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)

Description

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.