A Phase 1/2a Open-Label, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Mirdametinib in Combination With BGB-3245 in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 23
- 试验地点
- 16
- 主要终点
- Incidence of treatment emergent adverse events
研究概览
简要总结
A Phase 1/2a open-label, multicenter, dose escalation and expansion study of mirdametinib in combination with BGB-3245 in adult participants with histologically confirmed, advanced (American Joint Committee on Cancer (AJCC) Stage III or IV) metastatic or unresectable solid cancer that is refractory to or has progressed during or after at least 1 line of appropriate prior systemic anti-cancer therapy including chemotherapy, immunotherapy, or appropriate targeted therapy, or for which there is no treatment available, or prior standard of care therapy was not tolerated.
详细描述
The study will be conducted in two sequential parts: Part 1 dose escalation (Phase 1) and Part 2 dose expansion (Phase 2a).
Participants will receive mirdametinib and brimarafenib administered by mouth every day on a continuous schedule. Mirdametinib will be dosed twice a day (BID) and brimarafenib will be dosed once a day (QD). One treatment cycle will be 28 days.
Part 1 of the study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and preliminary evidence of anti-tumor efficacy. Part 1 will also identify the MTD and the RP2D for the combination of mirdametinib with brimarafenib.
Part 2 will confirm the safety, tolerability, efficacy, PK, and PDx for the combination of mirdametinib and brimarafenib. It will follow a parallel design and include one or more dose expansion cohorts, where each participant would be treated with the combination of mirdametinib and brimarafenib at the RP2D. It will begin after the RP2D for the combination of mirdametinib and brimarafenib is identified in Part 1. Part 2 may start either in parallel with, or after, the conduct and analysis of the PDx Expansion Cohort in Part 1.
Participants who experience a TEAE requiring treatment modification will be managed according to the applicable guidelines in the protocol.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to provide informed consent
- •At least 18 years of age on day of signing ICF
- •Advanced, metastatic or unresectable solid cancer that has not responded to or progressed during or after at least 1 line of appropriate therapy or for which there is no treatment available or prior therapy was not tolerated.
- •Part 1: oncogenic mutation or other genomic aberration of the MAPK pathway
- •Part 2: oncogenic mutation or genomic aberration defined below:
- •Cohort A: cutaneous melanoma harboring NRAS mutations.
- •Cohort B: non-small cell lung cancer (NSCLC) harboring a KRAS mutation.
- •Cohort C: NSCLC or cutaneous melanoma harboring BRAF Class II or Class III mutations or BRAF Fusion mutation.
- •Must have archival tumor tissue or agree to a fresh tumor biopsy at screening
- •Measurable disease per RECIST 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- •Adequate organ function and no transfusion within 14 days of first dose
排除标准
- •Central Nervous System metastases, leptomeningeal carcinomatosis or untreated spinal cord compression
- •History of glaucoma
- •Active parathyroid disorder or history of malignancy associated hypercalcemia
- •Clinically significant cardiac disease within the past 6 months of signing ICF
- •History of toxicity from another RAF, MEK, ERK inhibitor requiring discontinuation of treatment from these agents
- •Severe or uncontrolled systemic disease
- •Inability to swallow oral medications
- •Clinically significant active infection (HIV, Hepatitis B or Hepatitis C)
- •History of or ongoing Immune Thrombocytopenia (ITP), Von Willebrand disease and/or other past or present bleeding disorders
- •Underlying medical conditions in investigator's opinion to be unfavorable to be a part of the study
- •Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose or anticipates need for major surgery while on study
- •Systemic anti-cancer therapy within 2 weeks or 5 half-lives before first dose
- •Concomitant systemic or glucocorticoid therapy within 2 weeks before first dose
- •Concomitant medicines that are strong CYP3A4 inhibitors or inducers within 2 weeks or 5 half-lives before first dose
- •Live vaccine within 4 weeks before first dose
研究组 & 干预措施
Phase 1 Dose Escalation, Cohort 3
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: BGB-3245 20mg (Drug)
Phase 1 Dose Escalation, Cohort 4
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: Mirdametinib 3mg (Drug)
Phase 1 Dose Escalation, Cohort 1
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: BGB-3245 5mg (Drug)
Phase 1 Dose Escalation, Cohort 2
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: BGB-3245 10mg (Drug)
Phase 1 Dose Escalation, Cohort 4
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: BGB-3245 10mg (Drug)
Phase 1 Dose Escalation, Cohort 5
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: Mirdametinib 4mg (Drug)
Phase 1 Dose Escalation, Cohort 1
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: Mirdametinib 2mg (Drug)
Phase 1 Dose Escalation, Cohort 2
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: Mirdametinib 2mg (Drug)
Phase 1 Dose Escalation, Cohort 5
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: BGB-3245 10mg (Drug)
Phase 1 Dose Escalation, Cohort 3
Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway
干预措施: Mirdametinib 2mg (Drug)
结局指标
主要结局
Incidence of treatment emergent adverse events
时间窗: Up to 24 months
Safety and tolerability endpoint evaluation via incidence of treatment emergent Adverse Events (TEAEs). TEAEs severities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Maximum Tolerated Dose (Part 1 Only)
时间窗: Up to 18 months
The maximum tolerated dose (MTD) for mirdametinib and BGB-3245 administered as a combination, if any, will be based on safety and tolerability during the first 28 days of treatment in Cycle 1.
Recommended Phase 2 Dose (Part 1 Only)
时间窗: Up to 24 months
The recommended phase 2 dose (RP2D) for mirdametinib and BGB-3245 administered as a combination will be determined based on safety, tolerability, PK, preliminary anti-tumor efficacy, and other available data.
Objective Response Rate (Part 2 Only)
时间窗: Up to 24 months
Preliminary anti-tumor efficacy for the RP2D of mirdametinib and BGB-3245 administered as a combination as assessed by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). Objective Response Rate (ORR) defined as the proportion of participants with complete response (CR) + partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Incidence of Treatment Emergent Adverse Events
时间窗: All adverse events were collected from the time of signing ICF until 30 days after the last dose of study treatment (an average of 3.48 months and up to 16.76 months).
Safety and tolerability endpoint evaluation via incidence of treatment emergent Adverse Events (TEAEs). TEAE severities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0. AEs were coded using MedDRA Version 27.1.
Recommended Phase 2 Dose [RP2D] (Part 1 Only)
时间窗: Up to 24 months
The recommended phase 2 dose (RP2D) for mirdametinib and BGB-3245 administered as a combination will be determined based on safety, tolerability, PK, preliminary anti-tumor efficacy, and other available data.
次要结局
- Change in plasma concentrations of mirdametinib and BGB-3245(Up to 24 months)
- Objective Response Rate (Part 1 Only)(Up to 24 months)
- Duration of Response Rate(Up to 36 months)
- Objective Response Rate (Part 1 Only)(From participants' date of first dose of study treatment through end of treatment, an average of 3.5 months)
- Change in Plasma Concentrations of Mirdametinib and BGB-3245(Up to 24 months)