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

Official title

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.

Overview

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.

Detailed description

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 BRAF V600 mutations are 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 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 patient based on molecularly-defined cohorts.

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

Treatment: Patients will receive vemurafenib and cobimetinib 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.

Interventions

• Drug Vemurafenib
  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.
• Drug Cobimetinib
  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.

Primary outcome measures

• Objective Response (OR) [Time frame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.]
• Durable Clinical Benefit (DCB) [Time frame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.]

Secondary outcome measures (11)

• Duration of response (DR) [Time frame: 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) [Time frame: 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) [Time frame: From first dose of vemurafenib and cobimetinib to discontinuation of trial treatment up to 5 years.]
• Progression-Free Survival time (PFS) [Time frame: 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) [Time frame: 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.]
• Growth Modulation Index (GMI) [Time frame: 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.]
• Overall Survival time (OS) [Time frame: Time of death or up to 2 years after the EoT visit.]
• Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR) [Time frame: 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/or cobimetinib related AE [Time frame: 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-C30 Standardised Area Under Summary Score Curve (QLQSAUC) [Time frame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]
• EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) [Time frame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]

Eligibility criteria

THE PATIENT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL (NCT05722886) AND WITHIN THE TREATMENT ARM 05 (VEMURAFENIB AND COBIMETINIB) OUTLINED BELOW\*

\*When vemurafenib and cobimetinib-specific inclusion/exclusion criteria or precautions below differ from those specified in the Master Protocol, the vemurafenib and cobimetinib-specific criteria will take precedence.

Inclusion criteria

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:
• 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 (e.g. condom) to prevent drug exposure of the foetus or neonate.

All male patients must refrain from donating sperm for the same period.

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 >450 ms for males and >470 ms for females measured on triplicate ECG (if 1/3 readings show >450/470 ms 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 unable to swallow vemurafenib and cobimetinib intact, without chewing or crushing the tablets (as per the dosing schedule).

G. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during vemurafenib and cobimetinib treatment or within six months after the final dose of vemurafenib and cobimetinib.

H. 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 congestive heart failure,
• Left ventricular ejection fraction (LVEF) <50%,
• Myocardial infarction

I. 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.

J. History of pancreatitis.

K. History of central nervous system (CNS) or gastrointestinal (GI) haemorrhage within three months of trial entry.

L. Patients with any history of haemorrhagic stroke.

M. 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.

N. Any clinically significant concomitant disease or condition (or its 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.

O. Known active infections (bacterial, fungal or viral) that would interfere with the assessment of safety or efficacy of vemurafenib and cobimetinib, including human immunodeficiency virus (HIV) positivity. Patients with history of testing positive for HIV infection are eligible provided the 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 16 centers

• Belfast City Hospital — Belfast
• University Hospital Birmingham — Birmingham
• Bristol Haematology and Oncology Centre — Bristol
• Addenbrooke's Hospital — Cambridge
• Velindre Cancer Centre — Cardiff
• Western General Hospital — Edinburgh
• The Beatson Hospital — Glasgow
• Leicester Royal Infirmary — Leicester
• … and 8 more centers

Identifiers

NCT: NCT05768178 · CRUKD/21/004 - Treatment Arm 5 · IRAS ID: 1004057

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗