A First-in-human Study of BGB-53038, a Pan-KRAS Inhibitor, Alone or in Combinations in Participants With Advanced or Metastatic Solid Tumors With KRAS Mutations or Amplification

BeiGene

Status and phase: Enrolling; Phase 1

Conditions: Advanced Pancreatic Ductal Adenocarcinoma; Advanced Non-squamous Non-small-cell Lung Cancer; Advanced Esophageal Adenocarcinoma; Metastatic Solid Tumors; Advanced Gastroesophageal Junction Cancer; Advanced Colorectal Cancer; Advanced Gastric Cancer

Treatments: Drug: Cetuximab; Drug: BGB-53038; Drug: Tislelizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT06585488

2024-514704-13-00 (EU Trial (CTIS) Number)

BGB-53038-101

Details and patient eligibility

About

This is a first-in-human (FIH), open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BGB-53038 as monotherapy in participants with advanced or metastatic solid tumors harboring KRAS mutations or amplification, as well as when used in combination with tislelizumab (also known as BGB-A317) in participants with nonsquamous non-small cell lung cancer (NSCLC) and used in combination with cetuximab in participants with colorectal cancer (CRC). The study consists of 2 phases: Phase 1a Dose Escalation and Safety Expansion and Phase 1b Dose Expansion.

Enrollment: 177 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. Must sign a written ICF; and understand and agree to comply with the requirements of the study and the schedule of activities.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
3. Participants must have evidence of a KRAS mutation or wild-type amplification (copy number ≥ 8) based on testing of either tumor tissue or liquid biopsy (blood or plasma) as determined by local laboratory
4. Able to provide an archived tumor tissue sample or fresh biopsy sample.
5. ≥ 1 measurable lesion per RECIST v1.1.
6. Adequate organ function.
7. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, for > 7 days after the last dose of BGB-53038, > 120 days after the last dose of tislelizumab, or > 2 months after the last dose of cetuximab, whichever is later
8. Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study treatment period and for ≥ 4 months after the last dose of study drug(s).

Exclusion criteria

1. Participants with tumors harboring KRAS G12R mutation.
2. Participants who have prior therapy with other anti-RAS treatment, including, but not limited to, therapy targeting specific KRAS allele mutation inhibitors, pan-KRAS inhibitors, and other pan-RAS inhibitors
3. Participants with active leptomeningeal disease or uncontrolled, untreated brain metastasis. Participants with a history of treated and, at the time of screening, stable CNS metastases are eligible, provided they meet select criteria.
4. Any malignancy ≤ 2 years before the first dose of study treatment(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast).
5. Participants with untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 500 IU/mL (or ≥ 2500 copies/mL) at screening. Participants with active hepatitis C.
6. Participants with clinically significant infections (including tuberculosis infection) requiring systemic (oral or intravenous) antibacterial, antifungal, or antiviral therapy ≤ 14 days before the first dose of study treatment.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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177 participants in 5 patient groups

Phase 1a: Part A (Monotherapy Dose Escalation)

Experimental group

Description:

Sequential cohorts will be evaluated to determine the Recommended Dose for Expansion (RDFE) of BGB-53038 as a monotherapy.

Treatment:

Drug: BGB-53038

Phase 1a: Part B (Monotherapy Safety Expansion)

Experimental group

Description:

Participants will be enrolled at dose levels determined in Part A with the Safety Monitoring Committee to confirm the final RDFE(s) for BGB-53038 monotherapy.

Treatment:

Drug: BGB-53038

Phase 1a: Part C (Combination Therapy Dose Escalation)

Experimental group

Description:

Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab.

Treatment:

Drug: Tislelizumab

Drug: BGB-53038

Drug: Cetuximab

Phase 1b: Part D (Monotherapy Dose Expansion)

Experimental group

Description:

Participants will be enrolled to receive the RDFE(s) of BGB-53038 monotherapy

Treatment:

Drug: BGB-53038

Phase 1b: Part E (Combination Therapy Dose Expansion)

Experimental group

Description:

Participants will be enrolled to receive BGB-53038 at the RDFE(s) as determined in Part C of Phase 1a in combination with tislelizumab and in combination with cetuximab, respectively.

Treatment:

Drug: Tislelizumab

Drug: BGB-53038

Drug: Cetuximab