Vemurafenib With Sorafenib Tosylate or Crizotinib in Treating Patients With Advanced Malignancies With BRAF Mutations

A Phase I Trial of Sorafenib (CRAF, BRAF, KIT, RET, VEGFR, PDGFR Inhibitor) or Crizotinib (MET, ALK, ROS1 Inhibitor) in Combination With Vemurafenib (BRAF Inhibitor) in Patients With Advanced Malignancies

This phase I clinical trial studies vemurafenib with sorafenib tosylate or crizotinib in treating patients with advanced malignancies with BRAF mutations. Sorafenib tosylate and crizotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sorafenib tosylate may also stop the growth of advanced malignancies by blocking blood flow to tumors. Drugs used in chemotherapy, such as vemurafenib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vemurafenib together with sorafenib tosylate or crizotinib may kill more cancer cells.

Study Overview

• Status: Completed
• Conditions: Metastatic Malignant Neoplasm; Advanced Malignant Neoplasm; Recurrent Malignant Neoplasm; Refractory Malignant Neoplasm; BRAF Gene Mutation
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Crizotinib; Drug: Vemurafenib; Drug: Sorafenib Tosylate

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of sorafenib tosylate (sorafenib) or crizotinib in combination with vemurafenib in patients with advanced cancers who progressed on standard therapy.

SECONDARY OBJECTIVES:

I. Preliminary assessment of antitumor efficacy of sorafenib or crizotinib combination with vemurafenib in patients with advanced cancers.

II. Preliminary assessment of the pharmacokinetic (PK) profile of sorafenib or crizotinib in combination with vemurafenib.

III. Preliminary assessment of biomarkers.

OUTLINE: This is a dose-escalation study of vemurafenib and sorafenib tosylate. Patients are assigned to 1 of 2 treatment arms by their physician.

ARM I: Patients receive vemurafenib orally (PO) twice daily (BID) and sorafenib tosylate PO BID on days 1-28.

ARM II: Patients receive vemurafenib as in Arm I and crizotinib PO once daily (QD) or BID on days 1-28.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

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 advanced or metastatic cancers and BRAF mutations that are refractory to standard therapy, relapsed after standard therapy, or who have no standard therapy available that improves survival by at least three months; patients with BRAF mutation in cell free deoxyribonucleic acid (DNA) (tested in Clinical Laboratory Improvement Amendments [CLIA] lab) are also eligible
• Patients must be >= 3 weeks beyond treatment with a cytotoxic chemotherapy regimen, or therapeutic radiation, or major surgery; patients may have received palliative localized radiation immediately before or during treatment provided that radiation is not delivered to the only site of disease being treated under this protocol; for biologic/targeted agents patients must be >= 5 half-lives or >= 3 weeks from the last dose (whichever comes first); patients previously treated with vemurafenib monotherapy do not have to stop medication before they start on the protocol
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) >= 1,000/mL
• Platelets >= 75,000/mL
• Creatinine =< 2 X upper limit of normal (ULN)
• Total bilirubin =< 2 X ULN (exceptions may apply to benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome)
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and/or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 5 X ULN
• Exception for patients with liver metastasis: total bilirubin =< 3 x ULN; ALT (SGPT) =< 8 X ULN
• Dermatology evaluation with excision of any suspicious lesions prior to initiation of therapy
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after the last dose
• Women of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to initiation of therapy
• Life expectancy > 12 weeks in the opinion of the investigator
• Patients must be able to understand and be willing to sign a written informed consent document
• Patient must be able to swallow pills

Exclusion Criteria:

• Uncontrolled intercurrent illness, including, but not limited to, uncontrolled infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support
• Syndrome of congenital corrected QT interval (QTc) prolongation or QTc > 500 msec
• Patients with clinically significant cardiovascular disease: history of cerebrovascular accident (CVA) within 6 months, myocardial infarction or unstable angina within 6 months, or unstable angina pectoris
• Pregnant or lactating women
• History of hypersensitivity to vemurafenib
• History of hypersensitivity to sorafenib for vemurafenib/sorafenib arm
• History of hypersensitivity to crizotinib for vemurafenib/crizotinib arm
• History of hypersensitivity to any component of the formulation
• Patients unwilling or unable to sign informed consent document
• Patients using any of the following medications: mesoridazine, dronedarone, thioridazine, ziprasidone, levomethadyl, and saquinavir for vemurafenib/sorafenib arm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm I (vemurafenib and sorafenib tosylate); Patients receive vemurafenib PO BID and sorafenib tosylate PO BID on days 1-28.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Vemurafenib; Given PO; Other Names: BRAF (V600E) kinase inhibitor RO5185426; BRAF(V600E) Kinase Inhibitor RO5185426; PLX-4032; PLX4032; RG 7204; RG7204; RO 5185426; Zelboraf; Drug: Sorafenib Tosylate; Given PO; Other Names: BAY 54-9085; Nexavar; BAY 43-9006 Tosylate; sorafenib
EXPERIMENTAL: Arm II (vemurafenib and crizotinib); Patients receive vemurafenib as in Arm I and crizotinib PO QD or BID on days 1-28.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Crizotinib; Given PO; Other Names: MET Tyrosine Kinase Inhibitor PF-02341066; PF-02341066; PF-2341066; Xalkori; Drug: Vemurafenib; Given PO; Other Names: BRAF (V600E) kinase inhibitor RO5185426; BRAF(V600E) Kinase Inhibitor RO5185426; PLX-4032; PLX4032; RG 7204; RG7204; RO 5185426; Zelboraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of vemurafenib and sorafenib tosylate or crizotinib, defined as the highest dose studied in which the incidence of dose limiting toxicity was less than 33%	28 days

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 6, 2012
• Primary Completion (ACTUAL): January 13, 2021
• Study Completion (ACTUAL): January 13, 2021

Study Registration Dates

• First Submitted: February 6, 2012
• First Submitted That Met QC Criteria: February 8, 2012
• First Posted (ESTIMATE): February 10, 2012

Study Record Updates

• Last Update Posted (ACTUAL): January 22, 2021
• Last Update Submitted That Met QC Criteria: January 19, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Neoplasms; Recurrence; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib; Vemurafenib; Crizotinib
• Other Study ID Numbers: 2011-1183 (OTHER: M D Anderson Cancer Center); P30CA016672 (U.S. NIH Grant/Contract); NCI-2012-00217 (REGISTRY: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

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