| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| malignant solid tumors including Inflammatory myofibroblastic tumor (IMT) and anaplastic large-cell lymphoma (ALCL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors, Lymphoma, Neuroblastoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
E.2.1.1 To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of crizotinib (PF-02341066) administered orally twice daily to children with relapsed/refractory solid tumors and anaplastic large cell lymphoma (ALCL).
E.2.1.2 To define and describe the toxicities of crizotinib (PF-02341066) administered on this schedule.
E.2.1.3 To characterize the pharmacokinetics of crizotinib (PF-02341066) in children with refractory cancer. |
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| E.2.2 | Secondary objectives of the trial |
E.2.2.1 To preliminarily define the anti-tumor activity of crizotinib (PF-02341066) within the confines of a Phase 1 study.
E.2.2.2 To obtain initial Phase 2 data on the anti-tumor activity of crizotinib (PF-02341066) in children with relapsed/refractory neuroblastoma (NB) and ALCL.
E.2.2.3 To preliminarily examine the relationship between ALK status (e.g, the presence of a mutation, duplication, amplification, and/or translocation) in patients with NB or ALCL and response to crizotinib (PF-02341066).
E.2.2.4 To preliminarily examine the relationship between MRD status and clinical response to crizotinib (PF-02341066) in patients with ALCL.
E.2.2.5 To use a questionnaire to gather preliminary information on the palatability of the oral solution formulation of crizotinib (PF-02341066).
E.2.2.6 To evaluate for potential alterations in bone growth in pediatric patients. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must have had histologic verification of malignancy at original diagnosis or relapse • Phase 1 (Part A1): Patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (excluding patients with primary or metastatic central nervous system [CNS] tumors or patients with primary cutaneous ALCL) • Phase 1 (Part A2): Patients with confirmed ALK fusion proteins, ALK mutations, ALK amplification or MET proto-oncogene, receptor tyrosine kinase (MET) mutation or amplification; • Phase 1 (Part A3): Patients with relapsed or refractory neuroblastoma, with or without bone marrow involvement, who are not eligible for Part A1 or A2 • Phase 2 (Part B): Patients with ALK+ relapsed or refractory neuroblastoma • Phase 2 (Part C): Patients with ALK+ relapsed or refractory ALCL (excluding patients with primary cutaneous ALCL) • Phase 2 (Part A2): Patients with diagnoses other than neuroblastoma or ALCL with confirmed ALK fusion proteins, ALK mutations, ALK amplification or MET mutation or amplification; • Disease status: o Phase 1 (Part A): Patients must have either measurable and/or evaluable disease o Phase 2 (Part B): Patients with neuroblastoma must have proven ALK+ disease with either measurable and/or evaluable disease
Phase 2 (Part C): Patients must have proven ALK+ disease with either measurable or evaluable disease • Performance level: Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy: ▪ Patients with solid tumors must not have received chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea) ▪ Patients with lymphoma who relapse during standard maintenance therapy are eligible at time of relapse; for patients with ALCL who relapse while they are receiving cytotoxic therapy, at least 14 days must have elapsed since the completion of cytotoxic therapy; • >= 2 weeks (wks) for local palliative radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of MIBG; >= 6 months must have elapsed if prior total body irradiation (TBI), craniospinal XRT or >= 50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM) radiation • Bone marrow/stem cell transplant or infusion without TBI: o Part A1 or Part C: No evidence of active GVHD and >= 3 months must have elapsed since stem cell transplant or infusion o Part A2, Part A3, or Part B: No evidence of active GVHD and >= 6 weeks must have elapsed since stem cell transplant or infusion • At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines • Patients must not have received prior therapy with crizotinib o For patients with solid tumors or ALCL without bone marrow involvement enrolled in Part A1 or Part C of the study: ▪ Peripheral absolute neutrophil count (ANC) >= 1,000/mm3 ▪ Platelet count >= 75,000/mm3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment) ▪ Hemoglobin >= 8.0 g/dL (may receive RBC transfusions) o Patients with known bone marrow metastatic disease enrolled in Part A1 or Part C of the study, or Patients eligible for Part A2, Part A3, or Part B of the study: ▪ Peripheral absolute neutrophil count (ANC) >= 750/mm3 ▪ Platelet count >= 25,000/mm3 (may receive platelet transfusions) ▪ Hemoglobin >= 8.0 g/dL (may receive RBC transfusions) • Creatinine clearance or GFR >= 70 ml/min/1.73 m2 or a serum creatinine based on age/gender as follows:
o 1 to < 2 years: 0.6 mg/dL o 2 to < 6 years: 0.8 mg/dL o 6 to < 10 years: 1 mg/dL o 10 to < 13 years: 1.2 mg/dL o 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) o >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female) • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age • Serum SGPT [ALT]) =< 110 U/L; • Serum albumin >= 2 g/dL • Corrected QT interval (QTc) ≤ 480 msec • Patients receiving the formulated capsules must have a body surface area (BSA) >= 0.63 m2 at the time of study enrollment • Patients taking the capsule formulation must be able to swallow capsules; feeding tube administration is allowed for patients receiving the OS |
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| E.4 | Principal exclusion criteria |
•Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days are not eligible • Patients who are currently receiving another investigational drug are not eligible • Patients who are currently receiving other anti-cancer agents, with the exception of hydroxyurea for patients with ALCL, are not eligible • As Crizotinib is an inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), patients chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed • Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed • Patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, are not eligible; the topical use of these medications (if applicable) is allowed • Patients with known interstitial fibrosis or interstitial lung disease are not eligible • Patients with a known history of myocardial infarction or cerebrovascular accident are not eligible
• Patients with central nervous system (CNS) tumors or known CNS metastases are not eligible; patients with a history of CNS metastases that have been surgically resected are eligible only if the baseline evaluation shows no evidence of current CNS metastases; • Patients who have an uncontrolled infection are not eligible • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Maximum-tolerated Dose and Recommended Phase 2 Dose of Crizotinib [Time Frame: 28 days]
2. Number of Participants with Toxicities of Crizotinib [Time Frame: Up to 30 days post-treatment]
3. Steady State Cmax of Crizotinib [Time Frame: Cycle 1 (day 15- 28) pre-dose, 1, 2,4, 6-8 hours post dose]
4. Steady State C Average of Crizotinib [Time Frame: Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hours post-dose]
5. Steady State AUC of Crizotinib [Time Frame: Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hours post-dose]
6. Steady State Clearance of Crizotinib [Time Frame: Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hours post-dose |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Endpoint 1: 28 days
Endpoint 2: Up to 30 days post-treatment
Endpoints 3-6: Cycle 1 (day 15-28) pre-dose, 1, 2, 4, 6-8 hours post-dose |
|
| E.5.2 | Secondary end point(s) |
1. Number of Participants (Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma (ALCL))With Response to Crizotinib [ Time Frame: Up to 8 years ]
2. Number of Participants (Relapsed or Refractory Neuroblastoma or Anaplastic Large Cell Lymphoma (ALCL)) With Response to Crizotinib [ Time Frame: Up to 8 years ]
3. Number of Participants With Minimum Residual Disease (MRD) [ Time Frame: Up to 8 years ] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Endpoints 1-3: up to 8 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase II cohorts expansion |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
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