A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01154140
First received: June 29, 2010
Last updated: March 20, 2015
Last verified: March 2015
  Purpose

This study will evaluate the anti-cancer effects of crizotinib when compared with standard chemotherapy in patients with ALK positive lung cancer.


Condition Intervention Phase
Non Squamous Lung Cancer
Drug: treatment
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
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 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 Independent Radiology Review (IRR) by Treatment Arm [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: From randomization to death or last date known alive for those not known to have died (up to 35 months) ] [ Designated as safety issue: No ]
    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.

  • OS Probability at Months 12 and 18 [ Time Frame: Months 12 and 18 ] [ Designated as safety issue: No ]
    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.

  • Objective Response Rate - Percentage of Participants With Objective Response as Assessed by IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ] [ Designated as safety issue: No ]
    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.

  • 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 (up to 35 months). ] [ Designated as safety issue: No ]
    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. The median duration of response presented in below table was based on Brookmeyer and Crowley method.

  • Time to Tumor Response (TTR) Based on IRR [ Time Frame: Randomization to first documentation of objective tumor response (up to 35 months) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Disease Control at Week 12 Based on IRR [ Time Frame: From randomization to Week 12 ] [ Designated as safety issue: No ]
    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.

  • Time to Progression (TTP) Based on IRR [ Time Frame: Randomization to objective progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ] [ Designated as safety issue: No ]
    TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression (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. The median TTP presented in below table was based on Brookmeyer and Crowley method,

  • Time to Intracranial 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 (up to 35 months) ] [ Designated as safety issue: No ]
    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. The median IC-TTP presented in below table was based on Brookmeyer and Crowley method.

  • Time to Extracranial 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 (up to 35 months) ] [ Designated as safety issue: No ]
    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. The median EC-TTP presented in below table was based on Brookmeyer and Crowley method.

  • 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 ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: Yes ]
    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.

  • Plasma Predose Concentration (Trough Concentration [Ctrough]) of Crizotinib and Its Metabolite [ Time Frame: Cycle 2 Day 1, Cycle 3 Day 1 and Cycle 5 Day 1 ] [ Designated as safety issue: No ]
    This analysis was performed in crizotinib arm only. Plasma samples for pharmacokinetic (PK) assessment were to be obtained prior to (predose) and around the time to maximum plasma concentration (Tmax) following morning dosing (at 2 to 6 hours postdose until Protocol Amendment 6 which changed the timing of PK sampling to 3 and 5 hours postdose) on Day 1 of Cycles 2, 3, and 5.

  • Percentage of Participants for Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants [ Time Frame: Screening ] [ Designated as safety issue: No ]
    A mandatory tumor sample (archived or fresh) was required at screening for detecting ALK gene fusion events in order to determine the eligibility of participants to enter the study. The Vysis ALK Break Apart Fluorescence In Situ Hybridization (FISH) test was used as the primary assay. Only those participants whose tissue sample was positive for the ALK gene fusion by FISH testing by the central laboratory were allowed to enter the study. Testing for ALK gene fusion variants was performed using the Response Genetics, Inc. Echinoderm Microtubule Associated Protein Like 4 (EML4) ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test.

  • ORR Between ALK Variant Groups Based on IRR [ Time Frame: Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months) ] [ Designated as safety issue: No ]
    A mandatory tumor sample (archived or fresh) was required at screening for detecting ALK gene fusion events in order to determine the eligibility of participants to enter the study. The Vysis ALK Break Apart Fluorescence In Situ Hybridization (FISH) test was used as the primary assay. Only those participants whose tissue sample was positive for the ALK gene fusion by FISH testing by the central laboratory were allowed to enter the study. Testing for ALK gene fusion variants was performed using the Response Genetics, Inc. Echinoderm Microtubule Associated Protein Like 4 (EML4) ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test. Percentage of participant with complete or partial response was according to RECIST version 1.1 by type of ALK gene fusion variant.

  • Time to Deterioration (TTD) in Pain in Chest, Dyspnea, or Cough [ Time Frame: From Baseline to deterioration while on study treatment ] [ Designated as safety issue: No ]
    TTD in pain in chest, dyspnea, or cough from the Quality of Life Questionnaire Core 30 (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. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment (QLQ-LC13) for pain, dyspnea, or cough. A 10-point or higher change in the score was perceived by participants as clinically significant. The median TTD mentioned in below table was based on Brookmeyer and Crowley method.

  • 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 or crossover ] [ Designated as safety issue: No ]
    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). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.

  • 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 or crossover ] [ Designated as safety issue: No ]
    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). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.

  • 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 or crossover ] [ Designated as safety issue: No ]
    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 patients receiving chemotherapy. Scale score range: 0 to 100. Higher symptom score = greater degree of symptom severity.

  • Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS) [ Time Frame: From Baseline up to treatment withdrawal or crossover ] [ Designated as safety issue: No ]
    The EQ-5D is a validated and reliable self-report preference-based measure developed by the EuroQoL Group to assess health-related quality of life. It consists of the EQ-5D descriptive system and a visual analogue scale-the EQ VAS. The EQ-5D descriptive system measures a participants' health state on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting "no health problems," "moderate health problems," and "extreme health problems." The EQ VAS records the respondent's self-rated health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

  • Percentage of Participants With Hospital Admissions-Healthcare Resource Utilization (HCRU) [ Time Frame: From 28 days prior to the start of study treatment and up to 28 days post the last dose of study treatment ] [ Designated as safety issue: No ]
    Hospitalization details were evaluated in this study. Data regard to hospitalizations were summarized from information in the case report forms.


Enrollment: 343
Study Start Date: January 2011
Estimated Study Completion Date: July 2016
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A Drug: treatment
crizotinib 250mg orally continuous twice daily dosing
Active Comparator: B Drug: treatment
pemetrexed 500mg/m2 IV day 1 plus cisplatin 75mg/m2 IV day 1 every 21 days OR pemetrexed 500mg/m2 IV day 1 plus carboplatin AUC 5 or 6 day 1 every 21 days investigator's choice

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 with no ongoing requirement for corticosteroids
  • 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.
  • 18 years of age or older with the exception of India which has an upper age limit of 65 years old

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 CYP3A4 inducers/inhibitors Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices.
  • Known HIV infection
  • Known interstitial lung disease or interstitial fibrosis
  • Other severe acute or chronic medical conditions (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
  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: NCT01154140

  Show 243 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided by Pfizer

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01154140     History of Changes
Other Study ID Numbers: A8081014, 2010-021336-33, XALCORI
Study First Received: June 29, 2010
Results First Received: November 26, 2014
Last Updated: March 20, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
open label
randomized Phase 3
first line treatment
non squamous lung cancer
ALK translocation event positive

Additional relevant MeSH terms:
Carboplatin
Crizotinib
Pemetrexed
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on April 26, 2015