An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene

• ClinicalTrials.gov Identifier: NCT00932893
• Recruitment Status: Completed
• First Posted: July 3, 2009
• Results First Posted: June 6, 2013
• Last Update Posted: January 2, 2017
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: June 30, 2009
• First Posted Date: July 3, 2009
• Results First Submitted Date: March 13, 2013
• Results First Posted Date: June 6, 2013
• Last Update Posted Date: January 2, 2017
• Study Start Date: September 2009
• Actual Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 4, 2013)

Progression-Free Survival (PFS) [ Time Frame: Randomization until progressive disease (PD) or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks) ]

PFS: Time in months from randomization to first documentation of objective disease progression as determined by independent radiology review or to death due to any cause, whichever occurred first. PFS was calculated as (first event date minus the date of randomization plus 1) divided by 30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria version 1.1 (RECIST v1.1), as at least a 20% increase (including an absolute increase of at least 5 mm) 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.

• Original Primary Outcome Measures (submitted: July 2, 2009): Progression-Free Survival (PFS) of PF-02341066 vs Pemetrexed or Docetaxel [ Time Frame: 30 months ]

Current Secondary Outcome Measures (submitted: October 31, 2016)

• Overall Survival (OS) [ Time Frame: Randomization until death (up to 4.5 years) ]
  OS: Time in months from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 30.4.
• Overall Survival Probability at Months 6 and 12 [ Time Frame: Month 6, 12 ]
  Overall survival probability at Month 6 and 12 was defined as the probability of survival at 6 and 12 months respectively, after the randomization of study treatment. The survival probability was estimated using the Kaplan-Meier method.
• Percentage of Participants With Objective Response (OR) [ Time Frame: Randomization until PD or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks) ]
  Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 millimeter [mm] short axis). PR: at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Objective response is based on independent radiology review.
• Percentage of Participants With Disease Control at Week 6 [ Time Frame: Week 6 ]
  Disease control: participants with CR, PR, or stable disease (SD) according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). PR: at least 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD: at least a 20% increase (including an absolute increase of at least 5 mm) 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. Disease control is based on independent radiology review.
• Percentage of Participants With Disease Control at Week 12 [ Time Frame: Week 12 ]
  Disease control: participants with CR, PR, or SD according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). PR: at least 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase (including an absolute increase of at least 5 mm) 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.
• Duration of Response (DR) [ Time Frame: Randomization until PD or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks) ]
  Time in weeks from the first documentation of objective tumor response to objective tumor progression or death due to any cause. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to any cause minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 7.02. DR was calculated for the subgroup of participants with a confirmed objective tumor response.
• Time to Tumor Response (TTR) [ Time Frame: Randomization until PD or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks) ]
  Time from date of randomization to first documentation of objective tumor response. TTR was calculated for the subgroup of participants with objective tumor response. Objective tumor response was defined as CR or PR according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). PR: at least 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
• Plasma Concentration of Crizotinib [ Time Frame: Pre-dose on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of Cycles 2, 3, 5 ]
  Only participants receiving crizotinib were to be analyzed for this outcome measure as per planned analysis.
• Number of Participants With Categorical Maximum QTcF for Crizotinib [ Time Frame: Pre-dose on Day 1 of Cycle 1, 2 to 6 hours post-dose on Day 1 of Cycle 1, 2 ]
  QT interval corrected using Fridericia's formula (QTcF): QT interval (time corresponding to the beginning of depolarization to re-polarization of the ventricles) divided by cube root of RR interval. Maximum QTcF was categorized as less than (<) 450 milliseconds (msec), 450 msec to <480 msec, 480 msec to <500 msec, and more than or equal to (>=) 500 msec. A participant is reported only once under the maximum QTcF interval observed at any of the time-points. Only participants receiving crizotinib were to be analyzed for this outcome measure as per planned analysis.
• Plasma Concentration of Soluble c-Met Ectodomain and Hepatocyte Growth Factor Scatter Proteins [ Time Frame: Pre-dose on Day 1 of Cycle 1, 2 to 6 hours post-dose on Day 1 of Cycle 2, end of treatment (up to 112 weeks) ]
  Descriptive statistics (absolute value and change from baseline as measured by ratio to baseline) for each best overall response category (CR, PR, SD, PD or combined) have been used to summarize the data from optional soluble c-Met ectodomain assays for crizotinib treated patients.
• Time to Deterioration (TTD) in Participant Reported Pain, Dyspnea, and Cough [ Time Frame: Baseline up to end of treatment (up to 112 weeks) ]
  TTD in pain (pain in chest from European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Supplement Module for Lung Cancer [EORTC QLQ-LC13]), dyspnea (from EORTC QLQ-LC13), or cough (from EORTC QLQ-LC13) symptoms was defined as the time from randomization to the earliest time the participant's score showed a 10 point or higher increase from baseline in any of the three symptoms from the instrument. The transformed score of pain, dyspnea, and cough symptom scales of EORTC QLQ-LC13 range from 0 to 100, greater scores = higher symptom severity.
• European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [ Time Frame: Baseline, Day (D) 1 of each cycle (C) until disease progression, end of treatment (EOT, up to 112 weeks) ]
  EORTC QLQ-C30: included global health status/quality of life (QoL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, 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 for Global Qol/functional scales=better level of QoL/functioning or higher score for symptom scale=greater degree of symptoms.
• European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Supplement Module for Lung Cancer (EORTC QLQ-LC13) [ Time Frame: Baseline, Day 1 of each cycle until disease progression, end of treatment (up to 112 weeks) ]
  QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Recall period: past week; response range: 1 'Not at All' to 4 'Very Much'. Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms.
• European Quality of Life - 5 Dimensional (EQ-5D) Visual Analog Scale (VAS) [ Time Frame: Baseline, Day 1 of each cycle until disease progression, end of treatment (up to 112 weeks) ]
  EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. 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.

Original Secondary Outcome Measures (submitted: July 2, 2009)

• Objective Response Rate [ Time Frame: 23 months ]
• Duration of Response [ Time Frame: 23 months ]
• Disease Control Rate [ Time Frame: 30 months ]
• Overall Survival [ Time Frame: 30 months ]
• Patient reported symptoms of lung cancer and health-related quality of life [ Time Frame: 30 months ]
• Type, incidence, severity, seriousness and relationship to study medication of adverse events and laboratory test abnormalities [ Time Frame: 30 months ]
• Plasma concentrations of PF-02341066 [ Time Frame: 30 months ]
• Types of EML4-ALK fusion variants and ALK gene expression [ Time Frame: 30 months ]
• Plasma concentrations of pharmacodynamic biomarkers [ Time Frame: 30 months ]
• QTc [ Time Frame: 30 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
• Official Title: Phase 3, Randomized, Open-label Study Of The Efficacy And Safety Of Pf-02341066 Versus Standard Of Care Chemotherapy (Pemetrexed Or Docetaxel) In Patients With Advanced Non-small Cell Lung Cancer (Nsclc) Harboring A Translocation Or Inversion Event Involving The Anaplastic Lymphoma Kinase (Alk) Gene Locus
• Brief Summary: This is a Phase 3 trial comparing the safety and anti-tumor activity of PF-02341066 versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer with specific gene profile involving the ALK gene after failure of one previous chemotherapy regimen that included one platinum drug.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Non-Small-Cell Lung

Intervention

• Drug: PF-02341066
  PF-02341066, 250 mg BID will be administered orally on a continuous schedule
• Drug: Pemetrexed
  Pemetrexed, 500 mg/m^2, will be administered by i.v. infusion over 10 minutes on Day 1 of each 21-day cycle
• Drug: Docetaxel
  Docetaxel, 75 mg/m^2, will be administered by i.v. infusion over 1 hour on Day 1 of each 21-day cycle

Study Arms

• Experimental: PF-02341066
  Intervention: Drug: PF-02341066
• Active Comparator: Pemetrexed or Docetaxel
  Investigator selection of either pemetrexed or docetaxel as the active comparator
  Interventions:

  • Drug: Pemetrexed
  • Drug: Docetaxel

Publications *

• Camidge DR, Kim EE, Usari T, Polli A, Lewis I, Wilner KD. Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC. J Thorac Oncol. 2019 Jun;14(6):1077-1085. doi: 10.1016/j.jtho.2019.02.015. Epub 2019 Feb 26.
• Wilner KD, Usari T, Polli A, Kim EE. Comparison of cardiovascular effects of crizotinib and chemotherapy in ALK-positive advanced non-small-cell lung cancer. Future Oncol. 2019 Apr;15(10):1097-1103. doi: 10.2217/fon-2018-0869. Epub 2019 Jan 17.
• Yoneda KY, Scranton JR, Cadogan MA, Tassell V, Nadanaciva S, Wilner KD, Stollenwerk NS. Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials. Clin Lung Cancer. 2017 Sep;18(5):472-479. doi: 10.1016/j.cllc.2017.03.004. Epub 2017 Mar 14.
• Lin YT, Yu CJ, Yang JC, Shih JY. Anaplastic Lymphoma Kinase (ALK) Kinase Domain Mutation Following ALK Inhibitor(s) Failure in Advanced ALK Positive Non-Small-Cell Lung Cancer: Analysis and Literature Review. Clin Lung Cancer. 2016 Sep;17(5):e77-e94. doi: 10.1016/j.cllc.2016.03.005. Epub 2016 Mar 30.
• Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, Zhou C, Shreeve SM, Selaru P, Polli A, Schnell P, Wilner KD, Wiltshire R, Camidge DR, Crino L. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol. 2015 Jun 10;33(17):1881-8. doi: 10.1200/JCO.2014.59.0539. Epub 2015 Jan 26.
• Lin YT, Wang YF, Yang JC, Yu CJ, Wu SG, Shih JY, Yang PC. Development of renal cysts after crizotinib treatment in advanced ALK-positive non-small-cell lung cancer. J Thorac Oncol. 2014 Nov;9(11):1720-5. doi: 10.1097/JTO.0000000000000326.
• Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Janne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. doi: 10.1056/NEJMoa1214886. Epub 2013 Jun 1. Erratum In: N Engl J Med. 2015 Oct 15;373(16):1582.
• Tamiya A, Okamoto I, Miyazaki M, Shimizu S, Kitaichi M, Nakagawa K. Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALK-positive non-small-cell lung cancer. J Clin Oncol. 2013 Jan 1;31(1):e15-7. doi: 10.1200/JCO.2012.43.3730. Epub 2012 Nov 19. No abstract available.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2013): 347
• Original Estimated Enrollment (submitted: July 2, 2009): 318
• Actual Study Completion Date: January 2016
• Actual Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• histologically or cytologically proven diagnosis of non-small cell lung cancer
• positive for the ALK fusion gene (test provided by a central laboratory)
• must have had disease progression after only one prior chemotherapy and that regimen but must have included one platinum drug
• tumors must be measurable

Exclusion Criteria:

• prior treatment with PF-02341066
• current treatment in another clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Bulgaria, Canada, China, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Sweden, Taiwan, United Kingdom, United States
• Removed Location Countries: Argentina

Administrative Information

• NCT Number: NCT00932893
• Other Study ID Numbers: A8081007; 2009-012595-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pfizer
• Original Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc.
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: October 2016