| Eligibility |
Inclusion Criteria:
Informed consent
1. Signed written and voluntary informed consent.
2. Patient must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests and other study procedures.
3. Age > 18 years, male or female.
Disease characteristics
4. Patient must be diagnosed with a histologically or cytologically-documented,
locally-advanced, or metastatic solid malignancy that is incurable and has either (a)
failed prior standard therapy, (b) for which no standard therapy exists, or (c)
standard therapy is not considered appropriate by the patient and treating physician.
5. Measurable disease by RECIST v1.1 criteria.
6. Malignancy must express one of the following BRAF alterations: BRAF mutation affecting
codon: 241, 257, 367, 462, 463, 464, 466, 467, 469, 485, 581, 586, 594, 595, 596, 597
598, 599, 601; V600 BRAF mutations: V600K (for any malignancy except melanoma), V600D,
V600M, V600R; BRAF deletions ie. V600_K601delinsE or 1799_1801 del TGA; BRAF
insertions ie. T599dup; BRAF fusions ie. KIAA1549:BRAF
7. All patients enrolled must be willing and able to provide at least 1 archival and/or
fresh tumor biopsy at baseline for histopathological and molecular evaluation during
the screening period with binimetinib and encorafenib. Additional matched
pre-treatment and on-treatment fresh tumor biopsies are mandatory for 10 patients
enrolled in stage 2. Any patient with insufficient or inadequate archival tissue
samples will be required to provide a fresh tumor biopsy. For all other patients, a
fresh baseline biopsy is optional, but highly recommended. If a patient only has a
single measurable lesion by RECIST v1.1, this lesion can be used for baseline biopsy
if it is 2cm or greater.
8. Patient must be able to swallow pills
9. Patient must be willing to provide serial blood samples for molecular profiling of
ctDNA evolution
Patient characteristics
10. ECOG performance status 0-1.
11. Patient must have adequate organ function as determined by the following:
• Renal function: i. Serum creatinine < 1.5 ULN (upper limit of normal range) or a
calculated creatinine clearance of > 50mL/min using the following Cockcroft-Gault
formula:
Creatinine clearance = [(140-age) x wt (kg) x Constant*] / creatinine (umol/L)
*Constant = 1.23 for men, and 1.04 for women
• Bone marrow function (without hematopoietic growth factors or transfusion): i.
Absolute neutrophil count (ANC) > 1.0 x 109/L ii. Leukocytes > 2.0 x 109/L iii.
Hemoglobin > 90 g/L or > 9g/dL iv. Platelets > 75 x 109/L v. Previous blood
transfusions are acceptable, however patients must have achieved the above hemoglobin
and platelet targets without requiring a blood transfusion within 14 days prior to
study entry.
• Liver function: i. Total bilirubin = 1.5 × ULN and < 35 uMol/L; OR total bilirubin
>1.5 × ULN with indirect bilirubin < 1.5 × ULN. Total bilirubin < 1.5 x ULN or = 3 x
ULN for patients with Gilbert Syndrome.
ii. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) < 2
x ULN, unless patients are known to have liver metastases. For patients with known
liver metastases, Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase
(ALT/SGPT) < 5 x ULN
• Cardiac function: i. A normal left ventricular ejection fraction (LVEF) of = 50% by
a MUGA scan or echocardiogram performed within 4 weeks of the study commencement.
ii. QTc interval = 480 ms (triplicate ECGs)
12. Female participants of childbearing potential as described in Section 5.5.4, must have
a negative serum ß HCG test result.
13. Female participants of childbearing potential must agree to use methods of
contraception that are highly effective or acceptable, as described in Section 5.5.4,
and to not donate ova from Screening until 30 days after the last dose of study drug
14. Male participants must agree to use methods of contraception that are highly effective
or acceptable, as described in Section 5.5.4, and to not donate sperm from Screening
until 90 days after the last dose of study drug.
15. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
Exclusion Criteria:
Patients meeting any of the following criteria are excluded from the study:
1. Any patient with a tumor expressing a BRAF V600E mutation
2. Any patient with melanoma whose tumor expresses a BRAF V600K mutation
3. Prior therapy with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib)
and/or any MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).
4. Patients receiving any systemic chemotherapy, immunotherapy, or targeted therapy,
within 4 weeks from the last dose prior to study treatment. The patient can receive a
stable dose of bisphosphonates or denosumab for bone metastases, before and during the
study as long as these were started at least 4 weeks prior to treatment. Local
treatment (e.g. by local surgery or radiotherapy) of isolated lesions for palliative
intent is acceptable within 2 weeks, with prior consultation and in agreement with the
principal investigator.
5. Any symptomatic brain metastasis Note: Patients previously treated or untreated for
this condition who are asymptomatic in the absence of corticosteroid and
anti-epileptic therapy are allowed. Brain metastases must be stable for = 4 weeks,
with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT])
demonstrating no current evidence of progressive brain metastases at screening.
6. History or current evidence of retinal vein occlusion (RVO) or current risk factors to
RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes); history of retinal degenerative disease
7. Leptomeningeal disease
8. Previous or concurrent malignancy within 3 years of study entry, with the following
exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder
cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other
noninvasive or indolent malignancy; other solid tumors treated curatively without
evidence of recurrence for at least 3 years prior to study entry (note: based on
mechanism of action, BRAF inhibitors may cause progression of cancers associated with
RAS mutations)
9. Impaired cardiovascular function or clinically significant cardiovascular diseases,
including any of the following:
10. History of acute coronary syndromes (including myocardial infarction, unstable angina,
coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to
screening,
11. Symptomatic chronic heart failure (i.e. New York Heart Association Class = 2), history
or current evidence of clinically significant cardiac arrhythmia and/or conduction
abnormality <6 months prior to screening except atrial fibrillation and paroxysmal
supraventricular tachycardia;
12. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure =
150 mmHg or diastolic blood pressure = 100mmHg, despite current therapy;
13. Known positive serology for HIV (Human immunodeficiency virus) that is not currently
controlled with anti-retroviral therapy,
14. Has a known history of or is positive for active hepatitis B (defined as hepatitis B
surface antigen [HBsAg] reactive) or hepatitis C (defined as HCV RNA [qualitative] is
detected). HBV DNA must be undetectable and HBsAg negative at Screening Visit.
Participants who have had definitive treatment for HCV are permitted if HCV RNA is
undetectable at Screening Visit.
15. Known history of acute or chronic pancreatitis. Patients with previous history of
pancreatitis caused by immunotherapy are not excluded if pancreatitis is resolved.
16. History of chronic inflammatory bowel disease or Crohn's disease requiring medical
intervention (immunomodulatory or immunosuppressive medications or surgery) = 12
months prior to starting study treatment
17. Impaired gastrointestinal function or disease that may significantly alter the
absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled
vomiting, malabsorption syndrome, small bowel resection with decreased intestinal
absorption)
18. History of known hypercoaguability risk factors (other than cancer) ie. Factor V
Leiden. Patients with a history of previous DVT or PE who are currently asymptomatic
and treated with anticoagulation therapy are allowed.
19. Concurrent neuromuscular disorder that is associated with the potential of elevated CK
(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy)
20. Patients who are planning on embarking on a new strenuous exercise regimen after first
dose of study treatment. Note: Muscular activities, such as strenuous exercise, that
can result in significant increases in plasma CK levels should be avoided while on
binimetinib treatment
21. Any other condition that would, in the Investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g., active infection/inflammation requiring systemic
therapy, intestinal obstruction, unable to swallow medication, social/ psychological
issues, etc. Previous bacterial infections are acceptable if patients completed
antibiotic course 3 days prior to initiating study treatment.
22. Patients who have undergone major surgery = 3 weeks prior to starting study drug or
who have not recovered from side effects of such procedure;
23. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test;
24. Medical, psychiatric, cognitive or other conditions that may compromise the patient's
ability to understand the patient information, give informed consent, comply with the
study protocol or complete the study.
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