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

NCT06585488 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: BGB-53038-1012024-514704-13-00
• Study Type: interventional
• Target: 47
• Locations: 5 countries
• Sites: 17

Brief Summary

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.

Conditions

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

Keywords

KRAS wild type amplification; Metastatic Solid Tumors; Advanced Non-squamous Non-small-cell Lung Cancer; Advanced Colorectal Cancer; Advanced Pancreatic Ductal Adenocarcinoma; Advanced Gastric Cancer; Advanced Gastroesophageal Junction Cancer; Advanced Esophageal Adenocarcinoma

Outcome Measures

Primary Outcomes (5)

• Phase 1a: Number of Participants Experiencing Adverse Events (AEs)

  Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) characterized by type, frequency, severity (as graded by the National Cancer Institute-Common Terminology Criteria for Adverse Events \[NCICTCAE\] Version \[v\] 5.0), timing, seriousness, and relationship to study drug(s); and adverse events meeting protocol-defined dose-limiting toxicity (DLT) criteria

  Up to approximately 2 years

• Phase 1a: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-53038

  defined as the highest dose at which 30% of the participants experienced a DLT or the highest dose administered, respectively.

  Up to approximately 2 years

• Phase 1a: Recommended Dose for Expansion (RDFE) of BGB-53038

  The potential RDFE(s) of BGB-53038 as monotherapy or in combination with other antitumor therapies (tislelizumab or cetuximab) will be determined based on the totality of safety, tolerability, pharmacokinetics (PK), pharmacodynamics, preliminary antitumor activity, and any other relevant data, as available.

  Up to approximately 2 years

• Phase 1b: Overall Response Rate (ORR)

  ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) assessed by the investigator using RECIST v1.1

  Up to approximately 2 years

• Phase 1b: Recommended Phase 2 Dose (RP2D) of BGB-53038

  The RP2D of BGB-53038 as monotherapy or in combination with other antitumor therapies (tislelizumab or cetuximab) will be determined based on safety, long-term tolerability, PK, preliminary antitumor activity, and any other relevant data, as available

  Up to approximately 2 years

Secondary Outcomes (12)

• Phase 1a: Single-dose and steady-state area under the concentration-time curve (AUC) of BGB-53038

  Up to approximately 2 years

• Phase 1a: Single-dose and steady-state Half-life (t1/2) of BGB-53038

  Up to approximately 2 years

• Phase 1a: Single-dose and steady-state maximum observed plasma concentration (Cmax) of BGB-53038

  Up to approximately 2 years

• Phase 1a: Single-dose and steady-state trough concentration (Ctrough) of BGB-53038

  Up to approximately 2 years

• Phase 1b: ORR

  Up to approximately 2 years

Study Arms (5)

Phase 1a: Part A (Monotherapy Dose Escalation)

EXPERIMENTAL

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

Drug: BGB-53038

Phase 1a: Part B (Monotherapy Safety Expansion)

EXPERIMENTAL

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.

Drug: BGB-53038

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

EXPERIMENTAL

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

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

Phase 1b: Part D (Monotherapy Dose Expansion)

EXPERIMENTAL

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

Drug: BGB-53038

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

EXPERIMENTAL

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.

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

Interventions

Tislelizumab DRUG

administered by intravenous infusion

Also known as: Tevimbra

Phase 1a: Part C (Combination Therapy Dose Escalation); Phase 1b: Part E (Combination Therapy Dose Expansion)

Cetuximab DRUG

administered by intravenous infusion

Phase 1a: Part C (Combination Therapy Dose Escalation); Phase 1b: Part E (Combination Therapy Dose Expansion)

BGB-53038 DRUG

Administered orally

Phase 1a: Part A (Monotherapy Dose Escalation); Phase 1a: Part B (Monotherapy Safety Expansion); Phase 1a: Part C (Combination Therapy Dose Escalation); Phase 1b: Part D (Monotherapy Dose Expansion); Phase 1b: Part E (Combination Therapy Dose Expansion)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must sign a written ICF; and understand and agree to comply with the requirements of the study and the schedule of activities.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
• 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
• Able to provide an archived tumor tissue sample or fresh biopsy sample.
• ≥ 1 measurable lesion per RECIST v1.1.
• Adequate organ function.
• 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
• 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).

You may not qualify if:

• Participants with tumors harboring KRAS G12R mutation.
• 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
• 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.
• 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).
• 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.
• 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.

Sponsors & Collaborators

• BeOne Medicines: lead

Study Sites (17)

Usc Norris Comprehensive Cancer Center (Nccc)

Los Angeles, California, 90089-1019, United States

Location

University of Kansas Medical Center Research Institute

Kansas City, Kansas, 66160-8500, United States

Location

Sidney Kimmel Comprehensive Cancer At Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

The University of Texas Md Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Blacktown Cancer and Haematology Centre

Blacktown, New South Wales, NSW 2148, Australia

Location

Monash Health

Clayton, Victoria, VIC 3168, Australia

Location

Peter Maccallum Cancer Centre

Melbourne, Victoria, VIC 3000, Australia

Location

Linear Clinical Research

Nedlands, Western Australia, WA 6009, Australia

Location

Cancer Hospital Chinese Academy of Medical Sciences

Beijing, Beijing Municipality, 100021, China

Location

Beijing Cancer Hospital

Beijing, Beijing Municipality, 100142, China

Location

Shanxi Provincial Cancer Hospital

Taiyuan, Shanxi, 030013, China

Location

Auckland City Hospital

Auckland, 1023, New Zealand

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Samsung Medical Center

GangnamGu, Seoul Teugbyeolsi, 06351, South Korea

Location

Severance Hospital Yonsei University Health System

SeodaemunGu, Seoul Teugbyeolsi, 03722, South Korea

Location

Seoul National University Hospital

Seoul, Seoul Teugbyeolsi, 03080, South Korea

Location

Asan Medical Center

SongpaGu, Seoul Teugbyeolsi, 05505, South Korea

Location

MeSH Terms

Interventions

tislelizumab; Cetuximab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Study Director

  BeOne Medicines

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2024
• First Posted: September 5, 2024
• Study Start: December 13, 2024
• Primary Completion: April 23, 2026
• Study Completion: April 23, 2026
• Last Updated: June 3, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: See plan description
• Access Criteria: See plan description

Locations

US (4); KR (5); NZ (1); AU (4); CN (3)