Advanced/Metastatic Colorectal Adenocarcinoma
Conditions
Brief summary
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.
Interventions
DRUGBAY 3771249
Oral
DRUGCetuximab
Intravenous (IV) infusion
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with Treatment-emergent adverse events (TEAEs) | Up to approximately 2 years. | Applicable in Dosage escalation and expansion |
| Severity of TEAEs | Up to approximately 2 years. | Applicable in Dosage escalation and expansion |
| Change from baseline in vital signs: Pulse rate | Up to approximately 2 years | Applicable in Dosage escalation and expansion |
| Change from baseline in vital signs: Oxygen saturation | Up to approximately 2 years | Applicable in Dosage escalation and expansion |
| Change from baseline in vital signs: Respiratory rate | Up to approximately 2 years | Applicable in Dosage escalation and expansion |
| Change from baseline in vital signs: Blood pressure | Up to approximately 2 years | Applicable in Dosage escalation and expansion |
| Change from baseline in vital signs: Body temperature | Up to approximately 2 years | Applicable in Dosage escalation and expansion |
| Change from baseline in laboratory test results | Up to approximately 2 years | Hematology, serum chemistry, urinalysis and coagulation tests. Applicable in Dosage escalation and expansion |
| Number of participants experiencing a dose-limiting toxicity (DLT) at each dosage | Up to approximately 3 weeks | Applicable in Dose escalation part |
| Objective response rate (ORR) as determined by the Investigator according to RECIST v1.1 | Up to approximately 2 years | Applicable in Dosage escalation and expansion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) parameters such as area under the concentration vs time curve (AUC) | Up to approximately 2 years | Applicable in Dosage escalation |
| PK parameters such as maximum observed drug concentration (Cmax) | Up to approximately 2 years | Applicable in Dosage escalation |
Countries
Australia, Belgium, Denmark, Finland, Italy, Netherlands, Singapore, Spain, Sweden, United States
Contacts
CONTACTBayer Clinical Trials Contact
Outcome results
None listed