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

Inclusion Criteria: 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. 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 >450ms for males and >470ms for females measured on triplicate ECG (if 1/3 readings show >450/470ms 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 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 G. 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. H. History of pancreatitis. I. History of central nervous system (CNS) or gastrointestinal (GI) haemorrhage within three months of trial entry. J. Patients with any history of haemorrhagic stroke. K. 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. L. Patients with rapidly progressing or symptomatically deteriorating brain metastases. Patients with previously treated brain metastases are eligible, provided the patient has not experienced a seizure or had a clinically significant change in neurological status within the 14 days prior to the start of IMP administration. Such patients must be non-dependent on steroids or on a stable or reducing dose of steroid treatment for at least 14 days prior to the start of IMP administration. Primary brain or CNS malignancies are allowed providing the patient is clinically stable (if requiring corticosteroids must be at stable or decreasing doses for at least 14 days prior to the start of IMP administration). Patients who have received brain irradiation must have completed whole-brain radiotherapy and/or stereotactic radiosurgery at least 14 days prior to the start of IMP administration. M. 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.