be treated with either 3 or 4 drugs and will receive a detailed calendar explaining when each drug is given.

Retifanlimab is given every 4 weeks through an IV (an IV is tube attached to a needle inserted into a vein in the arm). N-803 is injected under the skin on the abdomen every 4 weeks.

TriAdeno vaccine is injected under the skin of the upper arm or thigh once a month for 3 doses and then once every 3 months.

Some participants will also receive a 4th drug. SX-682 is a pill taken by mouth. Participants will take this drug 2 times a day at home for about 3 weeks of each month.

Study treatment will continue up to 2 years. Follow-up phone calls/emails may continue for 3 more years.

Background:

* mCRC is incurable and available standard therapies offer a median overall survival of approximately 2 years.
* Most cases (approximately 95%) of mCRC have an intact expression of DNA mismatch repair enzymes (MLH1, MSH2, MSH6, and PMS2), and are commonly classified as having mismatch repair proficient (pMMR) or microsatellite stable (MSS) mCRC.
* MSS mCRC does not respond to immune checkpoint inhibitor (ICI) therapy whereas mismatch repair deficient (or microsatellite instability-high) mCRC is responsive to ICI therapy.
* Preclinical and clinical studies conducted at the NCI in the Laboratory of Tumor Immunology Biology (LTIB) indicate that the combination of programmed cell death protein 1 (PD-1) / Programmed death-ligand 1 (PD-L1) blockade, tumor-associated antigens (TAA) targeted vaccine, IL15 agonist, and CXCR1/2 inhibition may include sufficient immune enhancements to produce anti-tumor activity in MSS mCRC.
* Retifanlimab is a humanized IgG4 monoclonal antibody that targets PD-1. Retifanlimab has been studied in several clinical trials, and several malignancies, and has a safety and clinical activity profile similar to approved anti-PD-1 therapies (e.g., pembrolizumab).
* The TriAdeno Vaccine employs 3 adenovirus serotype 5 vectors, encoding three TAAs (CEA, MUC1, and brachyury). These vaccines have completed the phase 1 study and are safe and well tolerated. Vaccination generates antigen-specific T cell responses to CEA, MUC1, and brachyury.
* N-803 is an IL-15 agonist that activates and expands T cells and NK cells. N-803 enhances anti-tumor activity in combination with tumor-targeted vaccines. Clinically, multiple studies have demonstrated the safety of tumor-targeted vaccine in combination with PD- 1/PD-L1 blockade. Adding N-803 to PD-1/PD-L1 blockade can produce antitumor responses in disease states where responses to PD-1/PD-L1 alone would not be expected.
* SX-682 is a small molecule, orally bioavailable, allosteric antagonist of the chemokine receptors CXCR1 and CXCR2. Inhibition of CXCR1 and CXCR2 addresses a major component of intratumoral T cell suppression by myeloid-derived suppressor cells and tumor-associate macrophages. SX-682 has shown to be tolerable in combination with PD- 1/PD-L1 blockade.

Objectives:

* Phase I: to describe the safety profile of the Immuno-Oncology (IO) regimens consisting of retifanlimab, TriAdeno vaccine, N-803 (A1), and retifanlimab, TriAdeno vaccine, N- 803, SX 682 (A2) in participants with metastatic colorectal cancer (mCRC).
* Phase II: to determine the objective response rate (ORR) (complete response (CR) + partial response (PR)) of the IO regimen in mCRC.

Eligibility:

* Age \>=18 years.
* Previously treated metastatic colorectal cancer with measurable disease.
* Eastern Cooperative Oncology Group (ECOG) performance status \<= 2.
* Adequate organ function.

Design:

* This is an open-label Phase I/II trial to evaluate the safety and efficacy of the Immuno- Oncology regimen, consisting of retifanlimab, TriAdeno vaccine, N-803, and SX-682 in participants with mCRC.
* During Phase I, we will assess the safety of the three- and the four-drug IO regimens.
* During Phase II we will continue to evaluate the safety and examine the efficacy of the four drug IO regimen. If 0 to 1 of the first 9 participants treated with the 4-drug IO regimen have a clinical response, defined as complete response (CR) + partial response (PR) within the first 24 weeks after treatment initiation, then no further participants will be accrued using the quadruple combination. If 2 or more of the first 9 participants have a response, then accrual will continue until a total of 23 evaluable participants have been treated with a four-drug IO regimen.
* Participants will receive treatment in cycles consisting of 28 (+7) days for 2 years.
* To allow for a small number of inevaluable participants, and screen failures the accrual ceiling will be set at 60.

Phase I/II Study of the Combination Immunotherapy Regimen: SX-682, TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC)

.All collected IPD will be shared. All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Number of DLTs within DLT period (C1 days 1-28). Any toxicities identified.

The fraction of participants with a CR or PR (per RECIST v1.1) in Phase II will be reported along with a 95% confidence interval.

PFS will be determined by the Kaplan-Meier method and reported at 6, 12, and 24 months from the date the participant was enrolled in the trial, along with 95 percent confidence intervals at these times.

DCR at 6 and 12 months will be reported as a fraction along with a 95 percent confidence interval for each.

AEs will be reported by type and grade within Phase II.

Monitoring of participants from Day 1 of each cycle, at follow up visits and until date of death/closure of the study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I/II Study of the Combination Immunotherapy Regimen: SX-682, TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC)	NCT06149481	Metastatic Colo...	Retifanlimab Therapeutic CEA... N-803 SX-682	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Phase I/II Study of the Combination Immunotherapy Regimen: SX-682, TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC)	NCT06149481	Metastatic Colo...	Retifanlimab Therapeutic CEA... N-803 SX-682	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Phase I/II Study of the Combination Immunotherapy Regimen: SX-682, TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC)	NCT06149481	Metastatic Colo...	Retifanlimab Therapeutic CEA... N-803 SX-682	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

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