MEK162 and RAF265 in Adult Patients With Advanced Solid Tumors Harboring RAS or BRAFV600E Mutations

A Phase Ib Open-label Dose Escalation Study of MEK162 and RAF265 in Adult Patients With Advanced Solid Tumors Harboring RAS or BRAFV600E Mutations

This is a multi- center, open-label, dose finding, Phase Ib study to be conducted in two stages: a dose escalation part to determine the maximum tolerated dose (MTD) safety and tolerability of concurrent administration of MEK162 and RAF265, followed by an expansion part to further assess the safety and preliminary anti-tumor efficacy of this oral combination within two separate patient populations: i) patients with advanced solid tumors harboring BRAFV600E mutations or ii) patients with advanced solid tumors harboring RAS mutations.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: MEK162 + RAF265

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Pfizer Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E3
      • Pfizer Investigative Site
• Norway
  • Oslo, Norway, NO-0379
    • Pfizer Investigative Site
• Spain
  • Madrid, Spain, 28050
    • Pfizer Investigative Site
• Switzerland
  • Zürich, Switzerland, 8091
    • Pfizer Investigative Site
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute Moffitt 4
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University OHSU 3
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah / Huntsman Cancer Institute Huntman 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with histologically or cytologically confirmed and non-resectable advanced solid tumors for which no further effective standard therapy exists.

• The patients' tumors must contain documented activating somatic BRAFV600E* , NRAS or KRAS mutations (except for pancreatic cancer)
• All patients enrolled MUST provide fresh or archival tumor samples at baseline to enable central confirmation of BRAF or KRAS/NRAS mutations
• Measurable, or non-measurable but evaluable disease as determined by RECIST
• Adequate bone marrow function
• Adequate hepatic and renal function
• Adequate cardiovascular function
• Negative serum β HCG test (female patients of childbearing potential only) within 72 hrs prior to first dose

Exclusion Criteria:

• Patients with a history of primary central nervous system tumors or brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases
• Current evidence of retinal disease; or ophthalmopathy as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO (e.g., optic disc cupping, visual field defects, IOP > 21 mm Hg)

• Impaired cardio-/vascular function or clinically significant cardiovascular diseases, including any of the following:

  • History/evidence of acute coronary syndromes (including MI, unstable angina, CABG, coronary angioplasty, or stenting) ≤ 6 months prior to starting study drugs
  • Thromboembolic event (DVT, CVA, PE) ≤ 6 months prior to starting study
  • Symptomatic CHF, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality
  • Uncontrolled arterial hypertension, defined as BP > 140/100 mmHg (average of 3 consecutive readings)
• History of melena, hematemesis or hemoptysis within the last 3 months
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: MEK162 + RAF265	Drug: MEK162 + RAF265

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Dose Limiting Toxicities	during the first 28 days of treatment with RAF265 and MEK162

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events and serious adverse events		18 months
assess preliminary anti-tumor activity of the combination	CT scan will be performed	every 8 weeks of treatment
Tumor skin and blood samples will be collected before and during treatment with RAF265 and MEK162 to assess the combination's effects on the RAF/MEK/MAPK pathway with the clinical outcomes		18 months
Time versus plasma concentration profiles of RAF265 and MEK162		10 months

Collaborators and Investigators

• Sponsor: Array Biopharma, now a wholly owned subsidiary of Pfizer

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (ACTUAL): September 1, 2013
• Study Completion (ACTUAL): September 1, 2013

Study Registration Dates

• First Submitted: May 2, 2011
• First Submitted That Met QC Criteria: May 10, 2011
• First Posted (ESTIMATE): May 11, 2011

Study Record Updates

• Last Update Posted (ACTUAL): September 30, 2020
• Last Update Submitted That Met QC Criteria: September 28, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: advanced Solid tumors; harboring RAS; harboring BRAFV600E
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: CMEK162X2102; 2010-023812-14 (EUDRACT_NUMBER)