Malignancies carrying a genetic alteration of ALK, MET or ROS1
Conditions
Interventions
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Sponsors
Erasmus Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Stratum 1: •Histologically or cytologically confirmed diagnosis of ALCL •Target gene aberration as defined as: o A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism o 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 o A translocation in >15% of the tumor cells (by break apart FISH-assay) •Disease involvement: o For dose escalation measurable and non measurable disease is allowed o For does expansion measurable disease is mandated o Measurable disease is defined as at least one nodule with a longest diameter greater than 1.5 cm (paediatric NHL response criteria) Stratum 2: •Histologically or cytologically confirmed diagnosis NBL or RMS •Target gene aberration as defined as: o A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism o 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 o A translocation in >15% of the tumor cells (by break apart FISH-assay) OR o An amplification of the MET-gene, defined as of =5 MET signals per tumor cell (by break apart FISH) o A MET mutation, defined as the presence of a somatic mutation (Direct, bidirectional sequencing of exon 16-19 of MET) o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade break-apart TFE3 probe set: RP11-344N17 and RP11-552J9) •Disease involvement: o For dose escalation measurable and non-measurable disease is allowed o For does expansion measurable disease is mandated, except for neuroblastomas where MIBG disease is sufficient o For RMS: Measurable disease defined as per RECIST 1.1 with a target lesion of at least 10 mm o For NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease (I123 MIBG uptake with or without bone marrow metastases) Stratum 3: •Histologically or cytologically confirmed diagnosis of other solid tumor or lymphomas other than ALCL (at initial diagnosis) that is relapsed or refractory to standard therapy. Or patients with newly diagnosed IMT in whom radical surgery is deemed infeasible or will result in significant morbidity/mutilation •Target gene aberration as defined as: For ALK: o A point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism o 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 o A translocation in >15% of the tumor cells (by break apart FISH-assay) For ROS1 o A ROS1 rearrangement in >15% of the tumor cells (by break apart FISHassay) For MET o An amplification of the MET-gene, defined as of =5 MET signals per tumor cell (by break apart FISH) o A MET mutation, defined as the presence of a somatic mutation (Direct, bidirectional sequencing of exon 16-19 of MET ) o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade break-apart TFE3 probe set: RP11-34
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 tumours 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. • 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. Plus for stratum 1: • Patients with ALCL and skin lesions only, are excluded Plus for stratum 2: • Patients with neuroblastoma and bone marrow disease only, are excluded.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Stratum 1: To determine a safe dose (the recommended phase 2 dose (RP2D))of vinblastine in combination with crizotinib in relapsed/refractory ALCL with ALK aberrations Stratum 2: to determine a safe dose (the recommended phase 2 dose (RP2D)) of crizotinib in combination with temsirolimus in patients with relapsed/refractory RMS or NBL with ALK or MET aberrations Stratum 3: to determine the safety and preliminary activity of single-agent crizotinib for ALK/ROS1/MET aberrant malignancies or patients with newly diagnosed IMT ;Secondary Objective: >To study the preliminary activity of crizotinib in combination with standard relapse chemotherapy for ALCL, or crizotinib in combination with temsirolimus for NBL and RMS. >To study pharmacokinetics of single-agent crizotinib, and crizotinib in combination with vinblastine or temsirolimus to study potential drug-drug interactions >To assess the duration of response, time to progression, progression free survival and overall survival Biomarker/pharmacodynamic objectives >To confirm target gene aberrations at enrollment in a central laboratory >To study target activation at baseline >To study target inhibition of ALK, AKT and mTOR pathway in all patients using Platelets-Rich-Plasma (PRP) as surrogate tissue and tumour tissue when available. >To show pharmacodynamic effects of crizotinib alone or in combination with vinblastine or temsirolimus on ALK and PI3K/AKT pathways >To study mechanisms of primary or acquired resistance in patients with resistant or progressive disease >To asses;Primary end point(s): Stratum 1 and 2:Dose Limiting Toxicities (DLT) during the first cycle of crizotinib, in combination with either vinblastine, temsirolimus Stratum 3: overall response rate ;Timepoint(s) of evaluation of this end point: Assessed during the first 28 days of treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • 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);Timepoint(s) of evaluation of this end point: • Stratum 1: at the end of cycle 2, then every 4 months, and after a year every 6 months. • Solid tumors (stratum 2 and 3): at the end of cycle 2 and then every other cycle for stratum 2 and every 3 cycles for stratum 3. • Stratum 1, 2 and 3: PR and CR will have to be confirmed by repeated imaging at least 4 weeks after observation of response. • Blood samples for PK analysis: at the start of the 2nd cycle at the day that vinblastine (stratum 1) or temsirolimus (stratum 2) are also administered. • PFS: the time interval between the date of enrolment and the date of confirmed disease progression or death (events) whatever the cause, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow-up examination. | — |
Countries
Denmark, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom
Contacts
Public ContactCRISP Trial Coordinator
University of Birmingham
Outcome results
None listed