Secured access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug - AcSé crizotinib

Conditions: Patients with metastatic or unresectable locally advanced malignancies harboring specific genomic alterations regarding the biological crizotinib targets, and who are no more amenable to curative treatment
MedDRA version: 14.1Level: LLTClassification code 10007050Term: CancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10029260Term: NeuroblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10002227Term: Anaplastic large cell lymphoma T- and null-cell typesSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10067917Term: Inflammatory myofibroblastic tumourSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10008593Term: CholangiocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10067946Term: Renal cell carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10039022Term: RhabdomyosarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: PTClassification code 10017758Term: Gastric cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 14.1Level: LLTClassification code 10024658Term: Liver carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Registration Number: EUCTR2013-000885-13-FR

Lead Sponsor: ICANCER

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: Not specified

Inclusion Criteria

1.Male and female = 1 year of age
2.Diagnosis of unresectable locally advanced or metastatic malignant tumor (solid tumor or hematological malignancy) of any histological type (but Non Small Cell Lung Cancer with an ALK derived translocation) and considered by the investigator as not amenable to any other validated therapeutic option
3.At least one proven specific alterations among ALK, MET, RON and ROS1 genes determined on the primary and/or the metastatic lesion such as
•Any type of ALK translocation in Anaplastic Large Cell Lymphoma (ALCL), breast cancer, colorectal cancer, myofibroblastic inflammatory tumor and renal cell carcinoma
•ALK amplification/copy number gain (CNG) in rhabdomyosarcoma, renal cell carcinoma, neuroblastoma
•ALK mutation in neuroblastoma and anaplastic thyroid cancer
•MET amplification/CNG in gastric cancer, ovarian cancer, colorectal cancer, glioblastoma, hepatocarcinoma and NSCLC
•MET mutation in thyroid cancer as well as papillary renal cell carcinoma and colorectal cancer
•ROS1 translocation in cholangiocarcinoma and NSCLC
•RON mutation and amplification/CNG in gastric cancer (in a secondary phase of the trial)
•Any other pathology, except CNS tumors, harbouring one of these alterations, including in genomic AXL gene
Patients included in pangenomic research programs harbouring specific alterations in at least one crizotinib target different from those listed above (i.e AXL, etc.) are also eligible
The list of alterations, oncogenic variants and other target genes may be upgraded during the progress of the study considering the level of proof
4.Measurable disease according to RECIST 1.1 guidelines with target lesion of at least 20 mm (or 10 mm on spiral CT scans) and presence of at least one RECIST-measurable lesion outside of a previously radiated field or potential palliative irradiation fields
5.Patients who had received any previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, i.e. = grade1, with a mandatory free interval of at least 3 weeks for systemic treatments, and at least 5 half-lives for targeted drugs. ALCL patients receiving vincristine, vinblastine or non-hematologically toxic compounds can have a wash-out period shortened to 2 weeks
6.Patients who had received any investigational drug are eligible after a 4-week wash-out period or a wash-out period equivalent to 5 half-lifes of the product, depending on the longest period
7.Adequate hematologic function (ANC = 1.0x109/L, platelets = 75x109/L, platelets = 50x109/L for ALCL with bone marrow involved ; Hb = 8g/L), renal function (creatinine clearance = 60mL/min using Cockroft and Gault formula) and hepatic function (serum bilirubin = 1.5x ULN unless due to Gilbert’s syndrome ; ASAT and ALAT = 5x ULN if documented liver metastasis or = 3x ULN if documented liver metastasis associated with advanced fibrosis (FibroTest>0.48) or = 3x ULN without liver metastasis)
8.Patients presenting strictly normal values for calcium and magnesium levels, measured within 14 days of the treatment initiation, and strictly normal values for potassium level measured within 72 hours of the treatment initiation
9.Patients able to swallow and retain oral medication
10.ECOG Performance Status of 0 to 2, or Karnofsky scale > 50 % or Lansky Play scale (< 12 years) > 50%
11.Life expectancy = 3 months
12.Potentially reproductive patients must agree to use an effectiv

Exclusion Criteria

1.Non Small Cell Lung Cancer patients harbouring ALK derived translocations
2.Patient eligibile for a clinical trial with an anticancer drug (including crizotinib) targeting the same molecular alteration in the patient’s pathology open to accrual in France. Patients not eligible in this trial are still eligible for the AcSé study
3.Genomic alteration limited to an overexpression of ALK, MET, RON, ROS1 or any other crizotinib-target (i.e. without increased copy number or structural gene alteration) will not be sufficient for eligibility. Only patients with ALCL are eligible if their tumor is ALK positive as evidenced by immunohistochemistry
4.Patients with primary or secondary CNS disease
5.Previous treatment with crizotinib
6.Major surgery or tumor embolization within 4 weeks and minor surgery within 2 weeks prior to the initiation of the study drug
7.Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as, but not limited to :
a)Any of the following 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
b)Ongoing congestive heart failure
c)Congenital long QT syndrome
d)Heart rate = 45 beats/minute
e)Ongoing cardiac dysrhythmias of NCI CTCAE Grade =2, uncontrolled atrial fibrillation of any grade, or machine-read ECG with QTcF interval >470 msec
f)History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior radiation pneumonitis
g)Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function
h)Carcinomatous meningitis or leptomeningeal disease
i)Known HIV-positive, known active hepatitis A, B or C, or latent hepatitis B or C, or any other uncontrolled infection
j)Other severe acute or chronic medical (including severe gastrointestinal conditions such as diarrhea or ulcer) or psychiatric conditions, or end stage renal disease on hemodialysis or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for study entry
8.Patients using drugs that are known potent CYP3A4 inhibitors, (including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), or potent CYP3A4 inducers (including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort=millepertuis in French) are not eligible if those treatments can not be substituted
9.Patients using non-substitutable drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to dihydroergotamine, aripiprazole, ergotamine, halofantrine, pimozide, triazolam astemizole, cisapride, and terfenadine
10.Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geograph

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The objective of this study is to explore the efficacy of crizotinib as a single agent across diverse type of tumors guided by the presence of identified activating molecular alterations in the crizotinib-target genes, per cohort, per pathology and per target. ;Secondary Objective: -To assess the safety profile of crizotinib<br>-To explore whether molecularly driven, high quality multi-tumor screening Phase II trials are feasible in the French multiinstitutional, multidisciplinary setting.<br>;Primary end point(s): Anti-tumor activity of crizotinib, as the primary objective of the trial, will be carried out by the determination of the confirmed objective response rate (complete or partial response according to RECIST 1.1), assessed in each cohort defined by a pathology associated with a crizotinib target alteration.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): -Disease control rate<br>-Response duration<br>-Progression-free survival<br>-Overall Survival<br>-Safety (CTCAE v4.0)<br>-Correlative research endpoints<br>