A Study to Learn More About How Safe BAY 3771249 is and How Well it Works in People With Advanced or Metastatic Colorectal Cancer That Has a KRAS G12D Mutation

Master Protocol: An Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of BAY 3771249 as Monotherapy or Combination With Other Cancer Treatments in Participants With Solid Tumors Harboring a KRAS G12D Mutation. Substudy Protocol: An Open-label, Multi-cohort Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of BAY 3771249 as Monotherapy and in Combination With Cetuximab in Participants With Advanced/Metastatic Colorectal Adenocarcinoma Harboring a KRAS G12D Mutation

Researchers are looking for a better way to treat people who have advanced or metastatic colorectal cancer (CRC) with a specific mutation, the G12D mutation, in a protein called KRAS.

Colorectal cancer (CRC) is a common type of cancer that affects the large bowel (colon) or the rectum (the section at the end of the bowel). When CRC spreads to other parts of the body, it is called advanced or metastatic CRC. Some people with CRC have the G12D mutation in the KRAS protein. This mutation is linked to a poorer outlook and fewer treatment options. Currently, there are no approved treatments that specifically target this mutation.

KRAS is a protein that helps control how cells grow and divide. When it is mutated, it can cause cells to grow uncontrollably, leading to cancer. The study drug, BAY 3771249, is designed to block the activity of KRAS with G12D mutation, which may help slow or stop the growth of cancer cells. BAY 3771249 can be given alone or together with another drug called cetuximab.

The main purpose of this study is to learn how safe BAY 3771249 is, how well people tolerate it, how the body processes the drug, and whether it can help shrink or control tumors in people with advanced or metastatic CRC that has the KRAS G12D mutation. The study will also look at how BAY 3771249 works when given alone or with cetuximab, especially in people who have already tried other treatments for their cancer.

Researchers will measure, among others:

The number and seriousness of health problems (adverse events) after receiving BAY 3771249.

The number of participants who experience a dose-limiting side effect (DLT) at each dose level.

The number of participants whose tumors shrink or disappear (overall response rate, ORR) as measured by standard criteria.

How much of the drug is in the blood over time (AUC) and the highest amount in the blood (Cmax).

Some participants will receive BAY 3771249 alone (monotherapy), and others will receive BAY 3771249 with cetuximab (combination therapy).

The study will start with lower doses and gradually increase to find the highest safe dose (dosage escalation). After the safe dose is found, more participants may join the study to receive it (dosage expansion). In some parts of the study, participants may be randomly assigned to different groups or doses. The study is open-label, meaning both participants and doctors know which treatment is being given.

An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events, even if they do not think it is related to the study treatment.

The study doctors and their team will contact participants to learn about their health until they complete the study.

If a participant benefits from the treatment, it might be possible to continue receiving BAY 3771249 after the end of the study. The findings from this study may help develop a new treatment option for people with advanced or metastatic CRC with a KRAS G12D mutation.

Study Overview

• Status: Recruiting
• Conditions: Advanced/Metastatic Colorectal Adenocarcinoma
• Intervention / Treatment: Drug: Cetuximab; Drug: BAY 3771249

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Bayer Clinical Trials Contact; Phone Number: (+)1-888-84 22937; Email: clinical-trials-contact@bayer.com

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Not yet recruiting
      • Border Medical oncology - Albury Wodonga Regional Cancer Centre
    • Waratah, New South Wales, Australia, 2298
      • Recruiting
      • Calvary Mater Hospital Newcastle - Oncology
  • Victoria
    • Malvern, Victoria, Australia, 3144
      • Not yet recruiting
      • Cabrini Health Oncology Research
• Belgium
  • Ghent, Belgium, 9000
    • Not yet recruiting
    • Ghent University Hospital | Drug Research Unit Department
• Denmark
  • Capital Region
    • Copenhagen, Capital Region, Denmark, 2100
      • Not yet recruiting
      • Rigshospitalet - Kræftbehandling
  • Region Syddanmark
    • Odense, Region Syddanmark, Denmark, 5000
      • Not yet recruiting
      • Odense University Hospital - Oncology Department
• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00029
      • Not yet recruiting
      • HUS-Yhtymä, Helsingin yliopistollinen sairaala (HUS) - Syöpäkeskus
• Italy
  • Roma, Italy, 00128
    • Not yet recruiting
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS - UOC Fase I
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1066 CX
      • Not yet recruiting
      • Nederlands Kanker Instituut
• Singapore
  • Singapore, Singapore, 119074
    • Not yet recruiting
    • National University Hospital Medical Centre
  • Singapore, Singapore, 168583
    • Recruiting
    • National Cancer Center Singapore - Oncology Department
• Spain
  • Barcelona, Spain, 08035
    • Not yet recruiting
    • Hospital Universitari Vall D Hebron | Oncologia
  • Madrid, Spain, 28050
    • Not yet recruiting
    • Hospital Universitario Hm Sanchinarro | Oncologia
• Sweden
  • Stockholm County
    • Stockholm, Stockholm County, Sweden, 171 76
      • Not yet recruiting
      • Karolinska Universitetssjukhuset - Fas I-enheten Solna CKC
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Not yet recruiting
      • Mayo Clinic - Cancer Center - Phoenix
  • California
    • Duarte, California, United States, 91010
      • Not yet recruiting
      • City of Hope - Duarte Cancer Center
    • San Diego, California, United States, 92037
      • Not yet recruiting
      • UC San Diego Health - Moores Cancer Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Not yet recruiting
      • Sarah Cannon Research Institute at HCA HealthONE Presbyterian St. Luke's
  • New York
    • New York, New York, United States, 10029
      • Not yet recruiting
      • Icahn School of Medicine at Mount Sinai - Oncology
  • Texas
    • Irving, Texas, United States, 75039
      • Recruiting
      • NEXT Dallas - Oncology Department
    • San Antonio, Texas, United States, 78229
      • Not yet recruiting
      • START | San Antonio

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• KRAS G12D mutated solid tumor
• Participant must be ≥18 years old or the legal age of consent in the jurisdiction in which the study is taking place when signing the screening ICF
• At least one measurable lesion as per RECIST v1.1. outside the CNS
• Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1
• Male or Female: Contraceptive use by participant or participant's partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Life expectancy of at least 3 months in the opinion of the Investigator
• Histologically/pathologically documented diagnosis of advanced/metastatic adenocarcinoma of the colon and rectum.
• Adequate hematologic and end-organ function

Exclusion Criteria:

• Leptomeningeal disease or carcinomatous meningitis
• Uncontrolled and/or active/symptomatic brain metastases.
• Significant traumatic injury or major surgical procedure within 4 weeks of first dose of study intervention
• Known hypersensitivity to any component of study intervention
• Previous (within 3 years) or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in the respective substudy.
• Active infection requiring systemic anti-infective therapy within 14 days of first dose of study intervention
• Known HIV infection
• Active Hepatitis B virus (HBV) infection
• Active Hepatitis C virus (HCV) infection;
• Significant cardiac disorder
• History of risk factors for torsade de pointes (TdP) (e.g., heart failure, family history of long QT syndrome)
• Participants with inadequately managed diabetes as assessed by the Investigator
• Toxicities from prior anticancer therapy, defined as not having resolved to Grade ≤1 or as specified in the respective substudy protocol as per NCI CTCAE v.6.0 with the following exceptions: Alopecia of any grade, Peripheral neuropathy Grade ≤2, Autoimmune endocrine disorders Grade ≤2 managed with stable endocrine replacement therapy
• History of (non-infectious) pneumonitis/interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis (unless it has resolved without sequelae without use of steroids), or any evidence of clinically-active pneumonitis/ILD
• History of the following eye disorders: keratitis, ulcerative keratitis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dosage escalation; In the dosage escalation part, different dose levels of BAY 3771249 administered as monotherapy and in combination with cetuximab are planned.	Drug: Cetuximab; Intravenous (IV) infusion; Drug: BAY 3771249; Oral
Experimental: Dosage expansion; In the dosage expansion part, participants will receive BAY 3771249 either as monotherapy or in combination with cetuximab until disease progression as defined by RECIST v1.1, the occurrence of unacceptable toxicity, or the fulfillment of any other withdrawal criteria.	Drug: Cetuximab; Intravenous (IV) infusion; Drug: BAY 3771249; Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Treatment-emergent adverse events (TEAEs)	Applicable in Dosage escalation and expansion	Up to approximately 2 years.
Severity of TEAEs	Applicable in Dosage escalation and expansion	Up to approximately 2 years.
Change from baseline in vital signs: Pulse rate	Applicable in Dosage escalation and expansion	Up to approximately 2 years
Change from baseline in vital signs: Oxygen saturation	Applicable in Dosage escalation and expansion	Up to approximately 2 years
Change from baseline in vital signs: Respiratory rate	Applicable in Dosage escalation and expansion	Up to approximately 2 years
Change from baseline in vital signs: Blood pressure	Applicable in Dosage escalation and expansion	Up to approximately 2 years
Change from baseline in vital signs: Body temperature	Applicable in Dosage escalation and expansion	Up to approximately 2 years
Number of participants experiencing a dose-limiting toxicity (DLT) at each dosage	Applicable in Dose escalation part	Up to approximately 3 weeks
Objective response rate (ORR) as determined by the Investigator according to RECIST v1.1	Applicable in Dosage escalation and expansion	Up to approximately 2 years
Change from baseline in laboratory test results	Hematology, serum chemistry, urinalysis and coagulation tests. Applicable in Dosage escalation and expansion	Up to approximately 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) parameters such as area under the concentration vs time curve (AUC)	Applicable in Dosage escalation	Up to approximately 2 years
PK parameters such as maximum observed drug concentration (Cmax)	Applicable in Dosage escalation	Up to approximately 2 years

Collaborators and Investigators

• Sponsor: Bayer

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2026
• Primary Completion (Estimated): July 27, 2029
• Study Completion (Estimated): July 9, 2030

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 9, 2026
• First Posted (Actual): April 16, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab
• Other Study ID Numbers: 23111-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Currently, there is no established plan for the sharing of Individual Patient Data (IPD) from this study. The availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA 'Principles for responsible clinical trial data sharing.' This pertains to the scope, timepoint, and process of data access. As such, Bayer commits to considering requests from qualified researchers for patient- / study-level clinical trial data, and documents from clinical trials involving medicines and indications approved in the US and EU. However, this commitment does not reflect an active IPD sharing plan. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Researchers can use www.vivli.org to request access to IPD and documents from clinical studies to conduct research. Information on Bayer's criteria for listing studies is provided in the member section of the portal.

Drug and device information, study documents

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