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: Recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: Mirdametinib; Drug: BGB-3245

• Study Type: Interventional
• Enrollment (Estimated): 136
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: SpringWorks Clinical; Phone Number: 877-279-4870; Email: clinical@springworkstx.com

Study Locations

• Australia
  • Waratah, Australia, 2298
    • Recruiting
    • Calvary Mater Newcastle
    • Contact: Fiona Day, MD; Phone Number: 02 4014 3575; Email: Fiona.Day@calvarymater.org.au
    • Principal Investigator: Fiona Day, MD
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter MacCallum Cancer Centre
      • Principal Investigator: Jayesh Desai, MD
      • Contact: Email: pcctu.edd@petermac.org
• United States
  • California
    • La Jolla, California, United States, 92093
      • Recruiting
      • UC San Diego Moores Cancer Center
      • Principal Investigator: Gregory Daniels, MD
      • Contact: Katie O'Neil; Email: croneil@health.ucsd.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale-New Haven Hospital-Yale Cancer Center
      • Principal Investigator: Mario Sznol, MD
      • Contact: Leah Centanne; Phone Number: 203-785-2134; Email: leah.centanne@yale.edu
  • Florida
    • Orlando, Florida, United States, 32806
      • Withdrawn
      • Orlando Health Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Ryan J Sullivan, MD; Phone Number: 617-724-4000; Email: RSULLIVAN7@PARTNERS.ORG
      • Principal Investigator: Ryan J Sullivan, MD
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
      • Principal Investigator: Ankit Mangla, MD
      • Contact: Ankit Mangla, MD; Phone Number: 216-844-3951; Email: ankit.mangla@UHhospitals.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Hospital of the University of Pennsylvania
      • Contact: Jennifer Louie; Phone Number: 215-220-9668; Email: Jennifer.Louie2@pennmedicine.upenn.edu
      • Principal Investigator: Ravi Amaravadi, MD
  • Texas
    • Dallas, Texas, United States, 75246
      • Recruiting
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center
      • Contact: Christine Terraciano; Phone Number: 214-370-1942; Email: Christine.Terraciano@usoncology.com
      • Principal Investigator: Charles L Cowey, MD

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

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: SpringWorks Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): June 30, 2027

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): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• 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