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 Kinsase (ALK) Gene Locus

Summary

This is an open-label, multi-center, randomized Phase 3 efficacy and safety study of crizotinib versus first-line chemotherapy. A total of 334 patients will be randomized in a 1:1 ratio to receive crizotinib (Arm A) or chemotherapy with pemetrexed/carboplatin or pemetrexed/cisplatin (Arm B). The choice of the chemotherapy regimen to be used will be made by the treating investigator. Patients will continue with the assigned study treatment until RECIST-defined progression of disease is determined by independent radiology review, unacceptable toxicity, death or consent withdrawal. Patients may continue treatment as assigned beyond the time of RECIST-defined progression at the discretion of the investigator if the patient is perceived to be experiencing clinical benefit. Patients who are assigned to Arm B who progress as determined by the independent radiology review will be allowed to cross-over to the crizotinib treatment (Arm A) providing they meet screening eligibility criteria for safety relavent to crizotinib therapy.

Weickhardt et al, 201239 recently reported decreases in total testosterone levels in 19 of 19 patients on crizotinib treatment. There were several limitations of this analysis, including but not limited to diurnal timing of the blood samples and insufficient baseline versus on-treatment total and free testosterone levels over time, and thus a further systematic
assessment of testosterone levels to understand the validity of these data is warranted. Dual energy X-ray Absorptiometry (DXA) scans to measure bone mineral density and muscle mass will also be performed to understand the clinical relevance of any abnormally low testosterone levels observed. Protocol Amendment 6 includes these laboratory and
radiological assessments as part of the overall safety evaluation.

Participant Eligibility

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 chemotherapyradiation
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 #10-12.
5. Any major surgeries must have been completed at least 4 weeks prior to initiation of
study medication. Any prior radiation or minor surgeries/procedures must have been
completed at least 2 weeks prior to the initiation of study medication. Any acute toxicity
must have recovered to less than or equal to Grade 1 (except alopecia).
6. Tumors must have measurable disease as per RECIST (version 1.1).
7. Female or male, 18 years of age or older.
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.
 Total serum bilirubin <=1.5 x ULN.
Bone marrow function:
 Absolute neutrophil count (ANC) >=1500/L.
 Platelets >=100,000/L.
 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 legally acceptable 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 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.
13. Spanish-speaking subjects will be eligible for participation in this study.
14. All races, ethnicities and genders are eligible to participate.