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

• Status: Active, not recruiting
• Trial end date: 2022-07-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a biology driven, trans-tumoral, multicentric phase II trial assessing the efficacy and the safety of the targeted agent crizotinib as a monotherapy in 23 cohorts of patients with identified activating molecular alterations in the crizotinib target genes. A cohort is defined by a pathology and a crizotinib-target alteration (eg gastric cancer with MET amplification).

For each cohort a two-stage design will be implemented. In the situation where expected accrual allows for a sufficient number of patients to be accrued, the alpha and beta errors will be fixed at 10%. However, in very rare diseases, such as inflammatory myofibroblastic tumor (IMT), neuroblastoma, glioblastoma, and rhabdomyosarcoma (RMS), it is anticipated that the target number may not be achievable in a reasonable timeframe; for these cohorts, the alpha and beta errors will be fixed at 15%. Consequently three different statistical designs will be a priori considered according to the expected response rate and incidence.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: UNICANCER
• Collaborators: Fondation ARC; National Cancer Institute, France; Pfizer
• Treatments: Crizotinib

Criteria

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.