Study into the safety and activity of the drug Crizotinib for children with malignant tumors

Phase 1

• Conditions: Malignancies carrying a genetic alteration of ALK, MET or ROS1; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-005437-53-GB
• Lead Sponsor: Erasmus Medical Center

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-02-13
• Last Update Posted: 4 September 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 94

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

• 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 < 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.

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified