M9466 + Chemotherapy for Colorectal Cancer

Recruiting at 11 trial locations

Overseen By US Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: EMD Serono Research & Development Institute, Inc.

Disqualifiers: Recent malignancy, Brain metastases, others

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

Compensation: Varies

Number of Visits: 4

Duration: Varies per treatment cycle

54 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and preliminary clinical activity of M9466 in combination with topoisomerase 1 inhibitors-based regimens. As such the combination with FOLFIRI (folinic acid, fluorouracil, irinotecan) and Bevacizumab will be evaluated in participants with colorectal cancer, to establish the M9466 maximum tolerated dose if observed and the recommended dose for expansion. Study Duration: After a Screening period of up to 28 days, enrolled participants will remain in the study until they have completed all the study visits or until they withdraw consent, are lost to follow-up, or die. Visit Frequency: The participants will come for a Screening Visit and 1 to 2 visits per treatment cycle. After end of study intervention period, the participants will come for an End of Treatment Visit and a Safety Follow-up Visit.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you have persistent side effects from previous treatments, they must be resolved to a certain level unless they are stable on supportive therapy. It's best to discuss your specific medications with the trial investigator.

What data supports the idea that M9466 + Chemotherapy for Colorectal Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of M9466 + Chemotherapy for Colorectal Cancer. Instead, it discusses other treatments like TAS-102 and modified FOLFOX6, which have shown benefits in certain cases of colorectal cancer. For example, TAS-102 improves survival in patients with metastatic colorectal cancer who have not responded to standard treatments. Additionally, modified FOLFOX6 has been shown to improve survival in patients with locally advanced rectal cancer when used after chemoradiotherapy. However, there is no direct comparison or data provided for M9466 + Chemotherapy in the context of colorectal cancer. ^{1 2 3 4 5}

What safety data is available for the treatment M9466 + Chemotherapy for Colorectal Cancer?

The safety data for treatments involving irinotecan, a topoisomerase 1 inhibitor, can be inferred from studies on TAS-102, which is used in metastatic colorectal cancer. Common adverse reactions include anemia, neutropenia, fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and fever. Neutropenia is notably frequent and can impact treatment continuation. Adverse events led to discontinuation in 3.6% of patients and dose reduction in 13.7% of cases, primarily due to neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. ^{1 5 6 7 8}

Is the drug M9466 (HRS-1167) a promising treatment for colorectal cancer?

The information provided does not include any specific details about the drug M9466 (HRS-1167) or its effectiveness in treating colorectal cancer. Therefore, we cannot determine if it is a promising treatment based on the given research articles. ^{3 4 9 10 11}

Research Team

Medical Responsible

Principal Investigator

EMD Serono Research & Development Institute, Inc.

Eligibility Criteria

This trial is for individuals with advanced colorectal cancer or solid tumors. Participants must be able to receive the chemotherapy combination FOLFIRI and Bevacizumab. The study aims to find the highest dose of M9466 that's safe when given with these drugs, without causing severe side effects.

Inclusion Criteria

My cancer is advanced and hasn't responded to standard treatments.

I am fully active or can carry out light work.

My colorectal cancer is advanced and didn't respond well to standard treatments.

Exclusion Criteria

I was diagnosed with cancer within the last 3 years.

My side effects from previous treatments are mild or being managed.

My brain metastases are under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive M9466 in combination with topoisomerase 1 inhibitors-based regimens, including FOLFIRI and Bevacizumab, to evaluate safety and establish the maximum tolerated dose

Varies per treatment cycle

1 to 2 visits per treatment cycle

End of Treatment

Participants complete the study intervention period

1 visit (in-person)

Follow-up

Participants are monitored for safety after the end of treatment

1 Safety Follow-up Visit

Treatment Details

Interventions

• M9466
• Topoisomerase 1 Inhibitors-based Regimens

Trial Overview The trial tests a new drug, M9466, combined with a chemo regimen (FOLFIRI) and Bevacizumab in patients with colorectal cancer. It seeks to determine safety, tolerability, and preliminary effectiveness of this combination therapy.

Participant Groups

Group I: M9466 + Irinotecan (Run-in Cohort) Experimental Treatment 2 Interventions

Group II: M9466 + FOLFIRI (folinic acid, fluorouracil, irinotecan) + Bevacizumab (Dose Finding Cohorts) Experimental Treatment 5 Interventions

Who Is Running the Clinical Trial?

EMD Serono Research & Development Institute, Inc.

Lead Sponsor

Trials

86

Recruited

22,700+

Miguel Fernández Alcalde

EMD Serono Research & Development Institute, Inc.

Chief Executive Officer

Bachelor’s Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master’s Degree in Management from IESE Business School

Danny Bar-Zohar

EMD Serono Research & Development Institute, Inc.

Chief Medical Officer since 2022

MD

Merck KGaA, Darmstadt, Germany

Industry Sponsor

Trials

449

Recruited

122,000+

Danny Bar-Zohar

Merck KGaA, Darmstadt, Germany

Chief Medical Officer since 2022

MD

Belén Garijo

Merck KGaA, Darmstadt, Germany

Chief Executive Officer since 2021

MD

Findings from Research

In a study of 43 patients with metastatic colorectal cancer (mCRC) who were resistant to standard treatments, TAS-102 provided clinically relevant disease control in 30% of patients, particularly those treated for 6 or more cycles, with a median progression-free survival of 7.5 months and overall survival of 11.2 months.

A significant correlation was found between previous treatment success with regorafenib and the efficacy of TAS-102, suggesting that patients who responded well to regorafenib may benefit more from subsequent treatment with TAS-102.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome of patients with chemorefractory metastatic colorectal cancer treated with trifluridine/tipiracil (TAS-102): a single Italian institution compassionate use programme. Sforza, V., Martinelli, E., Cardone, C., et al.[2021]

In a meta-analysis of 21,590 patients with stage III colorectal cancer (CRC) who have microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status, adjuvant chemotherapy significantly improved overall survival (OS) compared to control treatments, with a hazard ratio of 0.42.

However, the study found no significant improvement in disease-free survival (DFS) with adjuvant chemotherapy, indicating that while MSI-H/dMMR status predicts better outcomes in terms of OS, it does not necessarily enhance the likelihood of remaining disease-free after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival benefit with adjuvant chemotherapy in stage III microsatellite-high/deficient mismatch repair colon cancer: a systematic review and meta-analysis. Tomasello, G., Ghidini, M., Galassi, B., et al.[2022]

In a nonrandomized phase II trial involving 259 patients with stage II or III rectal cancer, adding modified FOLFOX6 chemotherapy after chemoradiotherapy improved disease-free survival rates, indicating a potential benefit in treatment outcomes.

The study found that the number of chemotherapy cycles received was linked to better survival outcomes, suggesting that neoadjuvant consolidation chemotherapy not only enhances the likelihood of a complete pathological response but also improves overall treatment compliance and long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial. Marco, MR., Zhou, L., Patil, S., et al.[2019]

In a phase II clinical trial involving 49 patients who had liver metastases from colorectal cancer, the modified FOLFOX6 (mFOLFOX6) treatment showed a 2-year disease-free survival (DFS) rate of 59.2%, indicating its potential efficacy as an adjuvant therapy after surgery.

The treatment was generally well-tolerated, with no fatalities from adverse events, although 37.5% of patients experienced Grade 3 neutropenia, highlighting the need for monitoring side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility Assessment of Modified FOLFOX-6 as adjuvant treatment after resection of liver metastases from colorectal cancer: analyses of a multicenter phase II clinical trial (Miyagi-HBPCOG Trial-001). Katayose, Y., Yamamoto, K., Nakagawal, K., et al.[2018]

TAS-102, administered at the recommended dose of 35 mg/m² twice daily, demonstrated an acceptable safety profile in 27 Western patients with metastatic colorectal cancer (mCRC) who were refractory to standard treatments, with manageable side effects like fatigue and gastrointestinal disturbances.

The treatment showed preliminary efficacy, with 70% of patients achieving stable disease for at least 6 weeks, and median progression-free survival and overall survival rates of 5.3 and 7.5 months, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer. Bendell, JC., Rosen, LS., Mayer, RJ., et al.[2020]

In a clinical trial involving 800 patients with metastatic colorectal cancer, TAS-102 significantly improved overall survival, with a median survival of 7.1 months compared to 5.3 months for the placebo group, indicating its efficacy as a treatment option.

While TAS-102 was effective, it also had notable adverse reactions, including anemia and neutropenia, leading to dose reductions in 13.7% of patients and discontinuation in 3.6%, highlighting the importance of monitoring side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: TAS-102. Marcus, L., Lemery, SJ., Khasar, S., et al.[2022]

In a study of 41 patients with metastatic colorectal cancer, TAS-102 significantly improved overall survival and progression-free survival, especially when combined with bevacizumab.

Biweekly administration of TAS-102 resulted in significantly less grade ≥3 neutropenia compared to standard administration, suggesting that adjusting the administration method can help manage side effects while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biweekly Administration of TAS-102 for Neutropenia Prevention in Patients with Colorectal Cancer. Yoshida, Y., Sakamoto, R., Kajitani, R., et al.[2020]

TAS-102 significantly improves overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) in patients with metastatic colorectal cancer (mCRC) compared to placebo or best supportive care, based on a meta-analysis of 2903 patients.

The treatment is effective regardless of KRAS mutation status and does not increase the incidence of serious adverse events, indicating that TAS-102 is both effective and safe for patients whose standard therapies have failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trifluridine/tipiracil (TAS-102) in patients with metastatic colorectal cancer: a systematic review and meta-analysis. Huang, F., Yang, H., Bao, W., et al.[2023]

TAS-102 significantly improves overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer patients who have not responded to standard chemotherapy, with a hazard ratio of 0.70 for OS and 0.46 for PFS based on a meta-analysis of three randomized controlled trials involving 1318 patients.

The treatment is associated with manageable side effects, primarily neutropenia, leucopenia, anemia, and diarrhea, indicating that while TAS-102 is effective, it does come with some risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis. Chen, D., Wu, YS., Lin, H., et al.[2022]

In a study involving 20 Japanese patients with advanced colorectal cancer, the combination of MK-0646 with cetuximab and irinotecan was found to be well tolerated, with only one patient experiencing a dose-limiting toxicity (grade 3 hyperglycemia).

The combination therapy increased the exposure of MK-0646 by 25% without affecting the pharmacokinetics of cetuximab and irinotecan, although it did reduce the levels of SN-38, the active metabolite of irinotecan, indicating minimal drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer. Doi, T., Muro, K., Yoshino, T., et al.[2021]

In a phase II study involving 48 patients with unresectable or metastatic colorectal cancer, an alternating regimen of mFOLFOX6 and FOLFIRI resulted in a promising overall response rate of 58.7% and a median overall survival of 28.4 months.

The treatment was well tolerated, with a low incidence of severe neurotoxicity (0%) and manageable adverse events, indicating a favorable safety profile for this chemotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701). Oki, E., Emi, Y., Akagi, Y., et al.[2014]

References

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

Clinical outcome of patients with chemorefractory metastatic colorectal cancer treated with trifluridine/tipiracil (TAS-102): a single Italian institution compassionate use programme. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Survival benefit with adjuvant chemotherapy in stage III microsatellite-high/deficient mismatch repair colon cancer: a systematic review and meta-analysis. [2022]

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

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial. [2019]

4. Greece pubmed.ncbi.nlm.nih.gov

Feasibility Assessment of Modified FOLFOX-6 as adjuvant treatment after resection of liver metastases from colorectal cancer: analyses of a multicenter phase II clinical trial (Miyagi-HBPCOG Trial-001). [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer. [2020]

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

FDA Approval Summary: TAS-102. [2022]

7. Greece pubmed.ncbi.nlm.nih.gov

Biweekly Administration of TAS-102 for Neutropenia Prevention in Patients with Colorectal Cancer. [2020]

8. Italy pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trifluridine/tipiracil (TAS-102) in patients with metastatic colorectal cancer: a systematic review and meta-analysis. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701). [2014]