Melanoma
Conditions
Keywords
Adaptive Therapy
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.
Interventions
DRUGAdaptive Therapy
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 encorafenib and binimetinib treatment. This intermittent treatment is called 'adaptive therapy'.
DRUGStandard of Care
Encorafenib and binimetinib delivered to UK standard of care.
Sponsors
University of Manchester
University of Liverpool
The Christie NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
At Screening 1. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma 3. ≥ 18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1) 6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known) 7. ECOG performance status 0/1/2 8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 9. Adequate organ function as defined below: i. Haemoglobin ≥ 9 g/dL ii. White blood count ≥ 2 x109/L iii. ANCa ≥ 1.2 x109/L iv. Platelet count ≥ 75 x109/L v. Albumin ≥ 2.5 g/dL vi. Total bilirubinb ≤ 1.5 x ULNa vii. ASTa or ALTa ≤ 3 x ULNa viii. Calculated creatinine clearance ≥ 30ml/min 10. Women of childbearing potential participating in the study (WOCBP see Appendix B for definition) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug. 11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 28 days following last dose of drug (either encorafenib or binimetinib), (see Appendix B). 12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib), (see Appendix B). At randomisation: 13. Left Ventricular Ejection fraction (LVEF) ≥ 50% or ≥LLNa by ECHO 14. BRAF ctDNA TAB level of ≥15 copies/ml of plasma
Exclusion criteria
1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs) 2. BRAF wild-type malignant melanoma 3. Metastasis to the brain or leptomeninges 4. Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in Section 8.9 7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study 8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 11. Child Pugh B or C liver disease 12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina) 13. A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of \<50% (see appendix C) 14. Treatment refractory hypertension defined as a blood pressure of systolic \>150 mmHg and/or diastolic \>95 mm Hg on \>3 occasions which cannot be controlled by anti-hypertensive therapy 15. Uncorrectable electrolyte abnormalities \> CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥ 480msec) or taking medicinal products known to prolong the QT interval 16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes) 17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (see section 7.5) 18. Prisoners or patients who are involuntarily incarcerated 19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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 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 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 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 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 |
| To measure quality of life in Arm A vs. Arm B | 3 years (Longitudinally throughout the study) | Specific measure: EORTC QLQ-C30 (standardised tool, scored as outlined by EORTC) |
| 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 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 |
Contacts
Primary ContactTrial Project Manager
Backup ContactResearch Group Project Manager
Outcome results
None listed