DETERMINE Trial Treatment Arm 07: Dabrafenib in Combination With Trametinib in Adult, Paediatric and Teenage/Young Adult Patients With BRAF V600 Mutation-Positive Cancers.

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.

DETERMINE Treatment Arm 07 (dabrafenib and trametinib) aims to evaluate the efficacy of dabrafenib and trametinib adult, paediatric and TYA patients with rare* cancers with BRAF V600 mutations or with common cancers where BRAF V600 mutations are considered to be infrequent.

*Rare is defined generally as incidence less than 6 cases in 100,000 patients (includes paediatric and teenagers/young adult cancers) or common cancers with rare alterations.

This treatment arm has a target sample size of 30 evaluable patients. Sub-cohorts may be defined and further expanded to a target of 30 evaluable patients each.

The ultimate aim is to translate positive clinical findings to the NHS (Cancer Drugs Fund) to provide new treatment options for rare adult, paediatric and TYA cancers.

OUTLINE:

Pre-screening: The Molecular Tumour Board makes a treatment recommendation for the patient based on molecularly-defined cohorts (See information on Master Screening Protocol below).

Screening: Consenting patients undergo biopsy and collection of blood samples for research purposes.

Treatment: Patients will receive dabrafenib and trametinib until disease progression without clinical benefit, unacceptable adverse events (AEs) or withdrawal of consent. Patients will also undergo collection of blood samples at various intervals while receiving treatment and at End of Treatment (EoT).

After completion of study treatment, patients are followed up every 3 months for 2 years.

THE DETERMINE TRIAL MASTER (SCREENING) PROTOCOL: Please see DETERMINE Trial Master (Screening) Protocol record (NCT05722886) for information on the DETERMINE Trial Master Protocol and applicable documents.

THE PATIENT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL (NCT05722886) AND WITHIN THE TREATMENT ARM 07 (DABRAFENIB AND TRAMETINIB) OUTLINED BELOW* *When dabrafenib- and trametinib-specific inclusion/exclusion criteria or precautions below differ from those specified in the Master Protocol, the dabrafenib- and trametinib-specific criteria will take precedence.

Inclusion criteria:

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

Exclusion criteria:

A. Diagnosis of one of the following BRAF V600E mutation-positive cancers:

• Colorectal cancer in adult (≥18 years) patients;
• Unresectable or metastatic melanoma in adult (≥18 years) patients;
• Advanced non-small cell lung cancer in adult (≥18 years) patients;
• Gliomas harbouring a BRAF V600E mutation in paediatric (1 to <16 years) or TYA (16 to <18 years) patients.

B. Previous treatment with dabrafenib and trametinib in combination (or other BRAF and MEK inhibitors in combination) for the current indication.

C. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or for two weeks following their last dose of dabrafenib or 16 weeks following their last dose of trametinib, whichever is later.

D. Known hypersensitivity to dabrafenib or trametinib or any of the excipients. See the current relevant SmPCs (UK) for the full lists.

E. Patients with a history of retinal vein occlusion.

F. Any impairment of gastrointestinal (GI) function of uncontrolled GI disease that may significantly alter the administration or absorption of dabrafenib and/or trametinib (e.g. history of diverticulitis, metastases to the GI tract, uncontrolled Crohn's disease, uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome or short gut syndrome).

G. Clinically significant cardiac or cerebrovascular disease as defined by:

• Unstable angina within three months prior to screening;
• Myocardial infarction within three months prior to screening;
• History of documented congestive heart failure (New York Heart Association functional classification III/IV) etc.

Patients with a cerebrovascular event (including stroke or transient ischaemic attack [TIA]) within three months prior to screening.

• Patients with primary central nervous system (CNS) tumours may be considered unless intratumoural bleeding has occurred within two weeks prior to the first dose of dabrafenib and trametinib, and patients with punctate CNS haemorrhages <3 mm may be considered.

H. Patients who were administered a live, attenuated vaccine within 28 days prior to initiation of treatment, or anticipation of need for such a vaccine during investigational medicinal product (IMP) treatment or within six months after the final dose of dabrafenib and trametinib.

I. Known active infections (bacterial, fungal or viral) that would interfere with the assessment of safety or efficacy of dabrafenib and trametinib including human immunodeficiency virus (HIV) positivity. Patients with history of testing positive for HIV infection are eligible provided that 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 associated opportunistic infection in the last 12 months.

J. Any clinically significant concomitant disease or condition (or its treatment) that could interfere with the conduct of the trial (including absorption of oral medications) that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this trial.