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 07: Dabrafenib in Combination With Trametinib in Adult, Paediatric and TYA Patients With BRAF V600 Mutation-Positive Cancers.
This clinical trial is looking at two drugs called dabrafenib and trametinib. Dabrafenib and trametinib are approved as standard of care treatment for adult patients with melanoma (a type of skin cancer) or lung cancer and in children with glioma (a type of brain tumour). This means they have gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Dabrafenib and trametinib work in patients with a particular mutation in their cancer known as BRAF V600. Investigators now wish to find out if they will be useful in treating patients with other cancer types which have the same mutation. 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 an oncogenic alteration in BRAF V600, including Langerhans cell histiocytosis, using an analytically validated next-generation sequencing method.
⁃ B. Patients ≥1 year old and ≥8 kg in body weight.
⁃ C. 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 one form of a non-hormonal highly effective contraception method (a method that can achieve a failure rate of \<1% when used consistently and correctly; the requirement for non-hormonal method is because dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives), such as: i. intrauterine device (IUD), ii. bilateral tubal occlusion, bilateral tubal ligation (at least six weeks before taking trial treatment), iii. vasectomised partner, iv. total sexual abstinence. Effective from the first administration of dabrafenib and trametinib (whichever is first), throughout the trial and for two weeks following discontinuation of dabrafenib and for 16 weeks following discontinuation of trametinib (whichever is later).
⁃ Patients who are breastfeeding must be willing to discontinue breastfeeding from the start of treatment, throughout the trial and for two weeks following discontinuation of dabrafenib and for 16 weeks following discontinuation of trametinib (whichever is later).
⁃ D. Male patients with partners who are women of childbearing potential are eligible provided that they agree to the following, from the first administration of dabrafenib and trametinib (whichever is first), throughout the trial and for two weeks after the last administration of dabrafenib and 16 weeks after the last administration of trametinib (whichever is later):
• Agree to take measures not to father children by using a barrier method of contraception (male condom plus spermicide) or to sexual abstinence.
• Non-vasectomised male partners with partners who are women of childbearing potential should also be advised of the benefit for their partner of using a highly effective method of contraception, such as:
• i. combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation \[oral, intravaginal or transdermal\]), ii. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), iii. IUD, iv. intrauterine hormone-releasing system (IUS), v. bilateral tubal occlusion, vi. total sexual abstinence.
• Male patients with pregnant or breastfeeding partners must be advised to use barrier method contraception (male condom) to prevent drug exposure of the foetus or neonate, even if vasectomised.
• Male patients must refrain from donating sperm for the same period.
⁃ E. Patients must be able and willing to undergo a fresh tissue biopsy at baseline and blood samples for translational research. Note that for patients with haematological malignancies or neuroblastomas, blood, bone marrow aspiration and/or trephine or lymph node biopsy samples may be taken.
⁃ F. Adequate organ function as per haematological and biochemical indices within the ranges defined in the protocol. These measurements should be performed to confirm the patient's eligibility