DETERMINE Trial Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.

Launched by CANCER RESEARCH UK · Mar 2, 2023

Keywords

ClinConnect Summary

The DETERMINE Trial is studying the effects of two drugs, vemurafenib and cobimetinib, on adult patients with specific types of cancer that have a genetic change known as the BRAF V600 mutation. While vemurafenib is already used for treating advanced melanoma, researchers want to see if combining it with cobimetinib can also help patients with other BRAF V600 mutation-positive cancers, such as certain types of thyroid, ovarian, and lung cancers. If the trial shows positive results, there may be a chance for these drugs to become available for more patients in the future.

To participate in the trial, patients need to be at least 16 years old and have a confirmed diagnosis of a cancer with the BRAF V600 mutation. They should also be willing to have a fresh biopsy and meet certain health criteria, like having adequate organ function. If eligible, participants can expect to receive these medications and be closely monitored by healthcare professionals during the study. It's important for potential participants to know that there are specific guidelines regarding pregnancy and certain health conditions that may affect their eligibility.

Gender

ALL

Eligibility criteria

• • THE PATIENT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL (NCT05722886) AND WITHIN THE TREATMENT ARM 05 (VEMURAFENIB AND COBIMETINIB) OUTLINED BELOW\*
• • \*When vemurafenib and cobimetinib-specific inclusion/exclusion criteria or precautions below differ from those specified in the Master Protocol, the vemurafenib and cobimetinib-specific criteria will take precedence.
• Inclusion Criteria:
• • A. Confirmed diagnosis of a malignancy harbouring any actionable BRAF V600 mutation using an analytically validated sequencing technique.
• • B. Adult patients ≥18 years old.
• • C. Patients must be able and willing to undergo a fresh tissue biopsy.
• • D. Adequate organ function as per haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient's eligibility.
• • Haemoglobin (Hb): ≥90 g/L (transfusion allowed)
• • Absolute neutrophil count (ANC): ≥1.5 × 10\^9/L (no granulocyte colony-stimulating factor \[GCSF\] support in preceding 72 hours)
• • Platelet count: ≥100 × 10\^9/L (unsupported for 72 hours)
• • Bilirubin: \<1.5 × upper limit of normal (ULN)
• • Patients with known Gilbert disease: total bilirubin ≤3.0 × ULN
• • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN or ≤5 × ULN if raised due to presence of liver metastases
• • estimated glomerular filtration rate (eGFR): ≥30 mL/min (uncorrected value)
• • Coagulation - Prothrombin (PT) (or international normalized ratio (INR), and activated partial thromboplastin clotting time (aPTT): INR or PT ≤1.5 and aPTT \<1.5 × ULN (unless patient is on anticoagulants e.g. warfarin \[INR should be stable and within therapeutic range\], or direct oral anticoagulants \[DOAC\])
• • Electrolytes - Potassium (K), Magnesium (Mg) and Calcium (Ca): Electrolytes within normal range (electrolyte replacement permitted)
• E. Women of childbearing potential are eligible provided that they meet the following criteria:
• • Have a negative serum or urine pregnancy test before enrolment and;
• * Agree to sexual abstinence OR to use any two forms of highly effective or effective methods together (at least one to be non-hormonal) such as:
• * Highly effective methods:
• • combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
• • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
• • intrauterine device (IUD)
• • intrauterine hormone-releasing system (IUS)
• • bilateral tubal occlusion
• • vasectomised partner
• * Effective methods:
• • progestogen-only oral hormonal contraception not associated with inhibition of ovulation
• • male or female condom with or without spermicide
• • cap, diaphragm or sponge with spermicide
• • Effective from the first administration of vemurafenib or cobimetinib (whichever is first), throughout the trial and for six months after the last administration of vemurafenib or cobimetinib (whichever is later).
• F. Male patients with partners who are women of childbearing potential, are eligible provided that they agree to the following, from the first administration of vemurafenib or cobimetinib (whichever is first), throughout the trial and for six months after the last administration of vemurafenib or cobimetinib (whichever is later):
• • Agree to take measures not to father children by using a barrier method of contraception (condom plus spermicide) or to sexual abstinence
• • Non-vasectomised male patients with partners who are women of childbearing potential must also be willing to ensure that their partner uses a highly effective method of contraception as in E, above.
• • Male patients with pregnant or lactating partners must be advised to use barrier method contraception (e.g. condom) to prevent drug exposure of the foetus or neonate.
• • All male patients must refrain from donating sperm for the same period.
• Exclusion Criteria:
• • A. Diagnosis of unresectable or metastatic melanoma with a BRAF V600 mutation.
• • B. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or for six months following their last dose of vemurafenib or cobimetinib, whichever is later.
• • C. Patients with QTcF (Corrected QT interval by Fridericia) at screening of \>450 ms for males and \>470 ms for females measured on triplicate ECG (if 1/3 readings show \>450/470 ms then patient is ineligible).
• • D. Patients with any history of long QT syndrome or Torsades de Pointes (or any concurrent medication with a known risk of inducing Torsades de Pointes).
• • E. Known hypersensitivity to vemurafenib or cobimetinib or any of the excipients.
• • F. Patients unable to swallow vemurafenib and cobimetinib intact, without chewing or crushing the tablets (as per the dosing schedule).
• • G. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during vemurafenib and cobimetinib treatment or within six months after the final dose of vemurafenib and cobimetinib.
• H. Patients with clinically significant pre-existing cardiac conditions including (within the last three months prior to screening):
• • Uncontrolled or symptomatic angina,
• • Uncontrolled atrial or ventricular arrhythmias,
• • Class III \& IV New York Heart Association (NYHA) congestive heart failure,
• • Left ventricular ejection fraction (LVEF) \<50%,
• • Myocardial infarction
• • I. Ophthalmological disorders: History of retinal detachment, severe visual impairment, central serous chorioretinopathy, neovascular retinopathy, or retinopathy of prematurity.
• • Patients with low grade gliomas causing visual impairment may be considered eligible and monitored with close ophthalmological monitoring.
• • J. History of pancreatitis.
• • K. History of central nervous system (CNS) or gastrointestinal (GI) haemorrhage within three months of trial entry.
• • L. Patients with any history of haemorrhagic stroke.
• • M. Prior treatment with the same class of drug unless presence of a resistance alteration known to be potentially sensitive to either vemurafenib or cobimetinib. Prior sorafenib use is permissible following a washout period of 10 days.
• • N. Any clinically significant concomitant disease or condition (or it's treatment) that could interfere with, the conduct of the trial or absorption of oral medications that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this trial.
• O. Known active infections (bacterial, fungal or viral) that would interfere with the assessment of safety or efficacy of vemurafenib and cobimetinib, including human immunodeficiency virus (HIV) positivity. Patients with history of testing positive for HIV infection are eligible provided the each of the following conditions are met:
• • CD4 count ≥350/μL;
• • undetectable viral load;
• • receiving antiretroviral therapy (ART) that does not interact with IMP (patients should be on established ART for at least four weeks); and
• • no HIV/ acquired immune deficiency syndrome (AIDS)-associated opportunistic infection in the last 12 months.