Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy
NCT Number: NCT06470880
Acronym: DyNAMIc
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Melanoma
Interventions: DRUG: Adaptive Therapy|DRUG: Standard of Care
Sponsor: The Christie NHS Foundation Trust
Collaborators: University of Manchester|University of Liverpool
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 40
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: SINGLE (PARTICIPANT)|Primary Purpose: TREATMENT
Start Date: 2024-06
Completion Date: 2027-06

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.

Primary Outcome Measures: To measure tumour response to re-introduction of encorafenib plus binimetinib following the first "drug off " period., 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., 3 years (Longitudinally throughout the study)
Secondary Outcome Measures: 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., Specific measure: ctDNA mutant BRAF copies/ml of plasma, 3 years (Longitudinally throughout the study)|To measure maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) to therapy in Arm A vs. Arm B, Specific measure: Maximal radiological response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria, Randomisation until RECIST progression/clinical deterioration (estimated 12 months)|To measure progression free survival (PFS) in Arm A vs. Arm B, 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, 3 years (Continuously throughout the study)|To measure time to clinical deterioration in Arm A vs. Arm B., 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, 3 years (Continuously throughout the study)|To measure overall survival in Arm A vs. Arm B, Specific measure: Overall survival (OS) defined as time from randomisation until death from any cause, 3 years (Continuously throughout the study)|To measure melanoma specific overall survival in Arm A vs. Arm B, Specific measure: Overall survival (OS) defined as time from randomisation until death from melanoma, 3 years (Continuously throughout the study)|To measure number of adaptive therapy cycles completed by participants on Arm B, Specific measure: Number of adaptive therapy cycles completed, 3 years (Longitudinally throughout the study)|To measure median duration of adaptive therapy cycles completed by participants on Arm B, Specific measure: Median duration of adaptive therapy cycles, 3 years (Longitudinally throughout the study)|To measure whether ctDNA result can be provided within 5 working days from sample receipt into NBC, Specific measure: Percentage of ctDNA results reported within 5 days from sample receipt into NBC, 3 years (Longitudinally throughout the study)|To measure quality of life in Arm A vs. Arm B, Specific measure: EORTC QLQ-C30 (standardised tool, scored as outlined by EORTC), 3 years (Longitudinally throughout the study)|To measure quality of life in Arm A vs. Arm B, Specific measure: PRO-CTCAE (standardised tool, scored as outlined by NIH), 3 years (Longitudinally throughout the study)|To measure toxicity (all grade adverse events) in Arm A vs. Arm B, Specific measure: Adverse Events and Serious Adverse Events defined by CTCAE version 5, 3 years (Continuously throughout the study)