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

NCT05768178 | Recruiting Phase 2

• 2 other identifiers: CRUKD/21/004 - Treatment Arm 5IRAS ID: 1004057
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 16

Brief Summary

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. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. 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.

Conditions

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; Solid Tumour

Keywords

Adult; Antineoplastic Agents; Cancer; Malignancy; Malignant Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasms by Histologic Type; Neoplasms by Site; Precision Medicine; Cobimetinib; Proto-Oncogene Proteins B-raf; Rare; Tumour-agnostic; Vemurafenib

Outcome Measures

Primary Outcomes (2)

• 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 with 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) and, where relevant (e.g. for haematological malignancies), by standard bone marrow response assessment 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 Outcomes (11)

• Duration of response (DR)

  Disease assessment every 2 cycles (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits occur every 3 months after last dose of vemurafenib and cobimetinib for up to 2 years.

• Best percentage change in sum of target lesion / index lesion diameters (PCSD)

  Disease assessment every 2 cycles (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits occur every 3 months after last dose of vemurafenib and cobimetinib for up to 2 years.

• Time to treatment discontinuation (TTD)

  From first dose of vemurafenib and cobimetinib to discontinuation of trial treatment up to 5 years.

• Progression-Free Survival time (PFS)

  Disease assessment every 2 cycles (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits occur every 3 months after last dose of vemurafenib and cobimetinib for up to 2 years.

• Time to Progression (TTP)

  Disease assessment every 2 cycles (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits occur every 3 months after last dose of vemurafenib and cobimetinib for up to 2 years.

Study Arms (1)

Treatment Arm 05 - Vemurafenib and Cobimetinib

EXPERIMENTAL

This vemurafenib and cobimetinib treatment arm is for BRAF V600 mutation-positive cancers occurring in adults.

Drug: Vemurafenib; Drug: Cobimetinib

Interventions

Vemurafenib DRUG

Patients will receive vemurafenib at a dose of 960 mg orally (four tablets of 240 mg) on a twice daily schedule throughout a 28-day cycle. Patients may continue until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.

Also known as: Zelboraf

Treatment Arm 05 - Vemurafenib and Cobimetinib

Cobimetinib DRUG

Patients will receive cobimetinib at a dose of 60 mg (three 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. Patients may continue until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.

Also known as: Cotellic

Treatment Arm 05 - Vemurafenib and Cobimetinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• A. Confirmed diagnosis of a malignancy harbouring any actionable BRAF V600 mutation using an analytically validated next-generation sequencing method.
• B. Adult patients ≥18 years old.
• C. 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.
• D. 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.
• 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 sexual abstinence OR 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
• Effective methods:

Sponsors & Collaborators

• Cancer Research UK: lead
• University of Manchester: collaborator
• University of Birmingham: collaborator
• Royal Marsden NHS Foundation Trust: collaborator
• Hoffmann-La Roche: collaborator

Study Sites (16)

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

RECRUITING

University Hospital Birmingham

Birmingham, B15 2TT, United Kingdom

RECRUITING

Bristol Haematology and Oncology Centre

Bristol, BS2 8ED, United Kingdom

RECRUITING

Addenbrooke's Hospital

Cambridge, CB2 OQQ, United Kingdom

RECRUITING

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

RECRUITING

Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

RECRUITING

The Beatson Hospital

Glasgow, G12 OYN, United Kingdom

RECRUITING

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

RECRUITING

University College London Hospital

London, NW1 2BU, United Kingdom

RECRUITING

Guy's Hospital

London, SE1 9RT, United Kingdom

RECRUITING

The Christie Hospital

Manchester, M20 4BX, United Kingdom

RECRUITING

Clatterbridge Cancer Centre

Metropolitan Borough of Wirral, CH63 4JY, United Kingdom

RECRUITING

Freeman Hospital

Newcastle, NE7 7DN, United Kingdom

RECRUITING

Churchill Hospital

Oxford, OX3 7LE, United Kingdom

RECRUITING

Weston Park Hospital

Sheffield, S10 2SJ, United Kingdom

RECRUITING

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

RECRUITING

Related Links

• Overview of the DETERMINE trial
• ClinicalTrials.gov record for DETERMINE Trial Master Screening Protocol (NCT05722886).

MeSH Terms

Conditions

Hematologic Neoplasms; Melanoma; Thyroid Cancer, Papillary; Ovarian Neoplasms; Colorectal Neoplasms; Laryngeal Neoplasms; Carcinoma, Non-Small-Cell Lung; Glioma; Multiple Myeloma; Erdheim-Chester Disease; Thyroid Carcinoma, Anaplastic; Neoplasms; Neoplasms by Histologic Type; Neoplasms by Site

Interventions

Vemurafenib; cobimetinib

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma, Papillary; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Thyroid Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Gonadal Disorders; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Otorhinolaryngologic Neoplasms; Laryngeal Diseases; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Otorhinolaryngologic Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Thoracic Neoplasms; Lung Diseases; Neoplasms, Neuroepithelial; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Matthew Krebs, Dr

  The Christie Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Aida Sarmiento Castro

CONTACT

+44 207 242 0200; determine@cancer.org.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2023
• First Posted: March 14, 2023
• Study Start: March 1, 2023
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029
• Last Updated: November 24, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: All requests for data relating to this treatment arm that are made within 5 years from last patient last visit for the vemurafenib and cobimetinib treatment arm will be considered; requests made subsequently will be considered where possible.
• Access Criteria: When a request has been approved, Cancer Research UK will provide access to the de-identified individual patient-level data and appropriate supporting information. A signed Data Sharing Agreement must be in place before accessing requested information. Requests should be submitted to drugdev@cancer.org.uk.

Locations

GB (16)