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A Study Of Crizotinib Versus Chemotherapy In Previously Untreated ALK Positive East Asian Non-Small Cell Lung Cancer Patients

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01639001
First received: July 10, 2012
Last updated: January 23, 2017
Last verified: January 2017
  Purpose
This is a Phase III, Randomized, Open-label, Efficacy and Safety Study of Crizotinib single agent versus Chemotherapy Regimens (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) in First-Line ALK (Anaplastic Lymphoma Kinase) Positive East Asian Non-Small Cell Lung Cancer Patients. The objective of the study is to demonstrate that Crizotinib is superior to first-line chemotherapy pemetrexed/cisplatin or pemetrexed/carboplatin in prolonging Progression Free Survival (PFS) in East Asian patients with advanced Non-Squamous NSCLC whose tumors harbor a translocation or inversion event involving the ALK (Anaplastic Lymphoma Kinase) gene locus.

Condition Intervention Phase
NSCLC (Non-small Cell Lung Cancer)
Drug: Crizotinib
Drug: Pemetrexed/Cisplatin
Drug: Pemetrexed/Carboplatin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase 3, Randomized, Open-label Study Of The Efficacy And Safety Of Crizotinib Versus Pemetrexed/Cisplatin Or Pemetrexed/Carboplatin In Previously Untreated East Asian Patients With Non-squamous Carcinoma Of The Lung Harboring A Translocation Or Inversion Event Involving The Anaplastic Lymphoma Kinase (Alk) Gene Locus

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Progression-Free Survival (PFS) Based on IRR by Treatment Arm [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months) ]
    PFS was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression (by IRR) or death on study due to any cause, whichever occured first. If tumor progression data included more than 1 date, the first date was used. PFS (in months) was calculated as (first event date − randomization date +1)/30.44. Progression is defined using RECIST v1.1, as at least a 20% increase (including an absolute increase of at least 5 millimeters) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.


Secondary Outcome Measures:
  • Objective Response Rate (ORR) - Percentage of Participants With Objective Response Based on IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (assessed up to 33 months) ]
    Percentage of participants with objective response of complete response (CR) or partial response (PR) according to RECIST version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

  • Overall Survival (OS) [ Time Frame: From randomization to death or last date known alive for those not known to have died (whichever occurred first, assessed up to 33 months) ]
    OS was defined as the time from randomization to the date of death due to any cause. OS (in months) was calculated as (date of death − date of randomization +1)/30.44.

  • Percentage of Participants With Disease Control at 12 Weeks Based on IRR [ Time Frame: From randomization to Week 12 ]
    Disease Control Rate (DCR) at 12 weeks is defined as the percent of participants with CR, PR or stable disease (SD) at 12 weeks according to RECIST version 1.1 as determined by the IRR. The best response of SD can be assigned if SD criteria were met at least once after randomization at a minimum interval of 6 weeks. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

  • Estimate of the Percentage of Participants Surviving at 1 Year and at 18 Months [ Time Frame: From randomization to 18 months ]
    Probability of survival 1 year and 18 month after randomization. The probability of survival at 1 year was estimated using the Kaplan Meier method and a 2-sided 95% CI for the log [-log(1-year survival probability)] was calculated using a normal approximation and then back transformed to give a CI for the 1-year survival probability itself. The probability of survival at 18 months was estimated similarly.

  • Duration of Response (DR) Based on IRR [ Time Frame: From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months) ]
    DR was defined as the time from the first documentation of objective tumor response (CR or PR), as determined by the IRR, to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. DR (in weeks) was calculated as (first date of PD or death − first date of CR or PR +1)/7. DR was only calculated for the subgroup of participants with an objective tumor response.

  • Time to Tumor Response (TTR) Based on IRR [ Time Frame: Randomization to first documentation of objective tumor response (assessed up to 33 months) ]
    TTR was defined as the time from randomization to first documentation of objective tumor response (CR or PR) as determined by the IRR. For participants proceeding from PR to CR, the onset of PR was taken as the onset of response. TTR was calculated for the subgroup of participants with objective tumor response.

  • Time To Progression (TTP) Based on IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months) ]
    TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression, as determined by IRR. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date − randomization date +1)/30.44.

  • Intracranial Time To Progression (IC-TTP) Based on IRR [ Time Frame: Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months) ]
    IC-TTP was defined similarly to TTP, but only considering intracranial disease (excluding extracranial disease) and the progression was determined based on either new brain metastases or progression of existing brain metastases.

  • Extracranial Time To Progression (EC-TTP) Based on IRR [ Time Frame: Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (whichever occurred first, assessed up to 33 months) ]
    EC-TTP was defined similarly to TTP, but only considering extracranial disease (excluding intracranial disease) and the progression was determined based on either new extracranial lesions or progression of existing extracranial lesions.

  • Time to Deterioration (TTD) in Participant Reported Pain, Dyspnea, or Cough [ Time Frame: From Baseline to deterioration while on study treatment. For participants with no deterioration, the data was censored at the last date when QLQ-LC13 assessment for pain, dyspnea, or cough was completed (assessed up to 33 months) ]
    TTD in pain in chest, dyspnea, or cough from the Quality of Life Questionnaire Supplement Module for Lung Cancer (QLQ-LC13) was a composite endpoint defined as the time from randomization to the earliest time the participant's scale scores showed a 10 point or greater increase after baseline in any of the 3 symptoms.

  • Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) [ Time Frame: Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to 33 months) ]
    EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). The QLQ-C30 Global QOL, Physical Functioning, Role Functioning, Cognitive Functioning, Emotional Functioning, and Social Functioning each ranged from 0-100 with higher scores indicating a better level of functioning or better quality of life.

  • Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the EORTC-QLQ-C30 [ Time Frame: Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to 33 months) ]
    EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). The QLQ-C30 Appetite loss, Constipation, Diarrhea, Dysponea, Fatigue, Financial difficulties, Insomnia, Nausea/vomiting, and Pain each ranged from 0-100 with higher scores indicating a high level of symptomatology/problems.

  • Change From Baseline in Lung Cancer Symptom Scores as Assessed by the EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) [ Time Frame: Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to 33 months) ]
    The QLQ-LC13 consisted of 1 multi-item scale and 9 single items that assessed the specific symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer participants receiving chemotherapy. The QLQ-LC13 Alopecia, Coughing, Dysphagia, Dyspnoea, Haemoptysis, Pain in arm or shoulder, Pain in chest, Pain in other parts, Peripheral neuropathy, and Sore mouth each ranged from 0-100 with higher scores indicating a high level of symptomatology/problems.

  • Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS) [ Time Frame: Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to 33 months) ]
    EQ-5D is a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a visual analog scale (VAS). The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.

  • Change From Baseline in General Health Status as Assessed by EQ-5D- Index [ Time Frame: Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to 33 months) ]
    EQ-5D is a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme problems) and a visual analog scale (VAS). EQ-5D summary index is obtained with a formula that weights each level of the 5 dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health).

  • Percentage of Participants With Visual Disturbance as Assessed by Visual Symptom Assessment Questionnaire (VSAQ-ALK) [ Time Frame: Cycle 1 Day 1 to end of treatment or withdrawal, no later than 4 weeks (+/- 1 week) from last dose of study medication or when the decision was taken to withdraw from the study (whichever was sooner, assessed up to 33 months) ]
    The participants who responded to the question: "Have you experienced any visual disturbances?" Only the participants who answered yes were instructed to complete the rest of the questionnaire. N was the number of participants who had completed the first question.

  • Agreement Between Central Laboratory ALK FISH and ALK IHC Test Results - Molecular Profiling Evaluable [ Time Frame: Screening, less than or equal to 28 days prior to dosing. ]
    Agreement between central laboratory anaplastic lymphoma kinase (ALK) fluorescence in situ hybridization (FISH) and ALK immunohistochemistry (IHC) test results is based on analysis of participants in the Molecular Profiling (MP) evaluable population that have an ALK IHC result and an ALK FISH result of either positive or negative only. This MP evaluable population included participants who screen failed, which their ALK test results were negative based on FISH test. Tumor tissue samples from these screen failure participants were consented and kept. These samples served as a part of negative sample set for evaluation of IHC test and/or polymerase chain reaction (PCR) to determine ALK fusion events. Participants with FISH results of uninformative and assay not performed and IHC results of valid IHC status not available were excluded from the analysis of agreement between central laboratory ALK FISH and ALK IHC test results.

  • Percentage of Participants With Treatment-emergent Adverse Events (AEs; All Causalities) [ Time Frame: From the first dose of study medication until 28 days after the last dose of study medication. However all AEs entered in the database from the treatment start were included in AE analyses (assessed up to 33 months) ]
    An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were to be collected from first dose until 28 days after the last dose of study medication. SAEs could be collected after this timeframe if considered to be treatment related. Grade 3 and 4 AEs in below table indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death due to AE. Chemotherapy group in the below table includes data before crossover to crizotinib for participants who crossed over to receive crizotinib.

  • Percentage of Participants With Treatment-emergent AEs (Treatment Related) [ Time Frame: From the first dose of study medication until 28 days after the last dose of study medication. However all AEs entered in the database from the treatment start were included in AE analyses (assessed up to 33 months) ]
    An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs were to be collected from first dose until 28 days after the last dose of study medication. SAEs could be collected after this timeframe if considered to be treatment related. Grade 3 and 4 AEs in the below table indicated severe AE and life-threatening consequences respectively; Grade 5 indicated death related to AE. Chemotherapy group in the below table, only includes data before crossover to crizotinib for those participants who crossed over to receive crizotinib treatment.


Enrollment: 207
Study Start Date: September 2012
Estimated Study Completion Date: January 2018
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Crizotinib
Crizotinib
Drug: Crizotinib
250 mg two times daily [BID], oral, on a continuous daily dosing schedule. Cycles are defined in 21 day periods.
Active Comparator: Chemotherapy
Chemotherapy [Option at Investigator's Choice]
Drug: Pemetrexed/Cisplatin
Option 1: Pemetrexed/Cisplatin; Pemetrexed, 500 mg/m^2, will be administered by intravenous infusion over 10 minutes or according to institutional administration timing on Day 1 of a 21-day cycle. Cisplatin, 75 mg/m^2 will be administered by infusion after adequate hydration according to institutional practices beginning approximately 30 minutes after the end of the pemetrexed infusion. Pemetrexed and cisplatin will be repeated every 3 weeks for a maximum of 6 cycles.
Drug: Pemetrexed/Carboplatin
Option 2: Pemetrexed/Carboplatin. Pemetrexed, 500 mg/m^2, will be administered by intravenous infusion over 10 minutes or according to institutional administration timing on Day 1 of a 21-day cycle. Carboplatin, at a dose calculated to produce an AUC of 5 or 6 mg.min/mL will be administered by infusion according to institutional practices beginning approximately 30 minutes after the end of the pemetrexed infusion. Pemetrexed and carboplatin will be repeated every 3 weeks for a maximum of 6 cycles.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • No prior systemic treatment for locally advanced or metastatic disease. Patients with brain metastases only if treated and neurologically stable for at least 2 weeks and are not taking any medications contraindicated in Exclusion Criteria
  • Evidence of a personally signed and dated informed consent document and willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures including completion of patient reported outcome [PRO] measures.

Exclusion Criteria:

  • Current treatment on another therapeutic clinical trial.
  • Prior therapy directly targeting ALK.
  • Any of the following within the 3 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack. Appropriate treatment with anticoagulants is permitted.
  • Ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, uncontrolled atrial fibrillation of any grade, or QTc interval >470 msec.
  • Pregnancy or breastfeeding.
  • Use of drugs or foods that are known potent CYP3A inducers/inhibitors Concurrent use of drugs that are CYP3A substrates with narrow therapeutic indices.
  • Known HIV infection
  • 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.
  • Other severe acute or chronic medical conditions (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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01639001

  Show 41 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01639001     History of Changes
Other Study ID Numbers: A8081029
Study First Received: July 10, 2012
Results First Received: June 8, 2016
Last Updated: January 23, 2017

Keywords provided by Pfizer:
Crizotinib
ALK positive
ALK
Anaplastic Lymphoma Kinase
NSCLC
Non-Small Cell Lung Cancer
Frontline
1L
Previously Untreated
East Asian
Non-Squamous

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Cisplatin
Carboplatin
Pemetrexed
Crizotinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on April 21, 2017