children, cancer, pediatric malignancies, ALK positive tumors, ROS1 positive tumors, MET positive tumors kinderen, kanker, pediatrische maligniteiten, tumoren positief voor ALK, ROS1, MET afwijkingen
Conditions
Interventions
Stratum 1: 12 cycles of 28 days Crizotinib daily and Vinblastine weekly, followed by 12 cycles of 28 days Crizotinib daily only.
Stratum 2: max 8 cycles of 28 days Crizotinib daily and Temsirolimus w
Sponsors
University Medical Center Erasmus Medical Center Rotterdam The Netherlands
Eligibility
Inclusion criteria
Inclusion criteria: Inclusion criteria stratum 1 • Histologically or cytologically confirmed diagnosis of ALCL • Age at diagnosis ≥1 year of age and ≤ 21 years • Lansky play score > 60%; or Karnofsky performance status > 60%. • Target gene aberration as defined as: - A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism - An amplification of the ALK gene, defined as ≥ 9 copies per cell, or 4 copies per haploid genome. When assessed by FISH, ALK amplification must be observed in focal clusters of tumor cells (not only single cells) or in more than one-third of the tumor cells - A translocation in >15% of the tumor cells (by break apart FISH-assay) • Life expectancy 12 weeks • Disease involvement : - For dose escalation measurable and non measurable disease is allowed - For does expansion measurable disease is mandated - Measurable disease is defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) 100, 101 • Any previous systemic anticancer therapy must have been completed at least 3 weeks prior to initiation of study medication. At least 1 week for oral metronomic chemotherapies (e.g. cyclofosphomide or etoposide) • No treatment with any other investigational drug within the past 3 weeks prior to initiation of study medication • Major surgery must have been completed at least 3 weeks prior to initiation of study medication (central venous access surgery or a needle biopsy are not considered major surgery) • No persistence of adverse events, more than grade 2, from prior anti-cancer therapy deemed clinically relevant • Adequate hematological function, unsupported, last platelet transfusion > 72 hours and off colony stimulating factors: - ANC ≥0.75x109/L and platelets ≥ 75x109/L for pts without bone marrow involvement. - Patients with bone marrow involvement will be allowed to enter with ANC ≥0.5x109/L and platelets ≥50x109/L but will not be counted for haematological DLTs. • Normal renal function defined as ≤1.5 x ULN adjusted for age • Normal liver function defined as ≤2.5 x ULN for transaminases and ≤1.5 x ULN bilirubin, but ≤5 x ULN (and ≤2.5 x ULN for bilirubin) in case of liver involvement by metastases • Written informed consent from patients and/or from parents or legal guardians, according to local law and regulations. • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up Inclusion criteria stratum 2 • Histologically or cytologically confirmed diagnosis NBL or RMS • Age at diagnosis ≥1 year of age and ≤21 years • Lansky play score > 60%; or Karnofsky performance status > 60%. • Target gene aberration as defined as: - A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism - An amplification of the ALK gene, defined as ≥ 9 copies per cell, or 4 copies per haploid genome. When assessed by FISH, ALK amplification must be observed in focal clusters of tumor cells (not only single cells) or in more than one-third of the tumor cells - A translocation in >15% of the tumor ce
Exclusion criteria
Exclusion criteria: Exclusion criteria: • Other serious illnesses or medical conditions • Current uncontrolled infection • History of allergic reactions to the compounds or their solvents • Patients with known 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 potent CYP3A4 inducers or inhibitors as well as medication with known QT-prolongation • 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 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. • Patients with ALCL and skin lesions only, are excluded • 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. Additional exclusion criteria stratum 2 • No evidence of active graft-vs-host disease (GVHD) and at least 3 months post-allogeneic HSCT. Must not receive GVHD prophylaxis. • Patients with neuroblastoma and bone marrow disease only, are excluded. Additional exclusion criteria stratum 3 • No evidence of active graft-vs-host disease (GVHD) and at least 3 months post-allogeneic HSCT. Must not receive GVHD prophylaxis.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| • Dose Limiting Toxicities (DLT) during the first cycle of crizotinib, in combination with either vinblastine, temsirolimus for stratum 1 and 2. • Overall response rate (descriptive) for stratum 3. | — |
Secondary
| Measure | Time frame |
|---|---|
| • Overall response rate defined as the number of patients achieving complete and partial responses by disease after 2 courses (8 weeks). • Overall response rate defined as the number of patient achieving complete and partial response during the total study period. • Plasma concentration time profiles, PK parameters, including but not limited to AUClast, AUCtau, Cmin, Cmax, Tmax, Racc, and T1/2,acc for crizotinib, temsirolimus and vinblastine. • Progression-free survival (PFS) | — |
Contacts
Public ContactC.M. Zwaan
Dept. of Pediatric Oncology-Hematology Erasmus MC-Sophia Children's Hospital POB 2060
Outcome results
None listed