Phase 2 Study Assessing Efficacy and Safety of Crizotinib in Patients Harboring an Alteration on ALK, MET or ROS1

Twenty cohorts are identified, a cohort being defined as [one pathology, one target alteration] such as [gastric cancer with MET amplification (6%)].

One cohort will be dedicated to miscellaneous, very rare pediatric diseases identified through INCa platforms or pan-genome programs (e.g. MOSKIDO, IGR) and will recruit up to 10 patients.

Two cohorts will be dedicated to a couple of diseases harbouring at least one specific alteration in one crizotinib target, same or different from those listed above, e.g. in AXL gene, arising from pan-genome trials.

• ALCL, adults and children, ALK-translocated
• Colorectal cancer, adults, ALK-translocated
• Colorectal cancer, adults, MET amplified
• Colorectal cancer, adults, MET mutated
• NSCLC, adults, MET amplified
• NSCLC, adults, ROS1-translocated
• Breast cancer, adults, ALK-translocated
• Gastric cancer, adults, MET amplified
• Cholangiocarcinoma, adults, ROS1-translocated
• Ovarian cancer, adults, MET amplified
• Clear cell renal cell carcinoma, adults, ALK-translocated
• Clear cell renal cell carcinoma, adults, ALK-amplified
• Papillary renal cell carcinoma, adults, MET mutated (+ MET amplified)
• Hepatocarcinoma, adults, MET amplified
• Neuroblastoma, adults and children, ALK-amplified + ALK mutated
• IMT, adults and children, ALK-translocated
• Rhabdomyosarcoma (alveolar and embryonal), adults and children, ALK-amplified
• Glioblastoma, adults, MET amplified. This cohort will only be open after amendment
• Anaplastic thyroid cancer, adults, ALK mutated
• Thyroid cancer (follicular + medullary + papillary), adults, MET mutated
• Miscellaneous rare pediatric diseases associated to at least one specific alteration in one crizotinib target, same or different from those listed above
• One another pathology associated to at least one specific alteration in one crizotinib target, same or different from those listed above.
• One another pathology associated to at least one specific alteration in one crizotinib target, same or different from those listed above.

Inclusion:

• Male and female ≥ 1 year of age
• unresectable locally advanced or metastatic malignant tumor of any histological type (but NSCLC with an ALK translocation) and not amenable to any other validated therapeutic option. ( for pediatrics a relapse after a first well-conducted standard treatment or a situation without any standard treatment and a survival <10%).
• one proven specific alterations among ALK, MET, RON and ROS1 genes determined on the primary and/or the metastatic lesion
• Measurable disease according to RECIST 1.1
• For patients with primary cerebral tumors (adults or children), measurable disease defined by bi-dimensional measurements : two perpendicular diameters of at least 10 mm on CT or MRI scan, outside of a previously radiated field within the last 3 months, to observe pseudoprogression
• hematologic function (ANC ≥ 1.0x10⁹/L, platelets ≥ 75x10⁹/L, platelets ≥ 50x10⁹/L for ALCL with bone marrow involved ; platelets ≥ 100x10⁹/L for primary or secondary cerebral tumors; Hb ≥ 8g/L), renal function (creat cl ≥ 50 mL/min Cockcroft and Gault) and hepatic function (serum bilirubin ≤ 1.5x ULN unless due to Gilbert's syndrome ; ASAT and ALAT ≤ 5x ULN if liver metastasis or ≤ 3x ULN if liver metastasis with advanced fibrosis (FibroTest>0.48) or ≤ 3x ULN without liver metastasis)
• normal values for calcium, magnesium and potassium levels
• able to swallow and retain oral medication
• ECOG Performance Status of 0 to 2, or Karnofsky scale > 50 % or Lansky Play scale (< 12 years) > 50%, (for CNS tumors, the neurological deficiency due to the disease itself)
• Life expectancy ≥ 3 months

Exclusion :

• NSCLC patients ALK translocations
• Patient eligible for a clinical trial with an anticancer drug (including crizotinib) targeting the same molecular alteration open to accrual in France.
• alteration limited to an overexpression of ALK, MET, RON, ROS1 or any other crizotinib-target. Only patients with ALCL are eligible if ALK is positive by immunohistochemistry
• Patients with primary or secondary central nervous system disease
• Previous treatment with crizotinib
• Major surgery or tumor embolization within 4 weeks and minor surgery within 2 weeks prior to the initiation of the study drug. Brain surgery is excluded within 4 weeks prior to starting crizotinib for primary or secondary cerebral tumors
• Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as, but not limited to :

• Within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, or cerebrovascular accident including transient ischemic attack
• Ongoing congestive heart failure
• Congenital long QT syndrome
• Heart rate ≤ 45 beats/minute
• Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, or with QTcF interval >470 msec
• For patients with a cerebral disease (primary or secondary) : uncontrolled hypertension [defined as SBP of ≥ 140 mmHg or DBP of ≥ 90mmHg]
• extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not prior radiation pneumonitis
• Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function
• Carcinomatous meningitis or leptomeningeal disease
• HIV-positive, active hepatitis A, B or C, or latent hepatitis B or C, or any other uncontrolled infection
• Other severe acute or chronic medical or psychiatric conditions, or end stage renal disease on hemodialysis or laboratory abnormalities
• For patients with a cerebral disease, detection on the MRI or the CTscan of a real arteriovenous malformation, or an untreated intracranial aneurysm, or a cavernous angioma, or an amyloid angiopathy, or any new or significant (≥ grade 2) intratumoral bleeding other than microbleeds on T2* weighted MRI in the previous 14 days before treatment initiation, or a recent and untreated subdural effusion.
• Patients using non-substitutable drugs that are potent CYP3A4 inhibitors, or potent CYP3A4 inducers
• Patients using non-substitutable drugs that are CYP3A4 substrates with narrow therapeutic indices
• Patients with cerebral disease using anti-platelet drugs or anticoagulant agents are not eligible if those treatments can not be stopped 7 days before day1.
• Patients with altered mental status or with psychological, familial, sociological or geographical condition potentially hampering compliance
• Individual deprived of liberty or placed under the authority of a tutor.