A phase 1B of crizotinib either in combination or as single agent in pediatric patients with ALK, ROS1 or MET positive malignancies

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• Other serious illnesses or medical conditions, • Active uncontrolled infection, • History of allergic reactions to the compounds or their solvents, • Patients with untreated CNS metastases and/or primary CNS tumors and/or meningeal, lymphoma involvement, defined as CNS3 status (patients with CNS2 are eligible), • Concurrent use of drugs or foods that are known CYP3A4 substrates with narrow therapeutic indices as well as medication with known QT‐prolongation, • Use of drugs or foods that are known strong CYP3A4 inhibitors within 7 days prior to the first dose of crizotinib. •Use of drugs that are known strong CYP3A4 inducers within 12 days prior to first dose of crizotinib.• Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure or cerebrovascular accident including transient ischemic attack. • Use of live vaccines within 30 days of first dosing * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the, absorption of crizotinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,, or malabsorption syndrome), • Not able to comply with scheduled follow‐up and with management of toxicity., • A cardiac shortening fraction < 29%, • Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any, grade, or QTcF interval >470 msec., • 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., • No evidence of active graft‐vs‐host disease (GVHD) and at least 3 months post‐allogeneic, HSCT. Must not receive GVHD prophylaxis., • For patients with childbearing potential, a negative test for pregnancy and agreement to use, effective contraceptive measures is required before entry on study.,• Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function. • Prior malignancy (other than current malignancy): patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer, or localized and presumed cured prostate cancer) within the last 3 years. • Carcinomatous meningitis or leptomeningeal disease Plus for stratum 2:, • Patients with neuroblastoma and bone marrow disease only, are excluded.

• 1b en 2:Histologically or cytologically confirmed diagnosis of relapsed/refractory ALCL, including first relapse, NBL or RMS 3: Histologically confirmed diagnosis of other solid tumor or lymphomas other than ALCL that is relapsed or refractory to standard therapy, or patients with newly diagnosed IMT for whom surgery may not be feasible for close proximity to vital structures, without prior tumor-shrinkage and no other feasible options are available as per local standard of care.when stratum 1b is completed, ALCL patients will be eligible to enroll into stratum 3 • Age at enrolment ≥1 year of age and ≤ 21 years • Lansky play score > 60%; or Karnofsky performance status > 60%. Target gene aberration as defined as: o stratum 1b: The t(2;5) translocation or rearrangement t(1;2), t(2;3), inv(2), t(2;22). proven by ALK- immunohistochemistry, FISH or NGS stratum 2: A point mutation in the kinase domain of ALK, An amplification of the ALK gene,rearrangement in >15% of the tumor cells or An amplification of the MET-gene,MET mutation, TFE3 rearrangement, stratum 3: o A point mutation in the kinase domain of ALK, or MET mutation o An amplification of the ALK or MET gene, o A ROS1 or TFE3 rearrangement in > 15% of the tumor cells • Life expectancy ≥ 12 weeks • Disease involvement : o stratum 1b Measurable disease defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) stratum 2: For dose escalation measurable and non-measurable disease is allowed; For dose expansion measurable disease is mandated, except for neuroblastomas where MIBG or FDG avidity is sufficient stratum 3:Measurable disease according to RECIST 1.1 Or, measurable disease as defined as at least one nodule with a longest diameter greater than 1,5 cm • Any previous systemic anticancer therapy must have been completed at least 2 weeks prior to initiation of study medication • No prior therapy directly targeting ALK or ROS1 or MET • No treatment with any other investigational drug within the past 2 weeks or major surgery Male and female patients of child-bearing potential must agree to use an effective method for males and a highly effective method for females