Mirdametinib + BGB-3245 in Advanced Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Mirdametinib
* Drug: BGB-3245


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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 Key Exclusion Criteria: 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

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: The study will be conducted in two sequential parts: Part 1 dose escalation (Phase 1) and Part 2 dose expansion (Phase 2a).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation Cohorts Ranging in Dose<br>Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway | Drug: Mirdametinib<br>* Mirdametinib administered orally<br>* Other names: PD-0325901;Drug: BGB-3245<br>* BGB-3245 administered orally<br>|
| Experimental: Phase 2 Dose Expansion A<br>Participants with cutaneous melanoma harboring NRAS mutations | Drug: Mirdametinib<br>* Mirdametinib administered orally<br>* Other names: PD-0325901;Drug: BGB-3245<br>* BGB-3245 administered orally<br>|
| Experimental: Phase 2 Dose Expansion B<br>Participants with NSCLC harboring KRAS mutations | Drug: Mirdametinib<br>* Mirdametinib administered orally<br>* Other names: PD-0325901;Drug: BGB-3245<br>* BGB-3245 administered orally<br>|
| Experimental: Phase 2 Dose Expansion C<br>Participants with NSCLC or cutaneous melanoma harboring BRAF Class II or Class III mutation or BRAF Fusion mutation | Drug: Mirdametinib<br>* Mirdametinib administered orally<br>* Other names: PD-0325901;Drug: BGB-3245<br>* BGB-3245 administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events | 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. | Up to 24 months | 
| Maximum Tolerated Dose (Part 1 Only) | 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. | Up to 18 months | 
| Recommended Phase 2 Dose (Part 1 Only) | 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. | Up to 24 months | 
| Objective Response Rate (Part 2 Only) | 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). | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Part 1 Only) | Preliminary anti-tumor efficacy for the RP2D of mirdametinib and BGB-3245 administered as a combination as assessed by CT or MRI. ORR defined as the proportion of participants with CR + PR using RECIST v1.1 | Up to 24 months | 
| Duration of Response Rate | Duration of response rate in participants treated with the combination of mirdametinib and BGB-3245, defined as the time from response (CR + PR using RECIST v1.1) to disease progression and/or death. | Up to 36 months | 
| Change in plasma concentrations of mirdametinib and BGB-3245 | To determine the PK of mirdametinib and BGB-3245 administered as a combination in the eligible participant population. Plasma concentrations of mirdametinib and BGB-3245 will be measured to evaluate systemic exposures (AUC, Cmax, Ctrough, and other PK parameters as data allow). | Up to 24 months |