Skin cancer Cancer
Conditions
Interventions
Pre-screening:
Potentially eligible patients will provide consent for their tumour sample (already obtained for diagnosis) to be sent to the Manchester Centre for Genomic Medicine to undergo mutationa
Sponsors
The Christie NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histological confirmation of cutaneous melanoma 2. >=16 years 3. Stage IIB or IIC or IIIA melanoma. SLNB is highly encouraged to ensure accurate staging but is not mandatory. If no SLNB is to be performed then the primary must be at least TIIIA 4. Complete resection (adequate margins as determined by multi-disciplinary team or local/national guidelines, including SLNB if performed) must have been performed within 12 weeks prior to randomisation. If a patient is randomised to Arm A, treatment should be commenced no later than 14 weeks following surgery and with complete wound healing from surgery. 5. Disease-free status documented both clinically and radiologically within 4 weeks prior to randomisation 6. Mutation confirmed in BRAF (p.V600E, p.V600K and p.V600R) /NRAS (p.Q61R, p.Q61K, p.Q61L and p.G12D) /TERT promoter (c.146 C> T and c.124 C> T), which can be tracked in ctDNA with exact point mutation known 7. No prior immunotherapy, chemotherapy, vaccine therapy or BRAF/MEK targeted therapy 8. ECOG performance status 0/1 9. Adequate organ function: 9.1. WBC >=2.0 x 10e9/L 9.2. Absolute neutrophil count (ANC) >=1.5 x 10e9/L 9.3. Platelets >=100 x 10e9/L 9.4. Haemoglobin >=90 g/L 9.5. Creatinine clearance >30 ml/minute using Cockcroft-Gault 9.6. AST <=1.5 x ULN 9.7. ALT <=1.5 x ULN 9.8. Bilirubin <= 1.5 x ULN unless the patient has familial hyperbilirubinaemia) 10. Written informed consent
Exclusion criteria
Exclusion criteria: 1. Known severe medical or physiological or psychological co-morbidities conditions that would compromise or impede participation or contraindications to therapeutics 2. Pregnant or breastfeeding females 3. Current other malignancy or history of another malignancy within the last 3 years. Patients who have been disease-free for 3 years, (i.e., patients with second malignancies that have been definitively treated at least 3 years ago) or patients with a history of completely resected non-melanoma skin cancer or melanoma in situ are eligible. 4. In patients planned to have immune therapy only (including BRAF wild type), patients with active, known or suspected autoimmune disease are excluded from enrolment apart from those patients with the following conditions 4.1. Type 1 diabetes mellitus 4.2. Rheumatoid arthritis not requiring disease-modifying drugs 4.3. Hypothyroidism only requiring hormone replacement 4.4. Skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment 4.5. Autoimmune conditions not expected to recur in the absence of an external trigger. Many patients with these conditions have now been treated with immune therapy. A discussion about the potential risk of worsening of these conditions should be had with the patient prior to consent. 5. In patients planned to have immune therapy only (including BRAF wild type), patients with a condition requiring ongoing/long-term (> 3 months) systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications. Inhaled or topical steroids and adrenal replacement steroid doses < = 10 mg daily prednisolone equivalent are permitted in the absence of active autoimmune disease. 6. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. 7. History of allergies or adverse drug reaction to any of the of the intended standard of care therapies or to any monoclonal antibody. 8. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Recruitment rate assessed by a randomised patient count following a recruitment period of 12 months (aim is for =50 patients randomised) 2. The proportion of ctDNA results returned to site =10 working days from the sample being taken (aim is for this proportion to be 95% or above) | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Relapse-free survival (RFS) defined as time from randomisation to radiological or clinical (confirmed histologically) relapse or death from any cause 2. Distant metastatic-free survival (DMFS) defined as time from randomisation to radiological distant metastatic relapse or death from any cause 3. Overall survival (OS) defined as the time from randomisation to death from any cause 4. Time from randomisation in Arm B to detection of ctDNA for those patients who had a ctDNA positive result 5. The number of patients in Arm B with undetectable ctDNA (according to the DETECTION-2 assay) but with clinical/radiological relapse and site of relapse (local or distant in addition to organ site) over the course of the trial 6. Sites of local and distant metastatic relapse determined using clinical judgement or CT/PET/MRI scans over the course of the trial 7. Adverse events measured according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (coded using MedDRA) over the course of the trial | — |
Countries
England, United Kingdom
Outcome results
None listed