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van CCT (UK)


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van CCT (UK)


A phase IB study of crizotinib in pediatric malignancies


- candidate number23573
- NTR NumberNTR5584
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR6-jan-2016
- Secondary IDsITCC-053 
- Public TitleA phase IB study of crizotinib in pediatric malignancies
- Scientific TitleA phase 1B study of crizotinib either in combination or as single agent in pediatric patients with ALK, ROS1 or MET positive malignancies
- ACRONYMCrizotinib study
- hypothesisObjectives:
To determine the RP2D of crizotinib in combination with vinblastine
To determine the RP2D of crizotinib in combination with temsirolimus
To determine the safety and preliminary activity of single-agent crizotinib in ALK, MET or ROS1 positive tumors
- Healt Condition(s) or Problem(s) studiedChildren, Carcinoma, Pediatric cancer patients
- Inclusion criteriaInclusion 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 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, except for neuroblastomas where MIBG disease is sufficient
- For RMS: Measurable disease defined as per RECIST 1.1 with a target lesion of at least 10 mm 102
- For NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease (I123 MIBG uptake with or without bone marrow metastases).
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 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
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:
For ALK:
- 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)
For ROS1
- A ROS1 rearrangement in > 15% of the tumor cells (by break apart FISH-assay)
For MET
- An amplification of the MET-gene, defined as of ≥5 MET signals per tumor cell (by break apart FISH)
- A MET mutation, defined as the presence of a somatic mutation (Direct, bi-directional sequencing of exon 16-19 of MET )
- 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:
- Measurable disease according to RECIST 1.1 with a target lesion of at least 10 mm102
- Or, measurable disease as defined as at least one nodule with a longest diameter greater than 1.5 cm (pediatric NHL response criteria)100
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
No prior therapy directly targeting ALK or ROS1 or MET
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
- Exclusion criteriaExclusion 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 < 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.
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.
- mec approval receivedno
- multicenter trialyes
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeintervention
- planned startdate 1-jun-2016
- planned closingdate1-jun-2021
- Target number of participants82
- InterventionsStratum 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 weekly
Stratum 3: Crizotinib daily for 12 cycles of 28 days
- Primary outcome 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 outcome 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)
- TimepointsBaseline, end of cycle 2, 4, 8, 12, 18, 24 (=End of study)
- Trial web sitenot applicable
- statusplanned
- CONTACT FOR PUBLIC QUERIESMD. PhD. C.M. Zwaan
- CONTACT for SCIENTIFIC QUERIESMD. PhD. C.M. Zwaan
- Sponsor/Initiator Erasmus Medical Center
- Funding
(Source(s) of Monetary or Material Support)
Pfizer, Go4Children
- Publications
- Brief summaryCrizotinib is a ALK, MET and ROS1 inhibitor that has proven to be effective and is registered for ALK positive non-small cell lung carcinoma in adults. In children, various tumors harbour ALK/MET/ROS1 aberrations, and children with these tumours may potentially benefit from treatment with crizotinib. Crizotinib as single-agent in the pediatric phase I dose-escalation study showed favorable results in terms of toxicity, but variable results in terms of efficacy, despite dose-escalation to much higher dosages than used in adults. Very promising results were obtained in a small cohort of patients with ALCL, although not all patients responded. Especially in patients with neuroblastoma and ALK point-mutations responses were less promising than was anticipated, but preclinical in-vitro and in-vivo studies have suggested that this may be overcome with the combined use of crizotinib with a TORC 1/2 inhibitor.
In this study we therefore aim to evaluate combination therapy for different strata. For strata 1 we will combine crizotinib with vinblastine, based one earlier studies showing efficacy of vinblastine in the group of relapsed, ALK positive ALCL patients (stratum 1). For stratum 2 a combination of crizotinib with temsirolimus will be given to patients with relapsed, ALK positive neuroblastoma and rhabdomyosarcoma (stratum 2). Children who have other ALK- ROS or MET positive tumors and who have no other treatment options, will be enrolled in a separate stratum with crizotinib only (stratum 3).
- Main changes (audit trail)
- RECORD6-jan-2016 - 14-feb-2016


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