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; MedDRA version: 20.0Level: LLTClassification code 10007050Term: CancerSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

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

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-06-22
• Last Update Posted: 12 March 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 71

Inclusion Criteria

Inclusion criteria stratum 1b
•Histologically or cytologically confirmed diagnosis of relapsed/refractory ALCL, including first relapse
•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:
oThe t(2;5) translocation or rearrangement t(1;2), t(2;3), inv(2), t(2;22). This should be apparent in all tumor cells
?This can be proven by ALK- immunohistochemistry, FISH or NGS
•Life expectancy ? 12 weeks
•Disease involvement :
oMeasurable disease defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) [Sandlund 2015]
•Adequate hematological function, unsupported, last platelet transfusion > 72 hours and off colony stimulating factors:
oANC =0.75x109/L and platelets = 75x109/L for pts without bone marrow involvement. Note: for patients in the UK the eligibility criteria require at least =1.0x109/L
oPatients with bone marrow involvement will be allowed to enter with ANC
=0.5x109/L and platelets =50x109/L

stratum 2:
•Histologically or cytologically confirmed diagnosis of relapsed/refractory NBL or RMS
•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:
oA point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism
oAn 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
oA rearrangement in >15% of the tumor cells (by break apart FISH-assay or RNAseq)
OR
oAn amplification of the MET-gene, defined as of =5 MET signals per tumor cell (by break apart FISH)
oA MET mutation, defined as the presence of a somatic mutation (Direct, bi- directional sequencing of exon 16-19 of MET )
oTFE3 rearrangement, define as at least 15% of cells rearranged (FISH home- made break-apart TFE3 probe set: RP11-344N17 and RP11-552J9)
•Life expectancy ? 12 weeks
•Disease involvement:
oFor dose escalation measurable and non-measurable disease is allowed
oFor dose expansion measurable disease is mandated, except for neuroblastomas where MIBG or FDG avidity is sufficient
oFor RMS: Measurable disease defined as per RECIST 1.1 [Eisenhauer 2009]
oFor NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease (I123 MIBG or FDG uptake with or without bone marrow metastases).

stratum 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.
Of note: when stratum 1b is completed, ALCL patients will be eligible to enroll into stratum 3 according to the criteria described in this section on stratum 3 eligibility.
•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: For ALK:
oA point mutation in the kinase domain of ALK that results in an amino-acid change, and is not a known polymorphism
oAn amplification of the ALK gene, defined as = 9 copies per

Exclusion Criteria

•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 potent CYP3A4 inducers or inhibitors, CYP3A4 substrates with narrow therapeutic indices as well as medication with known QT-prolongation see Appendix 2
•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.
•Evidence of active graft-vs-host disease (GVHD)
•less than 3 months post-allogeneic HSCT.
•Receiving GVHD prophylaxis
•Pregnant or lactating females
•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

stratum 2 as above +:
•Patients with neuroblastoma and bone marrow disease only, are excluded.

stratum 3 as above + •Receiving GVHD prophylaxis.

Study & Design

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