Combination Immunotherapy for Metastatic Colorectal Cancer

Overseen By Jason M Redman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Lung disease, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining up to four experimental drugs to treat metastatic colorectal cancer (mCRC), a cancer that has spread to other parts of the body. The trial aims to determine if these drugs—retifanlimab (an immunotherapy drug), TriAdeno vaccine, N-803 (an IL-15 superagonist complex), and SX-682—can help manage or slow the disease. Participants will receive either three or four of these drugs in various combinations. This trial suits adults with mCRC that has not responded to standard treatments or has returned after such treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive these new therapies.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had investigational drugs, chemotherapy, immunotherapy, or therapeutic radiotherapy within 14 days before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of drugs retifanlimab, the TriAdeno vaccine, and N-803 has been tested for safety in previous studies. Most patients tolerated this combination well. However, some reported side effects include tiredness and pain at the injection site, which are common for many cancer treatments.

For the combination that includes the additional drug SX-682, studies have also assessed its safety. This combination might cause similar mild to moderate side effects. SX-682 is a pill taken at home, and while specific side effects from SX-682 alone aren't highlighted, these medications can sometimes cause more noticeable reactions.

Since this trial is in the early stages, the main focus is on ensuring the drugs are safe. Early phase trials are designed to test drug safety, so researchers will closely monitor participants. Those considering joining should know that researchers will pay close attention to any side effects experienced. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for metastatic colorectal cancer because they use a combination of innovative immunotherapies that target the immune system in ways current treatments do not. Most traditional treatments involve chemotherapy or targeted therapy aimed directly at cancer cells. However, this trial features Retifanlimab, an immune checkpoint inhibitor, combined with the TriAdeno Vaccine, which stimulates the immune system to recognize and attack cancer cells more effectively. N-803 enhances the activity of natural killer cells, and SX-682 further disrupts the tumor's ability to evade the immune response. This multi-pronged approach aims to boost the body's natural defenses against cancer, offering hope for more effective and lasting control of the disease.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer?

This trial will study two different treatment combinations for metastatic colorectal cancer (mCRC). In one arm, participants will receive retifanlimab, the TriAdeno vaccine, and N-803. Research has shown that retifanlimab helps the immune system find and attack cancer cells, the TriAdeno vaccine uses a virus to help the body recognize and fight cancer, and N-803 further boosts the immune response. Early studies suggest that these treatments can work together to control cancer growth. In another arm, participants will receive the same combination with the addition of SX-682, which blocks signals that help cancer spread, potentially enhancing this effect. While more research is needed, these treatments are being studied for their potential to improve outcomes for people with mCRC. ^{1 2 3 5 6}

Who Is on the Research Team?

Nicholas P Tschernia, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with metastatic colorectal cancer who've had at least one line of systemic therapy can join this trial. They must be HIV or Hepatitis C positive under control, agree to use contraception, and have lesions for biopsy. Excluded are those recently on other treatments, with certain autoimmune diseases, organ transplants, unresolved infections, or uncontrolled illnesses.

Inclusion Criteria

Participants must be able to understand and willing to sign a written informed consent document

I have had one treatment with a checkpoint inhibitor for my advanced colon cancer.

Measurable disease per RECIST 1.1

Exclusion Criteria

I have had Hepatitis B but am either on suppressive therapy or it has resolved.

I haven't had any cancer treatment or experimental drugs in the last 14 days.

I stopped a previous cancer treatment due to severe side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a combination of up to 4 experimental anti-cancer drugs: retifanlimab, TriAdeno vaccine, N-803, and SX-682. Treatment cycles are 28 days long and continue for up to 2 years.

Up to 2 years

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up phone calls/emails may continue for 3 more years.

3 years

Regular follow-up calls/emails

What Are the Treatments Tested in This Trial?

Interventions

• N-803
• Retifanlimab
• SX-682
• Therapeutic CEA, Brachyury and MUC1 TriAdeno Vaccine Platform

Trial Overview The STAR15 trial is testing a combination of up to four experimental drugs (retifanlimab, TriAdeno vaccine, N-803, SX-682) against mCRC. Participants will receive these drugs through various methods including IVs and injections over two years with follow-ups extending three more years.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 4 Interventions

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

Group II: Arm 1 Experimental Treatment 3 Interventions

Retifanlimab + TriAdeno Vaccine + N-803

N-803 is already approved in United States for the following indications:

Approved in United States as N-803 for:

• Non-muscle invasive bladder cancer (NMIBC) in combination with BCG

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination therapy using αTIGIT and bintrafusp alfa effectively targets multiple immunosuppressive pathways, leading to significant antitumor activity and improved survival in mouse models of colorectal and HPV+ lung carcinomas.

This treatment not only generated memory immune responses that protected against tumor rechallenge but also enhanced the activation and cytotoxicity of CD8+ T cells, indicating a robust immune response against tumors resistant to traditional checkpoint blockade therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune targeting of three independent suppressive pathways (TIGIT, PD-L1, TGFβ) provides significant antitumor efficacy in immune checkpoint resistant models. Franks, SE., Fabian, KP., Santiago-Sánchez, G., et al.[2022]

The combination of five immunotherapy agents, known as pentatherapy, significantly inhibited tumor growth and enhanced immune responses in a murine colon carcinoma model, showing no toxicity, which suggests a promising approach for treating immunologically cold solid tumors.

Monotherapy with any of the individual agents showed little to no antitumor activity, highlighting the necessity of using multiple agents together to effectively engage and activate T cells and reduce immunosuppression in the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable. Fabian, KP., Malamas, AS., Padget, MR., et al.[2022]

In a study of 24 colorectal carcinoma patients, vaccination with recombinant carcinoembryonic antigen (CEA) combined with GM-CSF led to a strong immune response, with 100% of patients in the GM-CSF group developing specific T-cell and IgG responses.

The combination therapy was found to be nontoxic and resulted in durable immune responses, with higher anti-CEA IgG levels correlating with increased survival, suggesting potential for further trials in CRC immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor. Ullenhag, GJ., Frödin, JE., Jeddi-Tehrani, M., et al.[2019]

The CEA-TRICOM vaccines were found to be safe in a phase I trial involving 58 patients with advanced cancers, with no significant toxicity reported during the study.

The vaccines generated strong CEA-specific immune responses, with 40% of patients achieving stable disease for at least 4 months, indicating potential clinical benefits for some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. Marshall, JL., Gulley, JL., Arlen, PM., et al.[2023]

In a study of 74 patients with resected colorectal cancer metastases, both dendritic cell (DC) vaccines and poxvector vaccines showed similar efficacy in terms of recurrence-free survival, with rates of 47% and 55% respectively at 2 years.

Vaccinated patients had better overall survival compared to an unvaccinated group, indicating that these vaccines may provide a beneficial immune response that could help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Morse, MA., Niedzwiecki, D., Marshall, JL., et al.[2021]

The Ad5 PSA/MUC-1/brachyury vaccine targeting metastatic castration-resistant prostate cancer (mCRPC) was found to be safe and well-tolerated, with no severe treatment-related adverse events reported in a trial involving 18 patients.

The vaccine demonstrated clinical activity, with one patient achieving a partial response and five showing a decline in PSA levels, indicating potential effectiveness in generating an immune response against tumor-associated antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC). Bilusic, M., McMahon, S., Madan, RA., et al.[2021]

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, has shown promise in improving treatment outcomes for metastatic colorectal cancer (mCRC) by enhancing the effectiveness of chemotherapy and restoring sensitivity to irinotecan in pretreated patients.

Recent studies indicate that cetuximab can be effectively combined with standard chemotherapy regimens, leading to high response rates, and it may be administered on a more convenient 2-week schedule, optimizing patient management in mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on novel strategies to optimize cetuximab therapy in patients with metastatic colorectal cancer. Macarulla, T., Ramos, FJ., Elez, E., et al.[2015]

CEA-TRICOM is a promising vaccine designed to enhance the immune system's ability to target and destroy colorectal cancer cells, utilizing a combination of costimulatory molecules and the carcinoembryonic antigen (CEA).

A phase I trial involving up to 42 patients with advanced metastatic colorectal cancer is underway to assess the safety and immune response of CEA-TRICOM, focusing on the stimulation of CEA-specific T-cells as a primary outcome measure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Technology evaluation: CEA-TRICOM, Therion Biologics Corp. Morse, MA.[2006]

The MVA-brachyury-TRICOM vaccine, designed to target the brachyury transcription factor associated with cancer progression, was safely administered to 38 advanced cancer patients without any dose-limiting toxicities, indicating a favorable safety profile.

The vaccine successfully activated brachyury-specific T-cell responses in most patients, suggesting its potential efficacy in enhancing the immune response against tumors that express brachyury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. Heery, CR., Palena, C., McMahon, S., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06149481

NCT06149481 | Phase I/II Study of the Combination ... 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, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12487952/

Immunotherapy for precision medicine in colorectal cancer The following review focuses on immunological approaches for CRCs, including therapeutic monoclonal antibodies, immune checkpoint blockade, ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/adenovirus-5-cea-muc1-brachyury-vaccine-tri-ad5?pn=1

Clinical Trials Using Adenovirus 5 CEA/MUC1/Brachyury ... ... TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC). Status: Active. Location: National Institutes of ...

4. dana-farber.org dana-farber.org/clinical-trials/23-039

A Phase IIb Clinical Trial of the Multitargeted Recombinant ... This phase IIb trial tests whether Tri-Ad5 in combination with N-803 works to prevent colon and other cancers in participants with Lynch syndrome.

5. adisinsight.springer.com adisinsight.springer.com/trials/700369187

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

6. trial.medpath.com trial.medpath.com/clinical-trial/9b5589577ddf539b/nct06149481-combination-immunotherapy-metastatic-colorectal-cancer

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