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
- Conditions
- Interventions
- Registration Number
- NCT06585488
- Lead Sponsor
- BeiGene
- 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...
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 177
- 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).
- 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.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1a: Part A (Monotherapy Dose Escalation) BGB-53038 Sequential cohorts will be evaluated to determine the Recommended Dose for Expansion (RDFE) of BGB-53038 as a monotherapy. Phase 1a: Part B (Monotherapy Safety Expansion) BGB-53038 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. Phase 1a: Part C (Combination Therapy Dose Escalation) BGB-53038 Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab. Phase 1b: Part D (Monotherapy Dose Expansion) BGB-53038 Participants will be enrolled to receive the RDFE(s) of BGB-53038 monotherapy Phase 1b: Part E (Combination Therapy Dose Expansion) BGB-53038 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. Phase 1a: Part C (Combination Therapy Dose Escalation) Tislelizumab Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab. Phase 1a: Part C (Combination Therapy Dose Escalation) Cetuximab Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab. Phase 1b: Part E (Combination Therapy Dose Expansion) Tislelizumab 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. Phase 1b: Part E (Combination Therapy Dose Expansion) Cetuximab 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.
- Primary Outcome Measures
Name Time Method Phase 1a: Number of Participants Experiencing Adverse Events (AEs) Up to approximately 2 years 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 protoc...
Phase 1a: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-53038 Up to approximately 2 years defined as the highest dose at which 30% of the participants experienced a DLT or the highest dose administered, respectively.
Phase 1a: Recommended Dose for Expansion (RDFE) of BGB-53038 Up to approximately 2 years 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.
Phase 1b: Overall Response Rate (ORR) Up to approximately 2 years 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
Phase 1b: Recommended Phase 2 Dose (RP2D) of BGB-53038 Up to approximately 2 years 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
- Secondary Outcome Measures
Name Time Method 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 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.
Duration of Response (DOR) Up to approximately 2 years DOR is defined as the time from the first determination of an objective response per RECIST v1.1 until the first documentation of disease progression or death, whichever occurs first as assessed by the investigator.
Time to Response (TRR) Up to approximately 2 years defined as the time from the date of first dose of study drug to first documentation of response as assessed by the investigator per RECIST v1.1
Disease Control Rate (DCR) Up to approximately 2 years DCR is defined as the percentage of participants who achieve CR, PR, or stable disease (SD) lasting ≥ 24 weeks as assessed by the investigator per RECIST v1.1
Progression Free Survival (PFS) Up to approximately 2 years PFS is defined as the time from the date of the first dose of study drug(s) to the date of the first documentation of progressive disease assessed by the investigator using RECIST v1.1 or death, whichever occurs first.
Phase 1b: Overall Survival (OS) Up to approximately 2 years defined as the time from the date of first dose of study drug until the date of death from any cause
Phase 1b: Number of Participants Experiencing Adverse Events (AEs) Up to approximately 2 years Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) characterized by type, frequency, severity (as graded by the NCI-CTCAE v5.0), timing, seriousness, and relationship to study drug(s)
Plasma concentrations of BGB-53038 Up to approximately 2 years
Trial Locations
- Locations (15)
Usc Norris Comprehensive Cancer Center (Nccc)
🇺🇸Los Angeles, California, United States
University of Kansas Medical Center Research Institute
🇺🇸Kansas City, Kansas, United States
Sidney Kimmel Comprehensive Cancer At Johns Hopkins
🇺🇸Baltimore, Maryland, United States
The University of Texas Md Anderson Cancer Center
🇺🇸Houston, Texas, United States
Blacktown Cancer and Haematology Centre
🇦🇺Blacktown, New South Wales, Australia
Monash Health
🇦🇺Clayton, Victoria, Australia
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Linear Clinical Research
🇦🇺Nedlands, Western Australia, Australia
Cancer Hospital Chinese Academy of Medical Sciences
🇨🇳Beijing, Beijing, China
Beijing Cancer Hospital
🇨🇳Beijing, Beijing, China
Shanxi Provincial Cancer Hospital
🇨🇳Taiyuan, Shanxi, China
Auckland City Hospital
🇳🇿Auckland, New Zealand
Hospital Universitario Vall Dhebron
🇪🇸Barcelona, Spain
Start Madrid Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Clinico Universitario de Valencia Incliva
🇪🇸Valencia, Spain