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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the treatment for metastatic colorectal cancer?

Research shows that the CEA-TRICOM vaccine, which is part of the treatment, can boost the immune system to fight colorectal cancer by increasing specific immune cells that target cancer cells. Additionally, targeting multiple immune pathways has shown significant antitumor activity in models of colorectal cancer, suggesting potential benefits of the combination treatment. ^{1 2 3 4 5}

Is the combination immunotherapy for metastatic colorectal cancer safe for humans?

The CEA-TRICOM vaccine, used in combination immunotherapy for colorectal cancer, has been tested in early-phase clinical trials and shown to be generally safe, with most side effects being mild and temporary. In a study of a similar vaccine targeting the brachyury protein, no serious side effects were observed, and only one case of temporary diarrhea was reported. ^{1 3 4 6 7}

What makes the Combination Immunotherapy for Metastatic Colorectal Cancer treatment unique?

This treatment is unique because it combines multiple agents that target different immune pathways to enhance the body's immune response against cancer. It includes a novel vaccine platform and an IL-15 superagonist to activate tumor-specific T cells, aiming to improve antitumor efficacy in cases resistant to standard immune checkpoint therapies. ^{1 2 4 8 9}

Research Team

Nicholas P Tschernia, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. United States 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. [2022]

3. United States 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. [2019]

4. England 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). [2021]

5. United States 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. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. [2019]

7. United States 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. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Update on novel strategies to optimize cetuximab therapy in patients with metastatic colorectal cancer. [2015]