Study participants will consist of metastatic melanoma patients harboring BRAFV600E/K
mutation without previous frontline therapy or recently started treatment with up to 6 weeks
of targeted therapy (or > 6 months from adjuvant therapy). Toxicity from prior treatment must
have resolved to ≤ Grade 1 and not included previous Grade 3-4 immune-related adverse events
(irAEs) that required treatment discontinuation or previous Grade 2 immune-related uveitis or
pneumonitis.
Phase I, Cohort 1: Twelve patients will be treated with 300mg encorafenib and 3mg/kg
nivolumab and 1 mg/kg ipilimumab. The dose limiting toxicity (DLT) for cohort 1 will be
evaluated between weeks 1-6.
Phase I, Cohort 2: Upfront quadruple therapy with 450mg encorafenib, 45mg binimetinib, 3mg/kg
nivolumab and 1mg/kg ipilimumab will be investigated with 12 participants. DLT window for
phase I, cohort 2 will be evaluated at weeks 1-6.
Upon establishment of RP2R schedule, only participants with advanced melanoma who are
treatment naïve in metastatic setting or have had up to 6 weeks of targeted therapy or who
have progressed on adjuvant therapy for more than 6 months following completion of adjuvant
therapy (either BRAF-MEK or PD1 Ab) will be eligible for participation in high risk disease
cohort expansion (Groups 1 or 2).
Phase II will employ the RP2D schedule from Phase I and investigate the early efficacy in
participants with high risk features who are less likely to derive benefit from standard
treatment approaches and who may benefit from quadruple therapy despite the potential for
increased toxicity. These will include: Group 1) symptomatic brain metastases [up to 30
patients] and Group 2) Elevated LDH >1x upper limit of normal (ULN) with: a) liver metastases
OR b) bulky visceral disease (sum of longest diameter (SLD) > 44mm) [combined with Group 1 up
to 60 total patients].
Following initiation of triple or quadruple therapy, participants will be followed for safety
and response. Safety assessments will be a high priority with on-going Bayesian toxicity
monitoring and efficacy assessments every 12 weeks. Based on prior targeted, immune, and
triplet therapy studies, we anticipate up to 30-50% DLT and will consider temporary
suspension of trial enrollment with a DLT > 75% as determined by CTCAEv5. Treatment efficacy
will be documented using RECIST 1.1 and RANO-BM criteria, recorded every 4-12 weeks, and
immune-RECIST (iRECIST) and immune-RANO (iRANO) criteria.
Inclusion Criteria:
1. Signed Written Informed Consent
1. Participants must have signed and dated an IRB/IEC approved written informed
consent form in accordance with regulatory and institutional guidelines. This
must be obtained before the performance of any protocol-related procedures that
are not part of normal subject care.
2. Participants must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, and other requirements of the study.
2. Age ≥18 years
3. Histologically confirmed diagnosis of unresectable or metastatic melanoma
4. Presence of BRAFV600E/K mutation in tumor tissue as determined in a CLIA certified
laboratory
5. Patients are required to submit archival biopsy material, if available, and submit
research blood samples prior to first dose. Ten patients in each Phase Ib cohort will
undergo fresh biopsy. These will be the first 10 unless medical or societal factors
(e.g. COVID19) limit the pursuit of research biopsies.
6. Patients must be greater than 6 months from completion of adjuvant therapy (if any
given) and/or treatment naïve in the metastatic setting or have recently started
targeted therapy within the last 6 weeks.
7. Prior radiotherapy must have been completed at least 2 weeks prior to study drug
administration.
8. An ECOG Performance Status of 0 or 1. If enrolling in Group 1 of Phase II, can have
Performance Status from 0-2.
9. Measurable disease by CT or MRI per RANO-BM (brain metastases) OR RECIST v1.1 criteria
10. Must have high risk features described as described in Phase II expansion cohort -
EITHER brain metastases as described in Phase II Group 1 OR Elevated LDH/Bulky
Visceral Disease as described in Phase II Group 2.
11. Adequate bone marrow, organ function, and laboratory parameters:
1. ANC > 1.5 x 109 ¬ /L;
2. Hemoglobin > 8 g/dL with or without transfusions;
3. Platelet > 100 x 109 ¬ /L;
4. Serum creatinine ≤ 1.5 × ULN, OR calculated creatinine clearance > 50 mL/min by
Cockcroft-Gault formula, OR estimated glomerular filtration rate > 50 mL/min/1.73
m
12. Patient IS permitted to be on corticosteroids if related to disease burden and MAY
have symptomatic brain lesions as long as radiation or surgical intervention is not
deemed to be urgently necessary.
1. Symptomatic intracranial metastases may be on steroids at a total daily dose of
no higher than 4 mg of dexamethasone or equivalent that is stable or tapering for
10 days prior to first treatment,
2. have no immediate need for SRT or surgery (within 3 week prior to first
treatment),
3. have a performance status of 0-2 and
4. have had no experience of seizure within 10 days prior to first treatment.
13. Female patients of childbearing potential must have a negative serum β-HCG test result
during screening prior to first dose
14. Females of childbearing potential must agree to protocol-approved methods of
contraception, and to not donate Ova from Screening until 30 days of last dose of
study drug.
15. Male patients must use contraception that is highly effective or acceptable, and not
donate sperm from Screening until 90 days after the last dose of study drug.
16. The patient is deemed by the Investigator to have the initiative and means to comply
with scheduled visits, treatment plan and study procedures.
Exclusion Criteria:
1. Known hypersensitivity or contraindication to any component of study treatment or
their excipients.
2. Previous Grade 3-4 AEs, or discontinuation of PD-1 or CTLA-4 inhibitor therapy, or
BRAF/MEK inhibitor therapy
3. Inability to swallow and retain study treatment
4. Impairment of gastrointestinal function or disease which may significantly alter the
absorption of study treatment (e.g., active ulcerative disease; uncontrolled nausea,
vomiting or diarrhea; malabsorption syndrome; small bowel resection).
5. Participants with a non-melanoma related condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease.
6. Participants with active, known or suspected autoimmune disease including those who
have required systemic anti-rheumatic therapies in the preceding 2 years. Participants
with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll.
7. Impaired cardiovascular function or clinically significant cardiovascular disease
including, but not limited to, the following:
1. History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6
months prior to Screening
2. Congestive heart failure requiring treatment (New York Heart Association Grade ≥
2)
3. A known LVEF < 50% as determined by MUGA or ECHO
4. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150
mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy
5. History or presence of clinically significant cardiac arrhythmias (including
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal
supraventricular tachycardia)
6. Baseline QTcF interval ≥ 480 ms.
8. Second malignancy that requires active treatment or would interfere with treatment
efficacy evaluation. Participants with a second malignancy treated with curative
intent are eligible.
9. On-going or use of systemic antibiotics during the preceding 2 weeks prior to
enrollment
10. Known acute or chronic infection with hepatitis B or hepatitis C virus. Participants
treated with curative anti-viral therapy are eligible.
11. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART-due to
the unknown effects of HIV on the immune response to combined nivolumab plus
ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV.
12. History of a thromboembolic event < 12 weeks prior to starting study treatment.
Examples of thromboembolic events include transient ischemia attack, cerebrovascular
accident, deep vein thrombosis or pulmonary embolism. Catheter-related venous
thrombosis is not considered a thromboembolic event for this trial even if < 12 weeks
prior to starting study treatment.
13. Use of herbal supplements, medications or foods that are moderate or strong inhibitors
or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start of study
treatment (Section 4.5.1).
14. History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled
glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability
syndromes); history of retinal degenerative disease.
Phase II Group 1 Specific Criteria
1. For Phase II Group 1 (Brain Metastases): Patients may have an ECOG status of 0-2 and IS
permitted to be on corticosteroids if related to disease burden and MAY have symptomatic
brain lesions as long as radiation or surgical intervention is not deemed to be urgently
necessary.
1. Symptomatic intracranial metastases may be on steroids at a total daily dose of no
higher than 4 mg of dexamethasone or equivalent that is stable or tapering for 10 days
prior to first treatment,
2. have no immediate need for SRT or surgery (within 3 week prior to first treatment),
3. have had no experience of seizure within 10 days prior to first treatment.
