M9466 + Chemotherapy for Colorectal Cancer

Not currently recruiting at 15 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess the safety and early effectiveness of a new drug, M9466, when combined with standard chemotherapy treatments like FOLFIRI (a regimen that includes Topoisomerase 1 inhibitors such as Irinotecan, Fluorouracil, and Folinic acid) and Bevacizumab for people with advanced colorectal cancer. The goal is to determine the best dose of M9466 that can be safely used with these regimens. Individuals with advanced colorectal cancer who have not responded to typical treatments (such as Oxaliplatin or certain targeted therapies) might be suitable candidates for this trial. Participants will need to attend several visits during the treatment cycles to monitor their health and progress. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

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

Research has shown that M9466, a new treatment, is well-tolerated by patients with advanced solid tumors, meaning severe side effects are generally uncommon. The treatment's good safety record is encouraging for potential participants.

When combined with FOLFIRI (a chemotherapy mix of folinic acid, fluorouracil, and irinotecan) and Bevacizumab, FOLFIRI may cause more side effects than irinotecan alone. Side effects can be stronger, but they vary for each person. Discussing potential risks with a doctor is crucial.

Overall, early studies suggest that M9466 is generally safe, but combining it with other drugs like FOLFIRI may alter its effects on the body. Consider all information and consult healthcare professionals when contemplating joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for colorectal cancer?

Researchers are excited about M9466 for colorectal cancer because it represents a novel approach that enhances the effectiveness of existing chemotherapy regimens. Unlike standard treatments that rely solely on drugs like FOLFIRI or bevacizumab, M9466 is combined with these to potentially boost their effectiveness. It might offer a new mechanism of action or synergy that could improve outcomes. By targeting colorectal cancer differently, M9466 could be a game-changer in personalized cancer therapy, offering hope for better response rates and fewer side effects.

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

Research shows that M9466 is a promising treatment because it blocks a protein called PARP1. This action prevents cancer cells from repairing their DNA, leading to their death. Studies have demonstrated that M9466 effectively stops cancer cells from growing, especially in laboratory tests. In this trial, participants will receive M9466 combined with different chemotherapy regimens. One treatment arm will test M9466 with Irinotecan, while another will evaluate M9466 with FOLFIRI (a mix of chemotherapy drugs) and bevacizumab. FOLFIRI and bevacizumab are already known to shrink tumors and help patients with colorectal cancer live longer. These findings suggest that adding M9466 could enhance these effects, offering a potentially powerful treatment option. ^{1 4 5 6 7}

Who Is on the Research Team?

Medical Responsible

Principal Investigator

EMD Serono Research & Development Institute, Inc.

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: M9466 + Irinotecan (Run-in Cohort) Experimental Treatment 3 Interventions

Group II: M9466 + FOLFIRI (folinic acid, fluorouracil, irinotecan) + Bevacizumab (Dose Finding Cohorts) Experimental Treatment 6 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

Published Research Related to This Trial

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]

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 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, 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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06509906

Study Details | NCT06509906 | M9466 in Combination ... The purpose of this study is to evaluate the safety and preliminary clinical activity of M9466 in combination with topoisomerase 1 inhibitors-based regimens.

2. researchgate.net researchgate.net/publication/390994116_Abstract_1171_M9466_HRS-1167_A_highly_potent_and_selective_PARP1_inhibitor_with_DNA_trapping_activity_monotherapy_antitumor_activity_and_synergistic_potential_with_DDR_inhibitors_and_chemotherapies

M9466 (HRS-1167): A highly potent and selective PARP1 ... M9466 is a highly potent and selective PARP1 inhibitor with DNA trapping activity. It shows a highly potent antiproliferative efficacy in the DLD-1 (BRCA2 KO) ...

3. withpower.com withpower.com/trial/phase-1-colorectal-neoplasms-8-2024-96bd4

M9466 + Chemotherapy for Colorectal Cancer · Info for Participants The available research does not provide specific data on the effectiveness of M9466 + Chemotherapy for Colorectal Cancer. Instead, it discusses other ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12162764/

Targeting PARP1: A Promising Approach for Next- ... In this review, we discuss the next-generation PARPis that target PARP1 and show promise in terms of improved safety, tolerability, pharmacological profiles, ...

5. merckgroup.com merckgroup.com/en/news/oncology-update-03-06-2024.html

Merck's Innovative Oncology Pipeline of DDRi and ADC ... The recently opened DDRiver 501 study (NCT06421935) will evaluate M9466 in combination with tuvusertib in solid tumors with relevant mutations ...

6. researchgate.net researchgate.net/publication/381968607_A_phase_1_study_of_HRS-1167_M9466_a_highly_selective_PARP1_inhibitor_in_patients_pts_with_advanced_solid_tumors

A phase 1 study of HRS-1167 (M9466), a highly selective ... Conclusions: HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated ...

7. synapse.patsnap.com synapse.patsnap.com/drug/392fd0ce0992424da5853f06fabd3909

HRS-1167 - Drug Targets, Indications, Patents An Open Label, Multicenter, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the PARP1 Inhibitor M9466 in ...