The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At
present, patients are treated with targeted therapy until acquired resistance develops, and
then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results
in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors
but not resistant have been shown to have increased T cell infiltration, improved T cell
recognition of melanoma associated antigens and reduced production of immunosuppressive
cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with
decreased response to immune therapy reduces, which may improve efficacy of immunotherapy.
A precise definition of response is required in order to decide upon a switch to immune
therapy. A radiological definition of response is currently the standard assessment. However
a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response
dynamics or allow decision making on an individual patient basis. The investigators have
developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which
are able to accurately monitor tumour burden over time.
The aim of this pilot study is to provide a signal as to whether:
1. In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to
pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib.
2. Changes in ctDNA levels can be used to accurately inform when to switch from targeted to
immune therapy.
Data from this study will provide the basis for follow on studies with sufficient power to
assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can
improve efficacy of immune therapy.
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.
