DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.
This clinical trial is looking at a combination of drugs called vemurafenib and cobimetinib. Vemurafenib is approved as standard of care for adult patients with unresectable or metastatic melanoma. Cobimetinib is approved as standard of care in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma. Cobimetinib and vemurafenib work in patients with these types of cancers which have certain changes in the cancer cells called BRAF V600 mutation-positive. Investigators now wish to find out if it will be useful in treating patients with other cancer types which are also BRAF V600 mutation-positive. If the results are positive, the study team will work with the NHS and the Cancer Drugs Fund to see if these drugs can be routinely accessed for patients in the future. This trial is part of a trial programme called DETERMINE. The programme will also look at other anti-cancer drugs in the same way, through matching the drug to rare cancer types or ones with specific mutations.
‣ A. Confirmed diagnosis of a malignancy harbouring any actionable BRAF V600 mutation using an analytically validated sequencing technique (result does not need to be confirmed at screening unless not tested within 18 months, in which case, repeat analysis is required).
‣ B. Adult patients ≥16 years old.
‣ C. Patients must be able and willing to undergo a fresh 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 x upper limit of normal (ULN)
‣ Patients with known Gilbert disease: total bilirubin ≤3.0 x ULN
‣ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 x 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 \<1.5x 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 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
• sexual abstinence
⁃ 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 (for example, condom plus spermicide) to prevent drug exposure of the foetus or neonate.