Phase II Evaluation of Vemurafenib Monotherapy in Patients with Metastatic or Unresectable Locally Advanced Malignancies Harboring BRAF Genomic Alterations

Trial ID: 2024-514904-14-00
Protocol: UC-0105/1401
Sponsor: Unicancer

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Diseases & Conditions

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Objectives

The primary objective of this study is to explore the **efficacy** of vemurafenib as a single agent across diverse types of tumors. This is guided by the presence of identified activating molecular alterations in the vemurafenib target gene, per cohort. This objective is clinically relevant as it aims to determine the potential of vemurafenib in treating patients with metastatic or unresectable locally advanced malignancies harboring BRAF genomic alterations, who are no longer amenable to curative treatment.

Secondary objectives include:

Exploring the efficacy of vemurafenib per pathology and per target.
Assessing the safety profile of vemurafenib.
Exploring the feasibility of conducting molecularly driven, high-quality multi-tumor screening phase II trials in the French multi-institutional, multidisciplinary setting.

Participants

The clinical trial involves **participants** with metastatic or unresectable locally advanced malignancies harboring BRAF genomic alterations, which are the biological target of vemurafenib. The study population includes both **male and female** subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 or a Karnofsky scale greater than 50%, with a life expectancy of at least 3 months. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals with a histologically confirmed malignancy that is resistant or refractory to standard therapy, or for which standard therapy does not exist or is deemed inappropriate by the investigator. Participants must have a BRAF V600 mutation determined by the INCa platforms on the primary and/or metastatic lesion in specific pathologies such as non-small cell lung cancer (NSCLC), ovarian cancer, cholangiocarcinoma, thyroid cancer, prostatic cancer, bladder cancer, sarcoma/GIST, multiple myeloma, chronic lymphocytic leukemia (CLL), and hairy cell leukemia (HCL), excluding certain variants. The trial population is selected based on their ability to meet these criteria, and they must also have adequate hematologic, renal, and liver function. Participants are required to use effective contraceptive methods if they are potentially reproductive, and women of childbearing potential must have a negative pregnancy test prior to enrollment. The trial includes a vulnerable population, and all participants must be able to swallow and retain oral medication.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **vemurafenib** as a single agent in patients with metastatic or unresectable locally advanced malignancies harboring BRAF genomic alterations. This is a Phase II, randomized, double-blind, controlled study. The trial aims to explore the anti-tumor activity of vemurafenib across diverse tumor types, guided by the presence of identified activating molecular alterations in the BRAF target gene. The study is expected to run until December 21, 2025, with recruitment having started on October 8, 2014.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and life expectancy. The inclusion criteria require participants to be at least 18 years old, have an ECOG Performance Status of 0 to 2, and a life expectancy of at least 3 months. Eligible participants must also have a BRAF V600 mutation and measurable disease according to RECIST 1.1 guidelines. The screening visit will include a comprehensive evaluation of the patient's medical history, physical examination, and laboratory tests to ensure adequate hematologic, renal, and liver function.

Following the screening, participants will be randomized to receive vemurafenib in the form of 240 mg film-coated tablets, administered orally. The maximum daily dose is 1920 mg, with a treatment period of 28 days. Study visits will occur at regular intervals to monitor the patient's response to treatment, assess safety, and manage any adverse events. The primary endpoint is the confirmed objective response/remission rate, while secondary endpoints include disease control rate, response duration, progression-free survival, overall survival, and safety.

The expected length of participant involvement is until the end of the study or until disease progression, unacceptable toxicity, or withdrawal of consent occurs. Conditions that may lead to early termination from the study include non-compliance with study procedures, development of a serious adverse event, or any other reason deemed appropriate by the investigator. The end-of-study visit will involve a final assessment of the patient's health status and documentation of any ongoing adverse events or treatment-related issues.

Treatment

The clinical trial involves the administration of **Zelboraf** 240 mg film-coated tablets, which contain the active substance **vemurafenib**. Vemurafenib is a chemically synthesized compound, also known by its synonyms RO5185426 and PLX4032. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The maximum daily dose of vemurafenib is 1920 mg, with a total maximum dose of 53760 mg over a treatment period of 28 days. The medication is administered orally, and the dosing schedule is determined based on the specific requirements of the trial protocol. Compliance with the dosing regimen is monitored throughout the study to ensure adherence to the treatment plan.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy of vemurafenib as a single agent in patients with tumors harboring BRAF genomic alterations. The trial aims to explore the therapeutic potential of vemurafenib across diverse tumor types, guided by the presence of identified activating molecular alterations in the target gene. The study does not include any pediatric formulations, and the product is not classified as an orphan drug. The trial is conducted under the authorization of Roche Registration GmbH, with the product holding a marketing authorization number EU/1/12/751/001.

Efficacy

The efficacy of **vemurafenib** in this clinical trial will be assessed primarily through the determination of the confirmed objective response/remission rate. This will include both complete and partial responses/remissions, evaluated according to the RECIST criteria v1.1 for solid tumors, the IMWG Response Criteria for myeloma, and the IWCLL criteria for chronic lymphocytic leukemia (CLL). These criteria provide standardized methods for measuring tumor response and are widely used in oncology trials to ensure consistency and reliability in efficacy assessments.

Secondary endpoints for evaluating efficacy include the disease control rate, response duration, progression-free survival, and overall survival. These parameters will provide additional insights into the long-term benefits of the treatment. Safety will also be monitored using the CTCAE v4.0 criteria, and correlative research endpoints will be explored to further understand the treatment's impact.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male and female ≥ 18 years of age
Unresectable locally advanced or metastatic histologically confirmed malignancy (excluding melanoma V600 mutation) resistant or refractory to standard therapy or for which standard therapy does not exist or is not considered appropriate by the Investigator and are not eligible to an appropriate ongoing clinical trial. For Hairy Cell Leukemia: .patients must have relapsed and/or be refractory HCL candidate for treatment after 2 lines of purine analogues treatment.
Patient with BRAF V600 mutation determined by the INCa platforms on the primary and/or metastatic lesion in the following pathologies: . NSCLC . Ovarian cancer . Cholangiocarcinoma . Thyroid cancer . Prostatic cancer . Bladder cancer . Sarcoma/GIST . Multiple myeloma . Chronic Lymphocytic Leukemia (CLL) . Hairy cell leukaemia (HCL) (this excludes Hairy Cell Leukemia variant types, marginal zone splenic lymphoma (MZL), splenic red pulp lymphoma (SRPL) patients) Or patient with the same or another pre-listed pathology harboring any type of activating BRAF alteration determined from outside the INCa platforms network.
Measurable disease according to RECIST 1.1 guidelines for solid tumors with target lesion of at least 10 mm and presence of at least one RECIST-measurable lesion outside of a previously radiated field or potential palliative irradiation fields, International Myeloma Working group Response Criteria for myeloma, IWCLL Chronic Lymphocytic Leukemia and clinical/biological parameters for Hairy cell leukaemia (Serum M-protein > 0.5 g/dL; Urine Mprotein > 200 mg per 24 hours; Involved FLC level > 10 mg/dL (> 100 mg/L) provided serum FLC ratio is abnormal).
Patients who had received any previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, i.e. ≤ grade1, with a mandatory free interval of at least 3 weeks for systemic or radiotherapy treatments and at least 5 halflives for targeted drugs.
Patients who had received any investigational drug are eligible after a 4-week wash-out period or a wash-out period equivalent to 5 half-lives of the product, depending on the longest period
Adequate hematologic*, renal* and liver function*, as defined by the following laboratory values; test performed within 7 days prior to the first dose of vemurafenib: . Hemoglobin ≥ 9 g/dL . Absolute neutrophil count (ANC) ≥ 1.5 x 109/L . Platelet count ≥ 100 x 109/L . Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or creatine clearance (CrCl) > 50 mL/min by Cockroft–Gault formula (Protocol Appendix 1) . Aspartate aminotransferase (AST [SGOT]) and alanine aminotransferase (ALT [SGPT]) ≤ 2.5 times ULN (≤ 5 times ULN if considered due to primary or metastatic liver involvement) . Serum bilirubin ≤ 1.5 times ULN . Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if considered due to tumor)
Normal values for calcium, magnesium and potassium levels
Patients able to swallow and retain oral medication (tablet size: 19 mm. Can not be chewed or crushed)
ECOG Performance Status of 0 to 2, or Karnofsky scale > 50 %
Life expectancy ≥ 3 months
Potentially reproductive patients must agree to use an effective contraceptive method, practice adequate methods of birth control or practice complete abstinence while on treatment, beginning 2 weeks before the first dose of investigational product and for at least 6 months after the last dose of study drug
Women of childbearing potential must have a negative serum pregnancy test within 14 days of enrollment and/or urine pregnancy test 72 hours prior to the administration of the study drug
Women who are breastfeeding should discontinue nursing prior to the first day of study drug and permanently after the last dose
Patients must be affiliated to a Social Security System.
Patient information and written informed consent form signed.

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Exclusion Criteria

V600 BRAF mutated melanoma patients or colorectal cancer patients
Patient eligible to a clinical trial with an anticancer drug (including vemurafenib) targeting the same BRAF molecular alteration in the same type/localization as the patient’s cancer presentation open to accrual in France. Patient not eligible in this trial are still eligible for the AcSé study.
Prior treatment with a BRAF or MEK inhibitor
Major surgery or tumor embolization within 4 weeks and minor surgery within 2 weeks prior to the initiation of the study drug
Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as, but not limited to: a) Any of the following within the 6 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, or cerebrovascular accident including transient ischemic attack. Ongoing congestive heart failure. b) Pulmonary embolism within 30 days prior to first vemurafenib administration c) Hypertension not adequately controlled by current medications within 30 days prior to first vemurafenib administration d) Congenital long QT syndrome e) Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, uncontrolled atrial fibrillation of any grade, or machine-read ECG with QTc interval > 460 msec f) Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function g) Carcinomatous meningitis or leptomeningeal disease h) Any uncontrolled infection i) Other severe acute or chronic medical (including severe gastrointestinal conditions such as diarrhea or ulcer) or psychiatric conditions, or end stage renal disease on hemodialysis or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for study entry
For MM, solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia
Known hypersensitivity to vemurafenib or another BRAF inhibitor
Concurrent administration of any anti-cancer therapies (e.g., chemotherapy, other targeted therapy, experimental drug, etc.) other than those administered in this study
Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption.
Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Individual deprived of liberty or placed under the authority of a tutor.
Unwillingness to practice effective birth control. Pregnant or lactating women.