| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-small cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| non small cell lung cancer |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029519 |
| E.1.2 | Term | Non-small cell lung cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
• To demonstrate that crizotinib (Arm A) is superior to first-line chemotherapy
(pemetrexed/cisplatin or pemetrexed/carboplatin) (Arm B), in prolonging PFS in patients with advanced non-squamous NSCLC whose tumors harbor a translocation or inversion event involving the ALK gene locus. |
|
| E.2.2 | Secondary objectives of the trial |
•To compare secondary measures of clinical efficacy including objective response rate (ORR), overall survival (OS), disease control rate (DCR) at 12 weeks, times to overall, intracranial and extracranial progression (TTP, IC-TTP, EC-TTP) between the two treatment arms and evaluate OS at 1 year and 18 months, duration of response (DR), and time to tumor response (TTR).
•To evaluate the safety and tolerability of crizotinib compared to chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin).
•To evaluate PK of crizotinib (including its active moieties, if appropriate) in this patient population using population PK (POPPK) methods and explore correlations between PK, response and/or safety
findings, Arm A only.
•To correlate ALK gene fusion variants to outcome measures.
•To compare patient reported outcomes (PRO) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status in both treatment arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically proven diagnosis of locally advanced not suitable for local treatment, recurrent or metastatic non squamous non small cell carcinoma of the lung.
2. Positive for translocation or inversion events involving the ALK gene locus (eg, resulting in EML4-ALK fusion) as determined by an ALK break apart FISH assay and defined by an increase in the distance between 5’ and 3’ ALK probes or the loss of the 5’ probe.
3. No prior systemic treatment for locally advanced or metastatic disease (exception below):
- Prior adjuvant chemotherapy for Stage I-III or combined modality chemotherapy-radiation for locally advanced disease allowed if completed >12 months prior to documented disease progression.
4. Patients with brain metastases are only eligible if treated and neurologically stable with no ongoing requirement for corticosteroids, eg, dexamethasone, for at least 2 weeks and are not taking medications contraindicated in Exclusion Criteria # 12-14 (in the protocol).
5. Any major surgeries 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 completed 48 hrs prior to crizotinib therapy commencing. Any acute toxicity must have recovered to ≤ Grade 1 (except alopecia).
6. Tumors must have measurable disease as per RECIST
7. Female or male, 18 years of age or older (for patients enrolled in Japan: consent from a legally acceptable representative is required for all patients who are under 20 years old). For patients in India upper age limit is 65 years old.
8. ECOG performance status 0-2.
9. Adequate organ function as defined by the following criteria: Hepatic function:
- Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to underlying malignancy. Patients enrolled in France with ALT ≥3 and ≤5 x ULN must not have evidence of advanced fibrosis as detected by Fibrotest >0.48
- Total serum bilirubin ≤1.5 x ULN. Bone marrow function:
• Absolute neutrophil count (ANC) ≥1500/µL.
• Platelets ≥100,000/µL.
• Hemoglobin ≥9.0 g/dL. Renal function:
• Creatinine clearance (based on modified Cockcroft- Gault formula) ≥60 ml/min.
10. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study prior to enrollment.
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures including completion of PRO measures.
12. Male patients able to father children and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for 90 days after the last dose of assigned treatment. Male patients randomized to Arm B must use highly effective method of contraception for a total of 180 days after last dose of chemotherapy. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active. |
|
| E.4 | Principal exclusion criteria |
1. Current treatment on another therapeutic clinical trial. Patients who are investigational site staff members or relatives of those site staff members, or patients who are Pfizer employess directly involved in the conduct of the trial.
2. Prior therapy directly targeting ALK.
3. Carcinomatous meningitis, or leptomeningeal disease.
4. Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.
5. 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. Appropriate treatment with anticoagulants is permitted.
6. Ongoing congestive heart failure.
7. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, or machine-read ECG with QTc interval >470 msec.
8. Peripheral neuropathy with Grade ≥1 (CTCAE version 4.0).
9. 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.
10. Previous treatment with crizotinib.
11. Pregnancy or breastfeeding.
12. Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to the first dose of crizotinib, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconzole, and grapefruit or grapefruit juice. The topical use of these medications (if applicable), such as 2% ketoconazole cream, may be allowed.
13. Use of drugs that are known potent CYP3A4 inducers within 12 days prior to the first dose of crizotinib, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, , and St. John’s wort.
14. Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to dihydroergotamine, ergotamine, pimozide, astemizole*, cisapride*, and terfenadine* (*withdrawn from U.S. market).
15. Prior malignancy (other than current NSCLC): patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or in situ cervical cancer, or localized and presumed cured prostate cancer) within the last 3 years.
16. Known HIV infection.
17. Other severe acute or chronic medical (including severe gastrointestinal conditions such as diarrhea or ulcer) or psychiatric conditions, or end-stage renal disease on hemodialysis. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (documented by independent radiology laboratory). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| every 6 weeks from randomisation date |
|
| E.5.2 | Secondary end point(s) |
ORR (documented by independent radiology laboratory), OS, DCR at 12 weeks, TTP, IC-TTP, EC-TTP, OS at 1 year and 18 months ,DR and TTR.
Type, incidence, severity, seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities.
Plasma concentrations of crizotinib (including its active moieties, if appropriate).
Proportion of patients with each of the ALK fusion variants of the EML4-ALK fusion.
Time to deterioration in pain, dyspnea, or cough patient reported disease symptoms.
HRQoL, disease/treatment-related symptoms, and general health status.
HCRU with respect to hospitalizations and concomitant medication use for select adverse events (eg, hematologic events). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| India |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Luxembourg |
| Mexico |
| Netherlands |
| Norway |
| Peru |
| Portugal |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| End of trial in all participating countries is defined as the last contact check for survival follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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