Mirdametinib + BGB-3245 in Advanced Solid Tumors

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: Mirdametinib 2mg; Drug: BGB-3245 5mg; Drug: BGB-3245 10mg; Drug: BGB-3245 20mg; Drug: Mirdametinib 3mg; Drug: Mirdametinib 4mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Waratah, Australia, 2298
    • Calvary Mater Newcastle
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
• United States
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale-New Haven Hospital-Yale Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of The University of Pennsylvania
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Escalation, Cohort 1; Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway	Drug: Mirdametinib 2mg; Mirdametinib 2mg administered orally; Other Names: PD-0325901; Drug: BGB-3245 5mg; BGB-3245 5mg administered orally; Other Names: Brimarafenib
Experimental: Phase 1 Dose Escalation, Cohort 2; Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway	Drug: Mirdametinib 2mg; Mirdametinib 2mg administered orally; Other Names: PD-0325901; Drug: BGB-3245 10mg; BGB-3245 10mg administered orally; Other Names: Brimarafenib
Experimental: Phase 1 Dose Escalation, Cohort 3; Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway	Drug: Mirdametinib 2mg; Mirdametinib 2mg administered orally; Other Names: PD-0325901; Drug: BGB-3245 20mg; BGB-3245 20mg administered orally; Other Names: Brimarafenib
Experimental: Phase 1 Dose Escalation, Cohort 4; Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway	Drug: BGB-3245 10mg; BGB-3245 10mg administered orally; Other Names: Brimarafenib; Drug: Mirdametinib 3mg; Mirdametinib 3mg administered orally; Other Names: PD-0325901
Experimental: Phase 1 Dose Escalation, Cohort 5; Participants with an oncogenic mutation or other genomic aberration of the MAPK pathway	Drug: BGB-3245 10mg; BGB-3245 10mg administered orally; Other Names: Brimarafenib; Drug: Mirdametinib 4mg; Mirdametinib 4mg administered orally; Other Names: PD-0325901

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Incidence of Treatment Emergent Adverse Events	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.	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).
Recommended Phase 2 Dose [RP2D] (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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Objective Response Rate (Part 1 Only)	Preliminary anti-tumor efficacy of mirdametinib and BGB-3245 administered as a combination as assessed by CT or MRI. ORR defined as the proportion of participants with Complete Response (CR) + Partial Response (PR) using RECIST v1.1. Responses were as reported by the investigators.	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	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

Collaborators and Investigators

• Sponsor: SpringWorks Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2023
• Primary Completion (Actual): January 15, 2025
• Study Completion (Actual): January 15, 2025

Study Registration Dates

• First Submitted: September 22, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 14, 2022

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; mirdametinib
• Other Study ID Numbers: MEKRAF-AST-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No