DETECTION-2

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:

a. WBC > = 2.0x109/L,

b. Absolute neutrophil count (ANC) > = 1.5x109/L,

c. Platelets > = 100 x109/L,

d. Haemoglobin > = 90 g/L,

e. Creatinine clearance > 30mL/minute using Cockcroft-Gault,

f. AST < = 1.5 x ULN,

g. ALT < = 1.5 x ULN,

h. Bilirubin < = 1.5 x ULN unless the patient has familial hyperbilirubinaemia).

10. Written informed consent 

1. Known severe medical or physiological or psychological co-morbidities conditions that would compromise or impede participation or contraindications to therapeutics.

2. Pregnant or breast-feeding 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;

• Type 1 diabetes mellitus

• Rheumatoid arthritis not requiring disease modifying drugs

• Hypothyroidism only requiring hormone replacement

• Skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment

• 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 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. 

Research Nurse: Carolyn Hatch (x3921) Carolyn.Hatch@lthtr.nhs.uk

Administrator: Bethany Webster (x8475)