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A Phase III Double-Blind Trial for Surgically Resected Early Stage Non-Small Cell Lung Cancer: Crizotinib versus Placebo for Patients with Tumors Harboring the Anaplastic Lymphoma Kinase (ALK) Fusion Protein

Description

This randomized phase III trial studies how well Crizotinib works and compares it to placebo in treating patients with stage IB-IIIA non-small cell lung cancer that has been removed by surgery and has a mutation in a protein called Anaplastic Lymphoma Kinase (ALK). Mutations, or changes, in ALK can make it very active and important for tumor cell growth and progression. Tumors with this mutation may respond to treatments that target the mutation, such as Crizotinib. Crizotinib may stop the growth of tumor cells by blocking the ALK protein from working. Objectives: The primary objective is to evaluate whether adjuvant therapy with Crizotinib will result in improved overall survival (OS) over placebo for patients with stage IB >= 4 cm, II and IIIA, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) following surgical resection. Study Population: Participants 18 years and older who have undergone complete surgical resection of their stage IB ( 4 cm), II, or IIIA NSCLC and have had negative margins. N3 disease is not allowed. Study Arms: ARM A: Patients receive crizotinib orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive placebo PO BID on days 1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Follow up: After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years. Endpoint: Overall survival (OS) is defined as the time from randomization to death from any cause. Patients that have not had an event reported at analysis will be censored at their date of last follow up. Analysis: The primary analysis will include all patients who testing positive for ALK at the central reference lab (Response Genetics), however patients with a local positive test but negative central test can still be randomized on the trial and will be included in a secondary analysis. Secondary analyses will typically include the primary analysis population. Exception to this include: analysis of toxicity data, which will include all patients from the primary analysis who received study drug regardless of eligibility.

Phase

Phase 3 - a treatment has shown activity against a particular disease, where it is either added to existing treatment or compared to the standard treatment.

Inclusion and Exclusion Criteria

  • Inclusion Criteria:
  • Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II, or non-squamous IIIA NSCLC per American Joint Committee on Cancer (AJCC) 7th edition and have had negative margins; N3 disease is not allowed
  • Baseline chest computed tomography (CT) with or without contrast must be performed within 6 months (180 days) prior to randomization to ensure no evidence of disease; if clinically indicated additional imaging studies must be performed to rule out metastatic disease
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization
  • Positive for translocation or inversion events involving the ALK gene locus (e.g. resulting in echinoderm microtubule associated protein like 4 [EML4]-ALK fusion) as determined by the Vysis Break Point fluorescence in situ hybridization (FISH) assay and defined by an increase in the distance between 5' and 3' ALK probes or the loss of the 5' probe; this must have been performed:
  • By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory: report must indicate the results as well as the CLIA number of the laboratory which performed the assay; tissue must be available for submission for central, retrospective confirmation of the ALK fusion status via ALCHEMIST-SCREEN (ALLIANCE A151216) OR
  • Patient registered to and the ALK fusion status performed centrally on the ALCHEMIST-SCREEN (ALLIANCE A151216)
  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood or urine pregnancy test within 72 hours prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Women of childbearing potential and sexually active males must be strongly advised to practice abstinence or use an accepted and effective method of contraception
  • Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • No known interstitial fibrosis or interstitial lung disease
  • No prior treatment with crizotinib or another ALK inhibitor
  • No ongoing cardiac dysrhythmias of grade >= 2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, uncontrolled atrial fibrillation (any grade), or corrected QT (QTc) interval > 470 msec
  • No use of medications, herbals, or foods that are known potent cytochrome P450, subfamily 3A, polypeptide 4 (CYP3A4) inhibitors or inducers, included but not limited to those outlined
  • Patients must be adequately recovered from surgery at the time of randomization
  • The minimum time requirement between date of surgery and randomization must be at least 4 weeks (28 days)
  • The maximum time requirement between surgery and randomization must be:
  • 3 months (90 days) if no adjuvant chemotherapy was administered
  • 8 months (240 days) if adjuvant chemotherapy was administered
  • 10 months (300 days) if adjuvant chemotherapy and radiation therapy were administered
  • Patients must have completed any prior adjuvant chemotherapy or radiation therapy 2 or more weeks (6 or more weeks for mitomycin and nitrosoureas) prior to randomization and be adequately recovered at the time of randomization
  • NOTE: Patients taking low dose methotrexate for non-malignant conditions and other cytotoxic agents for non-malignant conditions are allowed to continue treatment while on study
  • NOTE: Neo-adjuvant chemotherapy or radiation therapy for the resected lung cancer is not permitted
  • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
  • Total serum bilirubin =< 1.5 x ULN
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 30,000/mm^3
  • Hemoglobin >= 8.0 g/dL
  • Serum creatinine =< 2 x ULN
  • Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy, or radiation must have recovered to grade =< 1 with the exception of alopecia and the criteria outlined
  • Patients must not have any history of cancer within 5 years from randomization, with the exception of in-situ carcinomas and non-melanoma skin cancer
  • Patients may not be receiving any other investigational agents while on study

Sites

Please contact Carryl Du Bois to learn more about where you can participate in this trial. Please use the contact form on the right side.

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