Inclusion Criteria:
1. Patient capable of giving written informed consent. 2. Patients must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests and other requirements of the study.
3. Histological confirmation of cutaneous melanoma. 4. ≥ 16 years. 5. Stage III un-resectable/ IV disease. 6. BRAF p.V600E/K/R mutation confirmed (exact point mutation must be provided to the
investigators)
7. At least one target lesion measurable by CT or MRI as per RECIST 1.1. 8. Baseline ctDNA (as defined by the mutant BRAF VAF in plasma) ≥1.5%
9. Adequate organ function. 10. ECOG performance status 0/1. 11. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior
to the first dose of study drug. 12. Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
hours prior to the start of study drug.
13. WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drugs plus 5 half-lives of the drugs they are
taking at treatment completion (5 times the half-life = 125 days [nivolumab]; 5
times the half-life = 90 days [ipilimumab]; 5 times the half life = 40 hours
[dabrafenib]; 5 times the half life = 50 days [trametinib]) plus 30 days (duration
of ovulatory cycle).
14. Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment plus 5 half-lives of the
study drug as above plus 90 days (duration of sperm turnover).
15. Azoospermic males and WOCBP who are continuously not heterosexually active are
exempt from contraceptive requirements.
Exclusion Criteria:
1. Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine
therapy, or investigational treatment) for unresectable Stage III or Stage IV
melanoma.
2. Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with
combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1
inhibitor is allowed so long as relapse occurred > 6 months from discontinuation of
treatment and treatment not stopped due to grade 3 or 4 toxicity.
3. Current use of a prohibited medication. 4. 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) or patients with a history of completely resected
non-melanoma skin cancer. No additional therapy should be required whilst the
patient is on study.
5. Any serious or unstable pre-existing medical conditions (aside from malignancy
exceptions specified above), psychiatric disorders, or other conditions that could
interfere with the patients safety, obtaining informed consent, or compliance with
study procedures.
6. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
Virus (HCV) infection (patients with laboratory evidence of cleared or chronic (not
active) HBV and HCV infection will be permitted).
7. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
8. Patients with active, known or suspected autoimmune disease. Patients with type 1
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger will be
permitted to enrol.
9. Patients with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within
14 days of study drug administration. Inhaled or topical steroids and adrenal
replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the
absence of active autoimmune disease.
10. Patients with interstitial lung disease that is symptomatic or may interfere with
the detection or management of suspected drug-related pulmonary toxicity.
11. Brain metastases and leptomeningeal metastases are excluded unless:
- - Asymptomatic and untreated at presentation, OR.
- - Symptomatic lesions have been definitively treated with surgery or stereotactic
surgery (whole-brain radiation may be given as adjuvant treatment), and do not
require steroids for control of symptoms.
- - Symptomatic metastases, treated or untreated, or metastases requiring steroids
to control symptoms, are excluded.
12. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomisation. 13. Coronary syndromes (including myocardial infarction within 6 months or unstable
angina)
14. A history or evidence of current ≥ Class II congestive heart failure as defined by
the New York Heart Association (NYHA) guidelines with an ejection fraction of <50%
15. 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;
16. Known cardiac metastases;
17. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia,
hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the
QT interval.
18. 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)
19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study treatments including monoclonal antibodies, their
excipients, and/or dimethyl sulfoxide (DMSO) and/or Polysorbate-80-containing
infusions.
20. Females who are breast-feeding.
21. Prisoners or patients who are involuntarily incarcerated.
22. Patients who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness.
