Study of the Safety and Pharmacokinetics of BGB-283 (Lifirafenib) and PD-0325901 (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors

Study Overview
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Brief Summary
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This is a 2-part Phase 1b study of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib) combination in participants with tumors.

Official Title
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A Phase 1b, Open-Label, Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activities of a RAF Dimer Inhibitor BGB-283 in Combination With MEK Inhibitor PD-0325901 in Patients With Advanced or Refractory Solid Tumors

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Drug: Lifirafenib
* Drug: mirdametinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Able to provide informed consent Age 18 on day of signing informed consent form (ICF) or of the legal age of consent in the jurisdiction in which the study is taking place Advanced or metastatic, unresectable tumors (other than patients with tumors of the brain or central nervous system) who have experienced disease progression Part A: NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, melanoma, pancreatic cancer, and other) Part B: NRAS mutated solid tumors must have a known mutation status and a histologically or cytologically confirmed advanced or refractory solid tumor. Up to 40% Melanoma and Up to 20% CRC. Must have archival tumor tissue or agree to tumor biopsy Measurable disease per RECIST 1.1 Eastern Cooperative Oncology Group performance status of less than or equal to 1 Life expectancy is greater than 12 weeks of the signing of ICF. Adequate organ function and no transfusion within 14 days of first dose. Females are of non-child bearing potential or willing to use contraception. Males vasectomized or agree to use contraception. Key Exclusion Criteria: Central Nervous System metastasis Any retinal pathology considered to be a risk factor for central serous retinopathy History of glaucoma Active parathyroid disorder or history of malignancy associated hypercalcemia Clinically significant cardiac disease within the past 6 months of signing ICF. LVEF less than 50% Abnormal QT interval at Screening Severe uncontrolled systemic disease HIV Clinically significant active or known history of liver disease. (Hepatitis B and Hepatitis C) Hemorrhage or bleeding event at NCI-CTCAE v5.0 Grade 3 or higher within 28 days of first dose. history of or ongoing Von Willebrand disease and/or other past or present bleeding disorders Increased serum calcium Inability to swallow oral medications Ongoing radiation therapy or radio-cytotoxic therapy within prior 4 weeks. No chemotherapy, immunotherapy, biologic therapy, hormonal, or molecular targeted therapy within prior 2 weeks Concomitant systemic or glucocorticoid therapy within 2 weeks Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose or anticipates need for major surgery while on study Concomitant medicines that are strong CYP3A inhibitors History of toxicity from another RAF, MEK, ERK inhibitor requiring discontinuation of treatment from these drugs Underlying medical conditions in investigator's opinion to be unfavorable to be a part of the study Has been administered a live vaccine within 4 weeks (28 days) of initiation of study treatment. NOTE: injectable seasonal vaccines for influenza and COVID-19 are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A will consist of dose escalation and dose-finding components to establish the max tolerated dose and/or recommended Phase 2 dose Part B will investigate efficacy and further evaluate the PK, safety, and tolerability of the combination of PD-0325901 and BGB-283 (lifirafenib).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Dose Escalation/Dose finding Dose Level Cohorts ranging in dose levels and dose regimens.<br>Combination doses of, Mirdametinib at once a day and lifirafenib at once a day And Mirdametinib at twice a day and lifirafenib at once a day | Drug: Lifirafenib<br>* RAF Dimer Inhibitor<br>* Other names: BGB-283;Drug: mirdametinib<br>* MEK Inhibitor<br>* Other names: PD-0325901;|
| Experimental: Part B: Expansion<br>Approximately 20 participants with NRAS mutated solid tumors will be enrolled | Drug: Lifirafenib<br>* RAF Dimer Inhibitor<br>* Other names: BGB-283;Drug: mirdametinib<br>* MEK Inhibitor<br>* Other names: PD-0325901;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events and Serious Adverse Events | Incidence and severity of AEs and SAEs and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Approximately 2 years from date of the participants enrollment | 
| The incidence of DLT events and treatment-emergent AEs (TEAEs) |  | Approximately 2 years from date of the participants enrollment | 
| Objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in participants with selected tumor types |  | Approximately 2 years from date of the participants enrollment |