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|NCT02537600 : Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis|
|Ages||Min: 18 Years Max: N/A|
1. Men and women = 18 years of age.
2. Histologically confirmed metastatic cutaneous melanoma, mucous melanoma, or melanoma
of unknown primary origin (stage IV).
3. Documented BRAFV600 mutation determined in a hospital center specializing in the
molecular genetics of cancer that is certified by the French national cancer institute
4. Presence of Brain Metastases (BM) for which surgical resection is not a reasonable
treatment option but that may be amenable to treatment with targeted therapy, to be
decided in the onco-dermatology and/or neuro-oncology multidisciplinary team meeting
5. At least one measurable BM in at least one dimension between 5 and 40 mm on magnetic
resonance imaging (MRI) with gadolinium (modified RECIST 1.1).
6. Patients having previously received a maximum of two systemic therapies during the
metastatic phase, except BRAF, Map ERK Kinase (MEK) or Extracellular signal Regulated
Kinase (ERK) inhibitors or tyrosine kinase pan-inhibitors (TKIs); prior ipilimumab
therapy is allowed if patients have documented cerebral progression 12 weeks after the
last injection of treatment and if MRI confirms progression at least 4 weeks later. A
period of at least 6 weeks must be observed between the last dose of ipilimumab and
the first administration of the study treatments. Prior treatment with anti-programmed
cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
7. For patients who have received prior whole brain radiotherapy or radiosurgery and/or
surgery for BM (cohorts B and C) demonstration of a significant progression of at
least one lesion according to RECIST 1.1 criteria, . after at least 4 weeks have
elapsed since this treatment has ended, and MRI at inclusion must demonstrate a
significant progression of at least one lesion according to RECIST 1.1 criteria.
8. Patients with symptomatic or asymptomatic BM.
9. Eastern Cooperative Oncology Group (ECOG) performance status = 2.
10. Patients must have recovered from all the side effects (grade = 1 according to the
National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-Common
Toxicity Criteria for Adverse Event (CTCAE), version 4.03) of their most recent
systemic or local treatment (except alopecia).
11. Signed and dated informed consent before carrying out any procedures that are specific
to the trial and are not procedures (examinations) conducted as part of normal patient
12. Patients willing and able to comply with scheduled visits, treatment schedule,
laboratory testing and other trial procedures.
13. Negative serum pregnancy test within 10 days of the first dose of the study treatment
for women of childbearing age. Women of non-childbearing potential may be included if
they are surgically sterile or postmenopausal for = 1 year.
14. Fertile men and women must use an effective method of contraception during treatment
and for at least 6 months after the last administration of the study treatment.
Effective methods of contraception are defined as those that have a low failure rate
(i.e. less than 1% per year) when used consistently and correctly, such as injectable
implants combined with oral contraception or intra-uterine devices, or as total
abstinence in cases where the lifestyle of the patient ensures compliance.
15. Adequate hematologic, renal and hepatic function within 14 days of the administration
Hematologic Leucocytes > 2.0 x 109/L Neutrophils > 1.0 x 109/L Hemoglobin (transfusion
allowed) > 9 g/dL Platelets > 100 x 109/L Liver Total bilirubin < 1.5 x upper limit of
normal (ULN) (< 3.0 mg/dL for patients with Gilbert syndrome) Aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if there is liver metastasis)
Alkaline phosphatase (ALP) < 3 x ULN (< 5 x ULN if there is liver or bone metastasis)
Kidney Creatinine Or creatinine clearance < 1.5 x ULN = 40 mL/min (Cockcroft-Gault formula)
1. Uveal melanoma. Patients with mucous melanoma or melanoma of unknown primary origin
are eligible if BRAFV600 mutation is confirmed.
2. Symptomatic or diffuse leptomeningeal involvement.
3. Symptoms of uncontrolled intracranial pressure. Increasing corticosteroid dose during
the 7 days prior to the first dose of the study treatment is an exclusion criterion.
Patients receiving corticosteroids and patients presenting intermittent seizures may
be enrolled if the dose of corticosteroids and anti-epileptic treatments has been
stable for at least 2 weeks before inclusion.
4. Indication for urgent neurosurgery or radiotherapy.
5. Prior malignancy active within the previous 3 years except for locally curable cancers
that have been treated to complete remission or untreated stage I chronic lymphoid
6. Known human immunodeficiency virus (HIV) infection.
7. Prior treatment with BRAF, MEK, or ERK inhibitors or pan-TKIs.
8. Concurrent administration of any anticancer therapies other than those administered in
9. Treatment with any cytotoxic and/or investigational drug or targeted therapy within 4
weeks of the first dose of the study treatment, or ipilimumab, anti-PD-1 or anti-PD-L1
immunotherapy within 8 weeks of the study treatment and/or radiation therapy within 2
weeks of the study treatment.
10. Pregnant or breastfeeding women.
11. Refractory nausea and vomiting, intestinal malabsorption, or significant bowel
resection that would preclude adequate absorption or cause an inability to swallow
12. Ulcerative colitis, erosive esophagitis or gastritis, infectious or inflammatory bowel
disease, diverticula or other gastrointestinal condition increasing the risk of
13. Any of the following within the 6 months prior to the first dose of study treatment:
- myocardial infarction,
- severe/unstable angina,
- symptomatic congestive heart failure (New York Heart Association grade =2),
- cerebrovascular accident or transient ischemic attack,
- pulmonary embolism,
- grade > 2 hypertension not controlled by medications.
14. History or presence of clinically significant ventricular or atrial arrhythmia = grade
2 (NCI-CTCAE Version 4.03).
15. Corrected QT (cQT) interval = 450 ms and left ventricular ejection fraction (LVEF)
below the lower limit of normal (LLN) or < 50% (scintigraphy or ultrasound).
16. History, risk factor or retinal pathology that increases the risk of retinal vein
occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology
that is considered a risk factor for RVO or CSR, or a history of retinal detachment,
central serous chorioretinopathy or retinal vein thrombosis. The risk factors for RVO
are listed below:
- Uncontrolled glaucoma with intraocular pressures > 21 mm Hg,
- Serum cholesterol = Grade 2 (= 7.75 mmol/L),
- Hypertriglyceridemia = Grade 2 (= 3.42 mmol/L),
- Hyperglycemia (fasting) = Grade 2 (= 8.9 mmol/L).
17. Serious or uncontrolled medical disorders that, in the opinion of the investigator,
may increase the risk associated with study participation or study drug
administration, impair the ability of the patient to follow the protocol, or interfere
with the interpretation of study results.
18. Patients Under guardianship or curators, maintenance of justice, non-informed about
diagnosis, unable to follow study medical requirement for geographical, social or
19. Patients with abnormal blood electrolyte test (Ca, Mg, K and Na) that could not be
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