M9466 in Combination With Topoisomerase 1 Inhibitors-based Regimens in Advanced Solid Tumors and Colorectal Cancer (DDRiver 511)

An Open Label, Multicenter, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the PARP1 Inhibitor M9466 in Combination With Topoisomerase 1 Inhibitor-based Regimens in Advanced Solid Tumors and Colorectal Cancer (DDRiver 511)

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: M9466; Drug: Irinotecan; Drug: Folinic acid; Drug: Fluorouracil (5-FU); Drug: Bevacizumab; Drug: Granulocyte colony stimulating factor (G-CSF)

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Elizabeth Vale, Australia
    • Cancer Research SA
  • Kogarah, Australia
    • St George Private Hospital
  • Parkville, Australia
    • Peter MacCallum Cancer Centre - Use the one with Account 2 VCCC
• Japan
  • Chūōku, Japan
    • National Cancer Center Hospital
• South Korea
  • Seoul, South Korea
    • Samsung Medical Center
  • Seoul, South Korea
    • Seoul National University Hospital
• Spain
  • Barcelona, Spain
    • NEXT Barcelona - NEXT Barcelona
  • Pozuelo de Alarcón, Spain
    • NEXT Madrid - Hospital Universitario Quironsalud Madrid
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute at Health ONE
  • New Jersey
    • Pennington, New Jersey, United States, 08534
      • Carolina BioOncology Institute, LLC - Cancer Therapy and Research Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University - 150912667
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• M9466 + Irinotecan Run-in Cohort: Participants with locally advanced or metastatic disease that is refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator (that is [i.e.] participants who have exhausted all standard of care (SoC) options according to International Guidelines), and who may derive clinical benefit from the combination treatment with M9466 and irinotecan
• M9466 + FOLFIRI + Bevacizumab Dose Finding Cohorts: Participants with documented histopathological diagnosis of locally advanced or metastatic colorectal cancer (CRC), who were intolerant/refractory to or progressed after standard systemic therapies for the advanced/metastatic stage that included: Oxaliplatin and a fluoropyrimidine (administration in the adjuvant setting fulfills this criterion if progression occurred within 12 months of the last dose). Prior use of irinotecan is permitted; Either an anti- epidermal growth factor receptor (anti-EGFR) or an anti- Vascular endothelial growth factor (anti-VEGF) agent (not applicable if oxaliplatin was administered in the adjuvant setting); An immune checkpoint inhibitor for participants with known MSI-H status; Anti-EGFR agent and BRAF tyrosine kinase inhibitor ± MEK inhibitor, if locally available, for participants with BRAF V600E mutations. Participants may have received maximally 1 previous regimen for the treatment of metastatic disease (with the exception of participants with MSI-H disease or BRAF positive disease who are allowed to have had up to 2 previous lines of treatment)
• Eastern Cooperative Oncology Group performance status (ECOG PS) less than or equal to (<=) 1
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Persistence of AEs related to any prior treatments that have not recovered to Grade <= 1 by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) unless AEs are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator (for example [e.g.] neuropathy or alopecia)
• History of additional malignancy within 3 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, benign prostate neoplasm/hypertrophy, or malignancy that in the opinion of the Investigator, is considered cured with minimal risk of recurrence within 3 years). Participants with history of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) are excluded, irrespective of timeframe
• Participant with known polymorphisms in UGT1A1, DPYD or other enzymes known to predict for increased toxicity from irinotecan or 5 fluorouracil (5-FU) should be excluded; if status is unknown testing is not mandated, unless required by local guidance. Participants that discontinued prior 5-FU treatment due to toxicity are also excluded
• Participants with known brain metastases, except if clinically controlled, which is defined as individuals with central nervous system (CNS) tumors that have been treated and are asymptomatic, and who have discontinued steroids (for the treatment of CNS tumors) for > 28 days prior to first dose of study intervention
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: M9466 + Irinotecan (Run-in Cohort)	Drug: M9466; M9466 will be administered orally until progressive disease, unacceptable toxicity, death, or end of study.; Other Names: HRS-1167; Drug: Irinotecan; Irinotecan will be administered intravenously once every 2 weeks (q2w) until progressive disease, unacceptable toxicity, death, or end of study.; Drug: Granulocyte colony stimulating factor (G-CSF); G-CSF will be administered subcutaneously at every cycle of study intervention as per standard of care.
Experimental: M9466 + FOLFIRI (folinic acid, fluorouracil, irinotecan) + Bevacizumab (Dose Finding Cohorts)	Drug: M9466; M9466 will be administered orally until progressive disease, unacceptable toxicity, death, or end of study.; Other Names: HRS-1167; Drug: Irinotecan; Irinotecan will be administered intravenously once every 2 weeks (q2w) until progressive disease, unacceptable toxicity, death, or end of study.; Drug: Folinic acid; Folinic acid will be administered intravenously q2w as per standard of care.; Other Names: Calcium folinate Leucovorin; Drug: Fluorouracil (5-FU); Fluorouracil will be administered intravenously as per standard of care.; Other Names: 5-FU; Drug: Bevacizumab; Bevacizumab will be administered intravenously, q2w until progressive disease, unacceptable toxicity, death, or end of study.; Drug: Granulocyte colony stimulating factor (G-CSF); G-CSF will be administered subcutaneously at every cycle of study intervention as per standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs	Time from signing Informed Consent Form (ICF) up to 30 days after end of study intervention (approximately assessed up to 18.7 months)
Number of Participants with Dose Limiting Toxicity (DLT)	Day 1 up to Day 28 of the first two Cycles (each cycle is of 14 days)

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Assessed by Investigator	Time from first treatment of study intervention up to planned assessment at 18.7 months
Pharmacokinetic (PK) Plasma Concentration of M9466	Pre-dose up to 6 hours post-dose on Cycle 1 Day 1; (each cycle is of 14 days)

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, EMD Serono Research & Development Institute, Inc.

Publications and helpful links

Helpful Links

• US Medical Information website, Medical Resources
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2024
• Primary Completion (Actual): December 2, 2025
• Study Completion (Actual): December 2, 2025

Study Registration Dates

• First Submitted: July 15, 2024
• First Submitted That Met QC Criteria: July 15, 2024
• First Posted (Actual): July 19, 2024

Study Record Updates

• Last Update Posted (Actual): December 18, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: PARP inhibitor; Irinotecan; FOLFIRI; DNA repair inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Biological Factors; Carbohydrates; Camptothecin; Alkaloids; Enzymes and Coenzymes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pyrimidines; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Intercellular Signaling Peptides and Proteins; Coenzymes; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Bevacizumab; Irinotecan; Fluorouracil; Leucovorin; Granulocyte Colony-Stimulating Factor
• Other Study ID Numbers: MS202650_0001; 2024-514155-15-00 (Other Identifier: EU CTR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No