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

• ClinicalTrials.gov Identifier: NCT03905148
• Recruitment Status: Recruiting
• First Posted: April 5, 2019
• Last Update Posted: April 13, 2023
• Sponsor: BeiGene
• Collaborator: SpringWorks Therapeutics, Inc.
• Information provided by (Responsible Party): BeiGene

Tracking Information

• First Submitted Date: April 3, 2019
• First Posted Date: April 5, 2019
• Last Update Posted Date: April 13, 2023
• Actual Study Start Date: May 1, 2019
• Estimated Primary Completion Date: March 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 15, 2021)

• Adverse Events and Serious Adverse Events [ Time Frame: Approximately 2 years from date of the participants enrollment ]
  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
• The incidence of DLT events and treatment-emergent AEs (TEAEs) [ Time Frame: 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 [ Time Frame: Approximately 2 years from date of the participants enrollment ]

Original Primary Outcome Measures (submitted: April 4, 2019)

• Adverse Events and Serious Adverse Events [ Time Frame: Approximately 2 years from date of the patient enrollment ]
  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 4.03
• The incidence of DLT events and treatment-emergent AEs (TEAEs) [ Time Frame: Approximately 2 years from date of the patient enrollment ]
• Objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in subjects with selected tumor types [ Time Frame: Approximately 2 years from date of the patient enrollment ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of the Safety and Pharmacokinetics of BGB-283 (Lifirafenib) and PD-0325901 (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors
• Official Title: 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
• Brief Summary: This is a 2-part Phase 1b study of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib) combination in participants with tumors.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment

• Condition: Solid Tumor, Adult

Intervention

• Drug: Lifirafenib
  RAF Dimer Inhibitor
  Other Name: BGB-283
• Drug: mirdametinib
  MEK Inhibitor
  Other Name: PD-0325901

Study Arms

• Experimental: Part A: Dose Escalation/Dose finding Dose Level Cohorts ranging in dose levels and dose regimens.
  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
  Interventions:

  • Drug: Lifirafenib
  • Drug: mirdametinib
• Experimental: Part B: Group 1
  Non-small cell lung cancer with confirmed K-RAS mutations, approximately 15 participants
  Interventions:

  • Drug: Lifirafenib
  • Drug: mirdametinib
• Experimental: Part B: Group 2
  Endometrial cancer with confirmed K-RAS mutations, approximately 15 participants
  Interventions:

  • Drug: Lifirafenib
  • Drug: mirdametinib
• Experimental: Part B: Group 3
  Tumor type of interest based on preliminary anti-tumor clinical activities observed in Part A, approximately 15 participants
  Interventions:

  • Drug: Lifirafenib
  • Drug: mirdametinib

• Publications *: Desai J, Gan H, Barrow C, Jameson M, Atkinson V, Haydon A, Millward M, Begbie S, Brown M, Markman B, Patterson W, Hill A, Horvath L, Nagrial A, Richardson G, Jackson C, Friedlander M, Parente P, Tran B, Wang L, Chen Y, Tang Z, Huang W, Wu J, Zeng D, Luo L, Solomon B. Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors. J Clin Oncol. 2020 Jul 1;38(19):2140-2150. doi: 10.1200/JCO.19.02654. Epub 2020 Mar 17.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 24, 2021): 105
• Original Estimated Enrollment (submitted: April 4, 2019): 75
• Estimated Study Completion Date: April 29, 2024
• Estimated Primary Completion Date: March 30, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

1. Able to provide informed consent
2. 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

3. 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: Group 1: NSCLC, Group 2: endometrial cancer, Group 3: Tumor types of interest based on preliminary anti-tumor activities observed in Part A
4. Must have archival tumor tissue or agree to tumor biopsy
5. Measurable disease per RECIST 1.1
6. Eastern Cooperative Oncology Group performance status of less than or equal to 1
7. Life expectancy is greater than 12 weeks at the of signing ICF.
8. Adequate organ function and no transfusion within 14 days of first dose.
9. Females are of non-child bearing potential or willing to use contraception.
10. Males vasectomized or agree to use contraception.

Key Exclusion Criteria:

1. Central Nervous System metastasis
2. Any retinal pathology considered to be a risk factor for central serous retinopathy
3. History of glaucoma
4. Active parathyroid disorder or history of malignancy associated hypercalcemia
5. Clinically significant cardiac disease within the past 6 months of signing ICF.
6. LVEF less than 50%
7. Abnormal QT interval at Screening
8. Severe uncontrolled systemic disease
9. HIV
10. Clinically significant active or known history of liver disease. (Hepatitis B and Hepatitis C)
11. Hemorrhage or bleeding event at NCI-CTCAE v5.0 Grade 3 or higher within 28 days of first dose.
12. history of or ongoing Von Willebrand disease and/or other past or present bleeding disorders
13. Increased serum calcium
14. Inability to swallow oral medications
15. 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
16. Concomitant systemic or glucocorticoid therapy within 2 weeks
17. Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose or anticipates need for major surgery while on study
18. Concomitant medicines that are strong CYP3A inhibitors
19. History of toxicity from another RAF, MEK, ERK inhibitor requiring discontinuation of treatment from these drugs
20. Underlying medical conditions in investigator's opinion to be unfavorable to be a part of the study
21. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: BeiGene; 1 (877) 828-5568; clinicaltrials@beigene.com

• Listed Location Countries: Australia, United States

Administrative Information

• NCT Number: NCT03905148
• Other Study ID Numbers: BGB-283/PD-0325901-AU-001
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: BeiGene
• Original Responsible Party: Same as current
• Current Study Sponsor: BeiGene
• Original Study Sponsor: Same as current
• Collaborators: SpringWorks Therapeutics, Inc.
• Investigators: Not Provided
• PRS Account: BeiGene
• Verification Date: April 2023