| Eligibility |
Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for enrolment
into the study:
1. Signed written informed consent;
2. Male or female participant, aged = 18 years;
3. Histologically/cytologically confirmed diagnosis of locally advanced, unresectable or
metastatic solid tumors;
4. Presence of BRAF V600E or V600K mutation in tumour tissue prior to enrolment, as
previously determined using a local test at any time prior to Screening - Only PCR and
NGS-based local assays results will be acceptable;
5. Evidence of measurable or non-measurable lesions as detected by radiological or
photographic methods according to guidelines based on Response Evaluation Criteria in
solid tumors (RECIST) v. 1.1;
6. Unresectable locally advanced or metastatic solid tumor with no prior treatment or
progression on or after prior systemic therapy; Note: Prior therapy with a BRAF
inhibitor is permitted except in the regimen immediately prior to study entry.
Progression during prior BRAF/MEK inhibitor treatment is not required;
7. Blood pressure (BP; after 5 minutes resting in the supine position) at screening
within the following ranges: systolics, 90 to 150 mm Hg, diastolic, 50 to 100 mm Hg;
8. ECOG PS of 0 or 1;
9. Adequate bone marrow, organ function and laboratory parameters:
1. Absolute neutrophil count (ANC) = 1.5 x 109/L,
2. Haemoglobin (Hgb) = 9 g/dL without transfusions,
3. Platelets (PLT) = 100 x 109/L without transfusions,
4. International normalized ratio (INR) < 3 at screening or baseline (Day -1),
5. Creatinine = 1.5 mg/dL and calculated creatinine clearance (determined as per
Cockcroft-Gault) = 50 mL/min,
10. Hepatic function criteria:
- Inclusion criteria for participant with normal hepatic function (group I) only :
1. Total bilirubin =1.5 upper limit of normal (ULN) at screening and baseline
(Day -1)
2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transferase, and alkaline phosphatase = 1.5ULN at screening and
baseline (Day -1)
3. Serum amylase <140 and lipase < 160ULN at screening and baseline (Day -1)
- Inclusion Criteria for participants with Hepatic impairment according to
Child-Pugh
Classification System only:
- Group II: Child-Pugh Class B or moderate hepatic impairment (7 to 9 points),
- Group III: Child-Pugh Class C or severe hepatic impairment (10 to 15 points),
11. Able to take oral medications
12. Deemed by the Investigator to have the initiative and means to be compliant with the
protocol (treatment and follow-up);
13. Female participant of childbearing potential must be tested negative for pregnancy at
enrolment and during the study: Note: Negative serum beta-human chorionic gonadotropin
(ß-HCG) test (childbearing performed within 72 hours prior to first dose and consent
to ongoing urine pregnancy testing during the course of the study and agreement to go
on using it during the whole duration of the study and up to 1 month after last
administration. Use of an effective method of contraception (hormonal contraception or
intra-uterine device) assessed by the Investigator, for at least 2 months before the
first study treatment administration, and agreement to go on using it in addition to
condom during the whole duration of the study through 30 days after last study
treatment administration.
14. Male participants with partners of childbearing potential must be either vasectomized
or agree to use a condom in addition to having their partners use of an effective
method of contraception. Note: For partner of male participant, contraception should
be employed from the time of consent through 90 days after last study treatment
administration.
15. Affiliated to a social security system, or is a beneficiary (if applicable in the
national regulation)
Exclusion Criteria
Participants meeting any of the following criteria are not eligible for enrolment in the
study:
1. A calculated Child-Pugh score that showed impairment for a reason other than liver
dysfunction (e.g., cancer, cachexia);
2. History or symptoms of encephalopathy (Grade II or worse) within 4 weeks of Day -1 or
subjetcs who were treated to control encephalopathy within 4 weeks of Day -1;
3. Clinical evidence of severe ascites (NCI-CTCAE grade 3 or 4);
4. History of surgical portosystemic shunt with complications (i.e., hepatic
encephalopathy, heart failure). Trans jugular intrahepatic portosystemic shunt could
have been allowed if not in use for =1 year;
5. Active bleeding during the last 28 days prior to dosing including variceal bleeding;
6. Anticoagulant therapy within 7 days prior to the first dose of study treatment (Day
1);
7. Any of the following:
1. Nitrosourea or mitomycin-C within 6 weeks prior to start of study treatment,
2. Other chemotherapy, radiation therapy that included > 30% of the bone, marrow
reserve, or biological therapy (e.g., antibodies) within 4 weeks prior to start
of study treatment,
3. Continuous or intermittent small-molecule therapeutics or investigational agents
within 5 half-lives of the agent or within 2 weeks prior to start of study
treatment, whichever is the longest,
4. Residual Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 side
effects of any such therapy (residual Grade 2 alopecia is permitted),
8. Discontinuation of prior BRAF and/or MEK inhibitor treatment due to severe,
intolerable toxicity including left ventricular dysfunction, pneumonitis/interstitial
lung disease, or retinal vein occlusion, CK elevation and rhabdomyolysis, uveitis;
9. Symptomatic brain metastasis; Note: Participants previously treated or untreated for
these conditions 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);
10. Leptomeningeal disease;
11. Use, within 2 weeks prior to the first dose of the study treatment (Day 1)any herbal
medications/supplements or any medications or foods that are moderate or strong
inhibitors or inducers of CYP3A4/5;
12. Human immunodeficiency virus (HIV) infection;
13. Active viral hepatitis (HBV-HCV) within 1 month before the first dose of study
treatment (Day 1);
14. Known history of acute or chronic pancreatitis;
15. Concurrent neuromuscular disorder that is associated with the potential of elevated
creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic
lateral sclerosis, spinal muscular atrophy;
16. History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes);
17. Clinically significant cardiac disease including any of the following:
1. Congestive heart failure requiring treatment (New York Heart Association Grade =
2),
2. Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO,
3. Uncontrolled hypertension defined as persistent systolic blood pressure = 150
mmHg or diastolic blood pressure = 100 mmHg despite current therapy,
4. History or presence of clinically significant ventricular arrhythmias or atrial
fibrillation,
5. Clinically significant resting bradycardia,
6. Unstable angina pectoris = 3 months prior to the start of study treatment,
7. Acute myocardial infarction = 3 months prior to the start of study treatment,
8. Mean triplicate QT interval corrected for heart rate using Fridericia's formula
(QTcF) value >480 msec,
18. Impaired gastrointestinal function or disease which may significantly alter the
absorption of study treatments (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhoea, malabsorption syndrome, small bowel resection);
19. History of chronic inflammatory bowel disease or Crohn's disease requiring medical
intervention (immunomodulatory or immunosuppressive medications or surgery) =12 months
prior to to starting study treatment the first dose of study treatment (Day 1);
20. Thromboembolic event (e.g. including transient ischemic attacks, cerebrovascular
accidents, deep vein thrombosis or pulmonary emboli) except catheter-related venous
thrombosis = 12 weeks prior to starting study treatment (Day 1); Note: Participants
with catheter-related thromboembolic events are allowed;
21. Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
treatment administration or that may interfere with the interpretation of study
results and, in the judgement of the Investigator, would make the participant
inappropriate for the study;
22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until termination of gestation, confirmed by a positive ß-
hCG laboratory test (> 5 mIU/mL);
23. Known hypersensitivity or contraindication to any component of study treatment or
their excipients;
24. Ongoing/active participation in another interventional clinical trial;
25. Has participated in another clinical trial with the administration of an
investigational product within 4 weeks, or five times the half-life of the
investigational product, whichever is longer, before the first dose of study treatment
(Day 1);
26. Is a family member of the Investigator or any associate, colleague, and employee
assisting in the conduct of the study (secretary, nurse, technician…).
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