Triple Therapy for Colorectal Cancer

Not currently recruiting at 7 trial locations

Overseen By Neil H Segal, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active CNS metastases, Autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with advanced colorectal cancer that has spread and is MMR-proficient, meaning it lacks a specific genetic mismatch issue. Researchers are testing whether a combination of three drugs—cisplatin (a chemotherapy drug), nivolumab (an immunotherapy drug), and temozolomide (a chemotherapy drug)—is effective and safe. Suitable candidates for this trial have colorectal cancer that hasn't responded to at least two standard treatments and lack certain genetic markers like BRAF or POLE mutations. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer treatment.

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

The trial does not specify if you need to stop taking your current medications. However, you cannot be on systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before starting the trial treatment.

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

Research has shown that the combination of cisplatin, nivolumab, and temozolomide was tested for safety in earlier studies. Cisplatin and temozolomide are chemotherapy drugs, while nivolumab helps the immune system fight cancer.

In previous studies, this combination was tested in patients with colorectal cancer, and many tolerated the treatment well. However, like many cancer treatments, it can cause side effects such as nausea, tiredness, or low blood cell counts. These side effects are common with chemotherapy and immune therapies.

Prospective trial participants should discuss these possible side effects with their doctor to understand how they might be affected. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for colorectal cancer because it combines three potent drugs: Cisplatin, Nivolumab, and Temozolomide. Unlike traditional chemotherapy regimens, which often include drugs like 5-FU and oxaliplatin, this triple therapy incorporates Nivolumab, an immunotherapy, to enhance the body's immune response against cancer cells. Temozolomide, typically used in brain cancer, is being repurposed here for its ability to interfere with DNA repair in cancer cells. This unique combination aims to not only attack the cancer directly but also boost the immune system's ability to fight the tumor, offering a novel approach that could improve outcomes for patients.

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

This trial will evaluate the combination of cisplatin, nivolumab, and temozolomide for advanced colorectal cancer that doesn't easily repair its own DNA. Research has shown that using cisplatin and temozolomide together can increase cancer cells' sensitivity to treatment. Nivolumab, a drug that boosts the immune system, has shown promise in helping the body fight cancer cells more effectively. Using these three drugs together may shrink or stabilize tumors better than using them alone. This combination aims to enhance treatment effectiveness against this difficult-to-treat cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Neil H Segal,, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced colorectal cancer that's spread and hasn't responded to at least two standard chemotherapies can join this trial. They need a certain level of blood cells, good organ function, and no major health issues like HIV or active infections. Pregnant or breastfeeding individuals are excluded.

Inclusion Criteria

I am fully active or can carry out light work.

aCreatinine clearance should be calculated per institutional standard.

My recent tests show my organs are functioning well.

Exclusion Criteria

I have another cancer, but it's either not growing or doesn't need treatment, except for certain skin cancers or treated cervical cancer.

Subject is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.

Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral temozolomide at 150-200 mg/m2 day 1 to 5 every 4 weeks, cisplatin via IV infusion at 40 mg/m2 every two weeks, and nivolumab via IV infusion at 480 mg every four weeks

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Nivolumab
• Temozolomide

Trial Overview The study is testing a combination of three drugs: Temozolomide (TMZ), Cisplatin, and Nivolumab in people whose colorectal cancer has not been helped by standard treatments. It aims to see if this mix is safe and works better for those with specific genetic features in their tumors.

How Is the Trial Designed?

Group I: temozolomide, cisplatin and nivolumab Experimental Treatment 3 Interventions

Subjects will receive oral TMZ at 150-200 mg/m2 day 1 to 5 every 4 weeks, cisplatin via IV infusion at 40 mg/m2 every two weeks (Q2W), and nivolumab via IV infusion at 480 mg every four weeks (Q4W).

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

In a phase II trial involving 33 patients with recurrent malignant glioma, the combination of cisplatin and temozolomide showed a progression-free survival (PFS) rate of 52% at 6 months, indicating a potential benefit for patients with this aggressive cancer.

The treatment resulted in partial responses in 18.8% of patients and stable disease in 39.9%, but also led to significant toxic effects, including severe neutropenia and thrombocytopenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of cisplatin plus temozolomide, in recurrent and progressive malignant glioma patients. Silvani, A., Eoli, M., Salmaggi, A., et al.[2022]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

The modified DCS therapy (docetaxel, cisplatin, and S-1) demonstrated a high overall response rate of 79.1% in patients with unresectable gastric cancer, with 34.9% of patients eligible for curative conversion surgery.

While modified DCS resulted in fewer severe toxicities compared to the original regimen, significant side effects like grade 3/4 neutropenia (79.1%) and febrile neutropenia (34.9%) were still common, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer. Uemura, N., Kikuchi, S., Sato, Y., et al.[2022]

The study evaluated the safety of a triple combination therapy of Paclitaxel (PTX), Cisplatin (CDDP), and 5-fluorouracil (5-FU) in 12 patients with unresectable or recurrent gastric cancer, finding it to be a safe treatment option despite some cases of hematological and non-hematological toxicities.

While there were instances of grade 3 or higher toxicities, including leukopenia and neutropenia, no infections occurred, and the maximum tolerated dose of 5-FU was determined to be 400 mg, indicating that the combination therapy can be administered with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of paclitaxel, cisplatin and 5-fluorouracil combination chemotherapy for unresectable / recurrent gastric cancer. Kato, J., Nagahara, A., Iijima, K., et al.[2015]

In a study of 32 patients with brain metastases from solid tumors, the combination of temozolomide (TMZ) and cisplatin (CDDP) showed promising efficacy, with a 28.1% partial response rate and a median overall survival of 5.5 months.

The treatment was generally well-tolerated, although some patients experienced grade III-IV toxicities, including anemia and leukopenia, indicating that while the regimen is effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. Christodoulou, C., Bafaloukos, D., Linardou, H., et al.[2018]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1535610825002235

Cisplatin and temozolomide combinatorial treatment ... Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent ...

2. cancer.gov cancer.gov/clinicaltrials/NCI-2020-11619

Temozolomide, Cisplatin, and Nivolumab for the Treatment ... Giving cisplatin, nivolumab, and temozolomide together may work better to shrink or stabilize the cancer better than each drug alone in patients with colorectal ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04457284/temozolomide-cisplatin-and-nivolumab-in-people-with-colorectal-cancer

Temozolomide, Cisplatin, and Nivolumab in People With ... This study will test whether the combination of cisplatin, nivolumab, and temozolomide is an effective treatment for in people with advanced ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9932582/

A Phase II Clinical Trial of Nivolumab and Temozolomide for ... We present the results for a phase II trial of combination nivolumab and temozolomide ... The primary objective was efficacy of nivolumab in combination ...

5. opdivohcp.com opdivohcp.com/efficacy/crc

Efficacy Data for Colorectal Cancer (CRC) - Opdivo In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04457284/

Clinical Trial: NCT04457284 This study will test whether the combination of cisplatin, nivolumab, and temozolomide is an effective treatment for in people with advanced and ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/29/4/731/716477/A-Phase-II-Clinical-Trial-of-Nivolumab-and

A Phase II Clinical Trial of Nivolumab and Temozolomide for ... Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9913409/

Current Landscape and Potential Challenges of Immune ... The progression-free survival (PFS) and overall survival (OS) rates at 24 m were 61% and 66% in MSI mCRC, respectively [20]. Based on the results of this trial, ...