E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of tumors with translocation, mutation, or amplification of the anaplastic lymphoma kinase (ALK) gene locus |
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E.1.1.1 | Medical condition in easily understood language |
A phase I study for patients whose tumour may express a certain genetic mutation known as ‘EML4ALK” |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Assess the safety of oral single agent crizotinib administered to patients with advanced malignancy known to have an ALK genetic event and screen for efficacy in these patients.
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E.2.2 | Secondary objectives of the trial |
• To determine PK in this patient population using population PK (POPPK) methods and explore correlations between PK, response and/or safety findings. • To correlate ALK genetic events to outcome measures.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patient eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before patients are included in the study. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the trial: 1. Histologically or cytologically proven diagnosis of advanced malignancy other than NSCLC for whom no standard therapy is available 2. Positive for a. Translocation or inversion event involving the ALK gene locus (eg, NPM ALK fusion) as determined by immunohistochemistry (IHC) or any other suitable molecular tools such as FISH or RT-PCR or sequencing. Cases of ALK positive anaplastic large cell lymphoma must be positive for ALK expression by IHC. b. ALK amplification events defined as ALK/CEP2 ratio of ≥5 in ≥15% of evaluated cells by FISH or as greater than 7 copies by qPCR or aCGH. c. ALK activating point mutations determined by direct sequencing of the ALK gene locus including but not limited to G1128A, R1192P, R1275Q, D1091N, M1166R, I1171N, F1174I, F1174L, F1245C, F1245V, I1250T.ALK. 3. Patients with brain metastases are eligible if neurologically stable for at least 2 weeks, and have no ongoing requirement for corticosteroids, for example, dexamethasone and are not taking any medications contraindicated in Exclusion Criteria #10-12. 4. Any prior treatment (chemotherapy or major surgery) must have been completed at least 4 weeks prior to initiation of study medication. Any prior radiation (except palliative) or minor surgeries/procedures must have been completed at least 2 weeks prior to the initiation of study medication. Palliative radiation (≤10 fractions) must have been completed 48 hrs prior to crizotinib therapy commencing. Any acute toxicity must have been recovered to ≤ Grade 1 (except alopecia). 5. Female or male, 15 years of age or older. Admission of minors to the study will be as appropriate according to institutional approvals. For patients enrolled in Japan: consent from a legally acceptable representative is required for all patients who are under 20 years old. 6. ECOG performance status 0-3. 7. Adequate organ function as defined by the following criteria: • Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST/ALT ≤5 x ULN if the enzyme elevation is considered to be due to a cancer-related cause such as liver metastases • Patients with an ALT >5X ULN considered to be due to a cancer-related cause such as liver metastases, may enroll after discussion with the sponsor. • Total serum bilirubin ≤1.5 x ULN. • Absolute neutrophil count (ANC) ≥1000/µL (≥750/µL for hematologic malignancies). • Platelets ≥30,000/µL. • Hemoglobin ≥ 8.0 g/dL (≥ 7.0 g/dL for hematologic malignancies). • Serum creatinine ≤2.0 x ULN. 8. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment. 9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. |
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E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the trial: 1. Mutations or amplification involving the cMet gene but not the ALK gene locus. 2. Current treatment on another therapeutic clinical trial. 3. Prior therapy specifically directed against ALK. 4. Prior allogeneic bone marrow transplant. 5. Clinically apparent or known carcinomatous meningitis, or leptomeningeal disease unless under treatment. 6. Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function. 7. Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, or cerebrovascular accident including transient ischemic attack. 8. Ongoing uncontrolled congestive heart failure. 9. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, uncontrolled atrial fibrillation of any grade, or QTc interval >470 msec. 10. Known interstitial fibrosis or interstitial lung disease. 11. Pregnancy or breastfeeding. 12. Use of drugs or foods that are known potent CYP3A4 inhibitors, including but not limited to amprenavir, atazanavir, clarithromycin, delavirdine, diltiazem, erythromycin, indinavir, itraconazole, ketoconazole, miconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, verapamil, voriconazole, and grapefruit or grapefruit juice. 13. Concurrent use of drugs that are known potent CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, tipranavir, ritonavir, and St. John’s wort. 14. Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to aripiprazole, ergotamine, halofantrine, pimozide, triazolam, astemizole*, cisapride*, and terfenadine* (* withdrawn from U.S. market). 15. 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 in situ cervical cancer, or prostate cancer) within the last 3 years. 16. Active wound healing problems such as chronic wound. 17. Active gastrointestinal problems or symptoms such as a gastrointestinal ulcer or Grade ≥ 3 diarrhea. 18. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for entry into this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Type, incidence, severity, seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities. • Overall response rate (ORR) based on RECIST version 1.1.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• PFS, overall survival (OS) at 6 months and 1 year, OS and duration of response (DR). • Plasma concentrations of crizotinib. • Proportion of patients with each of the ALK genetic events (translocation, mutation, amplification). • Phosphorylation status of ALK in the tumor samples from surgery or biopsy pre and post treatment when available. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Taiwan |
China |
Italy |
Japan |
Korea, Republic of |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 12 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |