A Phase 1a/1b Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of BGB-53038, a Pan-KRAS Inhibitor, as Monotherapy or in Combinations in Patients With Advanced or Metastatic Solid Tumors With KRAS Mutations or Amplifications
概览
- 阶段
- 1 期
- 干预措施
- BGB-53038
- 疾病 / 适应症
- 未指定
- 发起方
- BeiGene
- 入组人数
- 514
- 试验地点
- 33
- 主要终点
- Phase 1a: Number of Participants Experiencing Adverse Events (AEs)
- 状态
- 招募中
- 最后更新
- 上个月
概览
简要总结
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.
研究者
入排标准
入选标准
- •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 ≤
- •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.
- •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).
排除标准
- •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.
研究组 & 干预措施
Phase 1a: Part A (Monotherapy Dose Escalation)
Sequential cohorts will be evaluated to determine the Recommended Dose for Expansion (RDFE) of BGB-53038 as a monotherapy.
干预措施: BGB-53038
Phase 1a: Part B (Monotherapy Safety Expansion)
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.
干预措施: BGB-53038
Phase 1a: Part C (Combination Therapy Dose Escalation)
Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab.
干预措施: BGB-53038
Phase 1a: Part C (Combination Therapy Dose Escalation)
Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab.
干预措施: Tislelizumab
Phase 1a: Part C (Combination Therapy Dose Escalation)
Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab.
干预措施: Cetuximab
Phase 1b: Part D (Monotherapy Dose Expansion)
Participants will be enrolled to receive the RDFE(s) of BGB-53038 monotherapy
干预措施: BGB-53038
Phase 1b: Part E (Combination Therapy Dose Expansion)
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.
干预措施: BGB-53038
Phase 1b: Part E (Combination Therapy Dose Expansion)
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.
干预措施: Tislelizumab
Phase 1b: Part E (Combination Therapy Dose Expansion)
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.
干预措施: Cetuximab
结局指标
主要结局
Phase 1a: Number of Participants Experiencing Adverse Events (AEs)
时间窗: 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 protocol-defined dose-limiting toxicity (DLT) criteria
Phase 1a: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-53038
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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
次要结局
- 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)
- Duration of Response (DOR)(Up to approximately 2 years)
- Time to Response (TRR)(Up to approximately 2 years)
- Disease Control Rate (DCR)(Up to approximately 2 years)
- Progression Free Survival (PFS)(Up to approximately 2 years)
- Phase 1b: Overall Survival (OS)(Up to approximately 2 years)
- Phase 1b: Number of Participants Experiencing Adverse Events (AEs)(Up to approximately 2 years)
- Plasma concentrations of BGB-53038(Up to approximately 2 years)