Assessing if stopping and starting standard of care medication for later stage melanoma can reduce the body's resistance to the treatment
- Conditions
- Cutaneous melanomaCancerMalignant melanoma of skin, unspecified
- Registration Number
- ISRCTN14643179
- Lead Sponsor
- The Christie NHS Foundation Trust
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 40
Patients eligible for the trial must comply with all of the following at randomisation:
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 mutation confirmed (exact point mutation must be known)
7. BRAF ctDNA TAB level of =15 copies/ml of plasma
8. ECOG performance status 0/1/2
9. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs
10. Adequate organ function as defined below:
10.1. Haemoglobin =9 g/dL
10.2. White blood count =2 x 10(9)/L
10.3. ANC =1.2 x 10(9)/L
10.4. Platelet count =75 x 10(9)/L
10.5. Albumin =2.5 g/dL
10.6. Total bilirubinb =1.5 x ULN
10.7. AST or ALT =3 x ULN
10.8. Calculated creatinine clearance =30 ml/min
10.9. Left Ventricular Ejection fraction (LVEF) =50% or =LLN by ECHO
11. Women of childbearing potential participating in the study (WOCBP) 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
12. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month following last dose of drug (either encorafenib or binimetinib)
13. 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)
14. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP participating in the study who are continuously not heterosexually active must still undergo pregnancy testing (as described in inclusion criterion 11)
Any patient meeting any of the criteria listed below at baseline will be excluded from study participation:
1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS =6 months 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 the protocol
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%
14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg 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 QTC interval =480 msec) 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 (as described in the protocol)
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Maximal reduction in percentage mutant copies/ml (ctDNA mutant BRAF copies/ml of plasma) from baseline 2 TAB level upon restart of drugs following first drug off period. Measured longitudinally throughout the study.
- Secondary Outcome Measures
Name Time Method