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

Study Overview
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Brief Summary
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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.

Detailed Description
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DETERMINE Treatment arm 05 (vemurafenib and Cobimetinib) aims to evaluate the efficacy of vemurafenib and cobimetinib in adult patients with rare* cancers with BRAF V600 mutations or in common cancers where BRAFV600 mutations and considered to be infrequent. *Rare is defined generally as incidence less than 6 cases in 100,000 patients 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 where promising activity is identified 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 cancers. OUTLINE: Pre-screening: The Molecular Tumour Board makes a treatment recommendation for the participant based on molecularly-defined cohorts. Screening: Consenting participants undergo biopsy and collection of blood samples for research purposes. Treatment: Participants will receive vemurafenib and cobimetinib until disease progression, unacceptable toxicity or withdrawal of consent. Participants will also undergo collection of blood samples at various intervals while receiving treatment and at 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.

Official Title
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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.

Conditions
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Solid Tumor, Haematological Malignancy, Melanoma, Thyroid Cancer, Papillary, Ovarian Neoplasms, Colorectal Neoplasms, Laryngeal Neoplasms, Carcinoma, Non-Small-Cell Lung, Glioma, Multiple Myeloma, Erdheim-Chester Disease, Thyroid Carcinoma, Anaplastic

Intervention / Treatment
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* Drug: Vemurafenib
* Drug: Cobimetinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 05- Vemurafenib and Cobimetinib<br>This vemurafenib and cobimetinib appendix is for BRAF V600 mutation-positive malignancies occurring in adults. | Drug: Vemurafenib<br>* Participants will receive vemurafenib at a dose of 960 mg orally on a twice daily schedule throughout a 28-day cycle.<br>* Other names: Zelboraf;Drug: Cobimetinib<br>* Participants will receive cobimetinib at a dose of 60 mg (3 tablets of 20 mg) to be taken orally, once daily for 21 consecutive days (days 1 to 21 in each 28-day cycle); followed by a 7-day break.<br>* Other names: Cotellic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related (ir)-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria (RANO)). In patients with leukaemia, OR will be defined as the occurrence of CR , CRi (CR incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval. | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | 
| Durable Clinical Benefit (DCB) | DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria). Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval. | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DR) | Duration of response, is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria to the date of disease progression. The trial will report the median DR and 95% credible interval. | Disease assessment every 2 cycles (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits occur every 12 weeks after last dose of vemurafenib and cobimetinib for up to 2 years. | 
| Best percentage change in sum of target lesion / index lesion diameters (PCSD) | PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 28 days). After 24 weeks, disease assessments can be repeated every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks following last dose for a period of up to 2 years. | 
| Time to treatment discontinuation (TTD) | TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval. | From first dose of vemurafenib and cobimetinib to discontinuation of trial treatment up to 5 years. | 
| Progression-Free Survival time (PFS) | PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution. | Disease assessment performed every 2 cycles (each cycle is 28 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks after last dose of vemurafenib and cobimetinib for up to 2 years. | 
| Time to Progression (TTP) | TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 28 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks after last dose of vemurafenib and cobimetinib for up to 2 years. | 
| Growth Modulation Index (GMI) | GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 28 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks after last dose of vemurafenib and cobimetinib for up to 2 years. | 
| Overall Survival time (OS) | OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution. | Time of death or up to 2 years after the End of Treatment (EoT) visit. | 
| Occurrence of at least one Suspected Unexpected Serious Adverse Event (SUSAR) | The trial will report the number of patients who experience at least one SUSAR to vemurafenib and cobimetinib. | From the time of consent until 28 days after last dose of vemurafenib or cobimetinib (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry. | 
| Occurrence of at least one Grade 3, 4 or 5 vemurafenib and cobimetinib related AE | Number of patients who experience at least one vemurafenib and cobimetinib related Grade 3, 4 or 5 AE according to NCI CTCAE Version 5.0. | From the time of consent until 28 days after last dose of vemurafenib or cobimetinib (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry. | 
| EORTC-QLQ-30 Standardised Area Under Summary Score Curve (QLQSAUC) | Multiple measures of QoL will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQC30 (EORTC-QLQC30) questionnaire (30 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval. | QoL surveys performed at baseline every 2 cycles (every cycle is 28 days) and after interrupting treatment (up to 5 years). | 
| EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) | Two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 28 days) and at EoT visit (up to 5 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms by Site, Adult, Antineoplastic Agents, Cancer, Malignancy, Malignant Neoplasms, Molecular Targeted Therapy, Mutation, Neoplasms by Histologic Type, Precision Medicine, Cobimetinib, Proto-Oncogene Proteins B-raf, Rare, Tumour-agnostic, Vemurafenib