Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy
- Conditions
- Melanoma
- Interventions
- Drug: Adaptive TherapyDrug: Standard of Care
- Registration Number
- NCT06470880
- Lead Sponsor
- The Christie NHS Foundation Trust
- Brief Summary
The goal of this clinical trial is to investigate adaptive therapy in late-stage cutaneous melanoma. The main question it aims to answer are:
If the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour less resistant to the treatment, an increasing the time it takes for the disease to progress?
Participants will
* Receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first.
* Attend fortnightly visits to hospital.
* Complete EORTC QLQ-C30 and PRO-CTCAE questionnaires, prior to treatment, every 12 weeks and at the point of cancer progression, to assess quality of life.
Researchers will compare the adaptive therapy participant arm with a standard of care arm to answer the research question described above.
- Detailed Description
Encorafenib and binimetinib given in combination ("the treatment") is a standard of care treatment in the UK for late stage cutaneous melanoma, a skin cancer that starts in the cells that produce skin pigmentation. 'Late stage' means it can't be surgically removed, or has spread. The treatment is taken daily. Resistance to the treatment can develop after about 12-15 months. During this period, the treatment will kill the less resistant cells, meaning the tumour has a greater proportion of cells that are resistant to the treatment.
This study aims to investigate if the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour as a whole less resistant to the treatment, and increasing the time it takes for the disease to progress. A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every two weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume treatment. This intermittent treatment is called 'adaptive therapy'. The investigators intend to recruit 40 participants with late stage cutaneous melanoma from NHS hospitals in the UK. Ten will receive the standard, daily treatment, and thirty will receive adaptive therapy. Patients will receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first. As well as the fortnightly visits to hospital, patients will required to complete EORTC QLQ-C30 and PRO-CTCAE questionnaires in order for their quality of life to be assessed. These will be completed before their treatment starts; every 12 weeks from when they start treatment; and again if their cancer progresses.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 40
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ARM B: Adaptive therapy Adaptive Therapy 4 weeks of encorafenib 450mg once daily plus binimetinib 45mg twice daily, followed by adaptive cycles based on ctDNA TAB level ARM A: Standard of care Standard of Care Continuous dosing of encorafenib 450mg once daily plus binimetinib 45mg twice daily.
- Primary Outcome Measures
Name Time Method To measure tumour response to re-introduction of encorafenib plus binimetinib following the first "drug off " period. 3 years (Longitudinally throughout the study) Specific measure: Maximal reduction in percentage ctDNA mutant BRAF copies/ml of plasma from baseline 2 TAB level upon restart of E+B following first drug off period.
- Secondary Outcome Measures
Name Time Method To measure the thresholds of percentage reduction in TAB level in ctDNA as a measure of response to stop drugs and the percentage increase in TAB as a decision to restart drugs. 3 years (Longitudinally throughout the study) Specific measure: ctDNA mutant BRAF copies/ml of plasma
To measure progression free survival (PFS) in Arm A vs. Arm B 3 years (Continuously throughout the study) Specific measure: Percentage of participants who have experienced disease progression or death. PFS defined as time from randomisation to radiological (RECIST v1.1 and in Arm B defined as radiological progression whilst on targeted therapy unless stopped due to toxicity/choice) progression
To measure melanoma specific overall survival in Arm A vs. Arm B 3 years (Continuously throughout the study) Specific measure: Overall survival (OS) defined as time from randomisation until death from melanoma
To measure toxicity (all grade adverse events) in Arm A vs. Arm B 3 years (Continuously throughout the study) Specific measure: Adverse Events and Serious Adverse Events defined by CTCAE version 5
To measure overall survival in Arm A vs. Arm B 3 years (Continuously throughout the study) Specific measure: Overall survival (OS) defined as time from randomisation until death from any cause
To measure maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) to therapy in Arm A vs. Arm B Randomisation until RECIST progression/clinical deterioration (estimated 12 months) Specific measure: Maximal radiological response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria
To measure number of adaptive therapy cycles completed by participants on Arm B 3 years (Longitudinally throughout the study) Specific measure: Number of adaptive therapy cycles completed
To measure median duration of adaptive therapy cycles completed by participants on Arm B 3 years (Longitudinally throughout the study) Specific measure: Median duration of adaptive therapy cycles
To measure quality of life in Arm A vs. Arm B 3 years (Longitudinally throughout the study) Specific measure: PRO-CTCAE (standardised tool, scored as outlined by NIH)
To measure time to clinical deterioration in Arm A vs. Arm B. 3 years (Continuously throughout the study) Specific measure:Time to clinical deterioration. Defined as either the point of radiological progression (defined as per RECIST v1.1) or in participants treated beyond radiological progression, at the time of clinically determined deterioration defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer
To measure whether ctDNA result can be provided within 5 working days from sample receipt into NBC 3 years (Longitudinally throughout the study) Specific measure: Percentage of ctDNA results reported within 5 days from sample receipt into NBC