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

Phase 1

• Conditions: Children and young adults with malignancies carrying a genetic alteration of ALK, MET or ROS1 with no better treatment options according to the current (inter)national guidelines; Therapeutic area: Diseases [C] - Cancer [C04]

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

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-05-23
• Last Update Posted: 29 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 82

Inclusion Criteria

• Histologically confirmed diagnosis of other solid tumor or lymphomas (including 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.
• 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:
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 rearrangement in >15% of the tumor cells (by break apart FISH-assay or RNAseq).
For ROS1
o A ROS1 rearrangement in > 15% of the tumor cells (by break apart FISH- assay or RNAseq).
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, bi- directional sequencing of exon 16-19 of MET ).
o TFE3 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:
o Measurable disease according to RECIST 1.1 [Eisenhauer 2009].
o Or, measurable disease as defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria) [Sandlund 2015].
• Any previous systemic anticancer therapy must have been completed at least 2 weeks prior to initiation of study medication. At least 1 week for oral metronomic chemotherapies (e.g. cyclophosphamide or etoposide) and the patient has to be recovered from any toxicity from this therapy.
• No treatment with any other investigational drug within the past 2 weeks prior to initiation of study medication.
• No prior therapy directly targeting ALK or ROS1 or MET.
• Major surgery must have been completed at least 2 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:
o ANC =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.
o Patients with bone marrow involvement will be allowed to enter with ANC =0.5x109/L and platelets =50x109/L.
• For clinical purposes normal renal function is defined as =1.5 x ULN for serum creatinine adjusted for age. If the serum creatinine is greater than 1.5 x institutional ULN, the patient must have a GFR > 90 ml/min/1.73 m2, using the Schwartz formula to estimate glomerular filtration rate (GFR) (Appendix 6) [Schwartz 2009]. To fulfill with regulatory requirements the Cockcroft Gault formula will be used to estimate GFR (Appendix 6).
• 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 involve

Exclusion Criteria

• Patients with neuroblastoma.
• 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 see Appendix 2.
• Use of drugs or foods that are known strong CYP3A4 inhibitors within 7 days prior to the first dose of crizotinib. The topical use of these medications (if appropriate), such as 2% ketoconazole cream, may be allowed.
• Use of drugs that are known potent 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.
• 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.

Study & Design

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