Phase 3, randomized, open-label study of the efficacy and safety of CRIZOTINIB versus pemetrexed/cisplatin or pemetrexed/carboplatin iN previously untreated PATIENTS WITH NON-Squamous Carcinoma OF THE LUNG harboring a translocation or inversion event involving the anaplastic lymphoma Kinase (ALK) gene locus.

Study Objective
 

Primary

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.

Secondary

To compare secondary measures of clinical efficacy including objective response rate (ORR), overall survival (OS) at 6 months and 1 year and OS between the two treatment arms and evaluate duration of response (DR).

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.

To assess HCRU with respect to hospitalization (ie, length of stay, frequency) and concomitant medication use for select adverse events (e.g., hematologic events).

Participation conditions

After a patient has provided written informed consent, has been shown to have NSCLC positive for the ALK fusion gene (by the central laboratory), and has completed the necessary screening and been found eligible, the patients will be randomized in a 1:1 ratio to receive crizotinib (Arm A) or chemotherapy pemetrexed/cisplatin or pemetrexed/carboplatin (Arm B).

Inclusion criteria

• Histologically or cytologically proven diagnosis of locally advanced not suitable for local treatment, recurrent and metastatic non-squamous cell carcinoma of the lung.
• Positive for translocation or inversion events involving the ALK gene locus (eg, resulting in EML4-ALK fusion).
• No prior systemic treatment for locally advanced or metastatic disease (exception below):
• Prior adjuvant chemotherapy for Stage I-III or combined modality chemotherapyradiation for locally advanced disease allowed if completed >12 months prior to randomization.
• 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 #10-12.
• 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).
• Tumors must have measurable disease as per RECIST.
• Female or male, 18 years of age or older.
• ECOG performance status 0-2.
• 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.
  • 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 ≥60 ml/min.
• Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study prior to enrollment.
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures including completion of PRO measures.

Exclusion criteria

• Current treatment on another therapeutic clinical trial.
• Prior therapy directly targeting ALK.
• Carcinomatous meningitis, or leptomeningeal disease.
• Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.
• 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.
  • Ongoing congestive heart failure.
  • Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, or QTc interval >470 msec.
  • Peripheral neuropathy with Grade ≥1.
  • Known interstitial fibrosis or interstitial lung disease.
• Previous treatment with crizotinib.
• Pregnancy or breastfeeding.
• 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, voriconzole, and grapefruit or grapefruit juice.
• 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.
• Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited aripiprazole, ergotamine, halofantrine, pimozide, triazolam, astemizole, cisapride, and terfenadine.
• 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.
• Known HIV infection.
• Other severe acute or chronic medical (including severe gastrointestinal conditions such as diarrhea or ulcer) 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.

Oncologists at Centre Hospitalier de Luxembourg