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Phase II Safety and Efficacy Study of Crizotinib in East Asian Patients With ROS1 Positive, ALK Negative Advanced NSCLC

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01945021
Recruitment Status : Completed
First Posted : September 18, 2013
Results First Posted : August 1, 2016
Last Update Posted : May 5, 2020
Sponsor:
Collaborator:
OxOnc Development LP
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Non Small Cell Lung Cancer
ROS1 Proto Oncogene
Crizotinib
Intervention Drug: Crizotinib
Enrollment 129
Recruitment Details  
Pre-assignment Details 129 patients were enrolled and consented; there were 2 screen failures and 127 received treatment
Arm/Group Title Crizotinib
Hide Arm/Group Description Single-arm trial whereby all consented, enrolled, eligible patients receive crizotinib
Period Title: Overall Study
Started 127 [1]
Safety Population 127 [2]
Response Evaluable Population 127 [3]
Patient Reported Outcome -Evaluable 123 [4]
Completed 80 [5]
Not Completed 47
Reason Not Completed
Adverse Event             8
Death             1
Pregnancy             1
Disease progression by RECIST v1.1             30
Global deterioration of health-related s             1
Withdrawal by Subject             2
Withdrawal of consent             3
Non-RECIST disease progression             1
[1]
127 pts with ROS1+ & ALK negative tumors were consented and started study (2 more were screen fails)
[2]
All enrolled patients who received at least 1 dose of study medication.
[3]
All patients in the safety population who had an adequate baseline tumor assessment
[4]
All patients from the safety population who completed a baseline and >/= 1 post-baseline assessment.
[5]
Completed is defined as patients who continued crizotinib at the time of final analysis (ongoing)
Arm/Group Title Crizotinib
Hide Arm/Group Description Single arm trial whereby all consented, enrolled, eligible patients receive crizotinib
Overall Number of Baseline Participants 127
Hide Baseline Analysis Population Description
The Safety Population (n=127) contains all enrolled patients who received at least one dose of study medication.
Age, Customized  
Measure Type: Number
Unit of measure:  Years
Number Analyzed 127 participants
< 65 106
> / = 65 21
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 127 participants
Female
73
  57.5%
Male
54
  42.5%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Asian Number Analyzed 127 participants
127
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 127 participants
China 74
Japan 26
Taiwan 15
Korea, Republic of 12
1.Primary Outcome
Title Independent Radiology Reviewed Overall Objective Response (ORR)
Hide Description Overall Objective Response (ORR) was defined as the number of patients with a best overall response of confirmed Complete Response or confirmed Partial Response according to RECIST v1.1 (as determined by Independent Radiology Review [IRR]), relative to the total population of response-evaluable patients (n=127). Confirmed responses were those that persisted on repeat imaging at least 4 weeks after the initial documentation of response.
Time Frame Starting from the first dose study treatment until the first documented CR or PR.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Response Evaluable Population
Hide Arm/Group Description:
The response-evaluable population (RES) is defined as all patients in the safety analysis population who have an adequate baseline tumor assessment (n=127).
Overall Number of Participants Analyzed 127
Measure Type: Number
Unit of Measure: participants
88
2.Secondary Outcome
Title Duration of Response by Independent Review
Hide Description The time from the first documentation of objective tumor response (CR or PR) according to Independent Review and that was subsequently confirmed to the first documentation of objective disease progression or to death due to any cause, whichever occurs first. It was calculated for the response evaluable population in the subgroup of patients with a confirmed objective response and who had a subsequent event of progression or death without progression. Patients who did not meet these criteria were censored on the date of the last on-study tumor assessment.
Time Frame Every 8 or 12 weeks until 6 months after the last patient was enrolled in the trial
Hide Outcome Measure Data
Hide Analysis Population Description
Duration of response was calculated for the response evaluable population in the subgroup of patients with a confirmed objective response by Independent Review and who either subsequently had objective progression or died, whichever occurred first.
Arm/Group Title Response Evaluable Population
Hide Arm/Group Description:
The response-evaluable population (RES) is defined as all patients in the safety analysis population who have an adequate baseline tumor assessment (n=127).
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: months
6.4  (2.4)
3.Secondary Outcome
Title Time to First Response
Hide Description Time to response is defined as the time from the date of first dose to first documentation of objective tumor response (CR or PR), as assessed by Independent Radiology Review, that is subsequently confirmed. For patients proceeding from PR to CR, the onset of PR is taken as the onset of response.
Time Frame From date of first dose of crizotinib every 8 weeks or 12 weeks until first documentation of objective response is observed, until 6 months after the last subject is enrolled on the trial
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis is based on 88 patients who achieved an objective response as assessed by Independent Radiology Review
Arm/Group Title Participants With Objective Response by Independent Review
Hide Arm/Group Description:
Defined as all patients in the safety analysis population who have an adequate baseline tumor assessment and an objective response determined by Independent Review (n=88).
Overall Number of Participants Analyzed 88
Median (Full Range)
Unit of Measure: months
1.9
(1.6 to 7.5)
4.Secondary Outcome
Title Disease Control Rate at 8 Weeks by Independent Radiology Review
Hide Description The Disease Control Rate at 8 weeks is defined as the number of patients with a confirmed CR, confirmed PR, or SD at 8 weeks, respectively, according to RECIST v1.1 (as determined by IRR), relative to the total population of response evaluable patients.
Time Frame Measured once at 8 weeks after the start of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Response Evaluable Population
Hide Arm/Group Description:
The response-evaluable population (RES) is defined as all patients in the safety analysis population who have an adequate baseline tumor assessment (n=127).
Overall Number of Participants Analyzed 127
Measure Type: Number
Unit of Measure: participants
112
5.Secondary Outcome
Title Progression Free Survival Assessed by Independent Radiology Review
Hide Description Progression Free Survival is defined as the time from the date of the first dose of crizotinib to first documentation of objective disease progression or to death on study due to any cause, whichever occurs first. Patients who had neither progression nor death without objective progression were censored at the time of data cut off.
Time Frame From the date of first dose of crizotinib every 8 weeks or 12 weeks until the first documentation of objective disease progression or death
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Safety Evaluable Population
Hide Arm/Group Description:
The safety analysis population (SAF) will include all enrolled patients who receive at least one dose of study medication. (n=127).
Overall Number of Participants Analyzed 127
Median (95% Confidence Interval)
Unit of Measure: months
13.4 [1] 
(10.3 to NA)
[1]
The upper limit of the confidence interval was not reached due to the majority of subjects (69 patients; 54.3%) still in follow-up for PFS at the time of the final analysis.
6.Secondary Outcome
Title Overall Survival
Hide Description [Not Specified]
Time Frame Assessed from date of date of the first dose of crizotinib until the date of death from any cause, assessed up to 6 months after the last subject is enrolled on the trial
Hide Outcome Measure Data
Hide Analysis Population Description
OS is defined as the time from the date of the first dose of crizotinib to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
Arm/Group Title Safety Evaluable Population
Hide Arm/Group Description:
The safety analysis population (SAF) will include all enrolled patients who receive at least one dose of study medication. (n=127).
Overall Number of Participants Analyzed 127
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
[1]
The median OS was not reached. Overall, 18 patients (14.2%) had died by the time of data cutoff for this final analysis and the majority of patients (81.1%) were still in follow-up.
7.Secondary Outcome
Title Type, Incidence, Severity, Seriousness and Relationship to Study Medications of Adverse Events (AE) and Any Laboratory Abnormalities
Hide Description Incidence of patients experiencing a treatment emergent adverse events were summarized by type, incidence, severity, seriousness and relationship to study medication.
Time Frame From the date of signed informed consent, then a minimum of every 4 weeks until 32 weeks, then a minimum of every 8 weeks, or until 4 weeks after last dose of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Safety Evaluable Population
Hide Arm/Group Description:
The safety analysis population (SAF) will include all enrolled patients who receive at least one dose of study medication. (n=127).
Overall Number of Participants Analyzed 127
Measure Type: Number
Unit of Measure: percentage of patients
Incidence of All-Causality Adverse Events 99.2
Incidence of Adverse Events Related to Crizotinib 95.3
Incidence of All-Causality Grade 3-4 Adverse Event 37.8
Incidence of All-Causality Serious Adverse Events 23.6
8.Secondary Outcome
Title Number of Patients With a Shift in Hematology Laboratory Results From Grade </=2 to Grade 3 or Grade 4
Hide Description A summary of the number of patients in the safety population with available laboratory data whose hematology laboratory results shifted from a baseline value of Grade </=2 to a post-baseline result of Grade 3 or Grade 4
Time Frame From time of baseline screening test every 4, 8, or 12 weeks until 28 days from last dose of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Safety Evaluable Population
Hide Arm/Group Description:
The safety analysis population (SAF) will include all enrolled patients who receive at least one dose of study medication. (n=127).
Overall Number of Participants Analyzed 127
Measure Type: Number
Unit of Measure: participants
Hemoglobin increased 0
Anemia 5
Platelet count decreased 0
Leukocytosis 0
White blood cells decreased 1
Lymphocyte count increased 0
Lymphocyte count decreased 2
Neutrophil count decreased 6
9.Secondary Outcome
Title Number of Patients With a Shift of Chemistry Laboratory Results From Grade </= 2 to Grade 3 or Grade 4
Hide Description A summary of the number of patients in the safety population with available laboratory data whose chemistry laboratory results shifted from a baseline value of Grade </=2 to a post-baseline result of Grade 3 or Grade 4
Time Frame From time of baseline screening test every 4, 8, or 12 weeks until 28 days from last dose of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Safety Evaluable Population
Hide Arm/Group Description:
The safety analysis population (SAF) included all enrolled patients who receive at least one dose of study medication. (n=127).
Overall Number of Participants Analyzed 127
Measure Type: Number
Unit of Measure: participants
ALT increased 8
Alkaline phosphatase increased 0
AST increased 5
Bilirubin (total) increased 1
Creatinine increased 0
Hypercalcemia 0
Hyperglycemia 0
Hyperkalemia 0
Hypermagnesemia 1
Hypernatremia 0
Hypoalbuminemia 3
Hypocalcemia 0
Hypoglycemia 0
Hypokalemia 2
Hypomagnesemia 0
Hyponatremia 7
Hypophosphatemia 8
10.Secondary Outcome
Title Change From Baseline Scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30)
Hide Description The QLQ-C30 consists of 30 questions which are incorporated into 5 functional domains (physical, role, cognitive, emotional, and social domains); a global health status/global QOL scale; 3 symptom scales (fatigue, pain, nausea and vomiting scales); and 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and the perceived financial burden of treatment. Scores for each sub-scale range from 0 to 100. Negative change from baseline scores indicated an improvement in symptoms, decreased functioning, or decreased global QOL, while positive change from baseline scores indicated an improvement in functioning, improvement in global QOL, or a worsening of symptoms. A clinically meaningful change was defined as a >/= 10-point change in mean scores. Changes were described as statistically significant if the 95% CI for the change did not include 0.
Time Frame From the date of informed consent every 8 weeks or 12 weeks until cycle 8
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants that had both a baseline assessment and an assessment at cycle 8
Arm/Group Title Crizotinib
Hide Arm/Group Description:
Single-arm trial whereby all consented, enrolled, eligible patients receive crizotinib
Overall Number of Participants Analyzed 83
Mean (Standard Deviation)
Unit of Measure: units on a scale
Global Health Status 5.31  (26.813)
Physical Functioning 3.94  (20.077)
Role Functioning -0.81  (27.535)
Emotional Functioning 0.88  (20.309)
Cognitive Functioning -2.81  (19.441)
Social Functioning 1.41  (26.953)
Fatigue -8.07  (26.539)
Nausea and Vomiting 1.61  (16.792)
Pain -8.84  (22.740)
Dyspnoea -10.44  (29.413)
Insomnia -7.23  (28.537)
Appetite loss -8.44  (32.024)
Constipation 3.61  (26.026)
Diarrhoea 12.44  (23.099)
Financial difficulties -5.62  (27.951)
11.Secondary Outcome
Title Change From Baseline Scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Lung Cancer Module 13
Hide Description The QLQ-LC13 consisted of 1 multi-item scale and 9 single items that assessed specific symptoms (dyspnea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use. Negative change from baseline scores indicated an improvement in symptoms, decreased functioning, or decreased global QOL, while positive change from baseline scores indicated an improvement in functioning, improvement in global QOL, or a worsening of symptoms. Scores on each sub-scale range from 0 - 100. A clinically meaningful change was defined as a >/= 10-point change in mean scores. Changes were described as statistically significant if the 95% CI for the change did not include 0.
Time Frame From the date of informed consent every 8 weeks or 12 weeks until cycle 8
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants that had both a baseline assessment and an assessment at cycle 8
Arm/Group Title Crizotinib
Hide Arm/Group Description:
Single-arm trial whereby all consented, enrolled, eligible patients receive crizotinib
Overall Number of Participants Analyzed 83
Mean (Standard Deviation)
Unit of Measure: units on a scale
Dyspnoea -6.58  (22.098)
Coughing -20.89  (33.221)
Haemoptysis -2.81  (14.905)
Sore mouth -0.81  (15.586)
Dysphagia -0.80  (17.241)
Peripheral neuropathy 2.41  (20.003)
Alopecia -6.42  (32.283)
Pain in chest -9.23  (24.032)
Pain in arm or shoulder -6.82  (25.371)
Pain in other parts -6.10  (25.187)
Time Frame AEs (non-serious) were collected from the time the patient took at least one dose of study treatment through 28 days after the last dose of study treatment. If a subject begins a new anticancer therapy, the AE reporting period for non serious AEs ends at the time the new treatment is started. The overall AE reporting period for the final analysis is 11 Oct 2013 (first patient first dose) to 30 Jul 2015 (last patient first visit plus 6 months).
Adverse Event Reporting Description SAE reporting began from the time that the subject provided informed consent through and including 28 days after the last dose of the crizotinib. Afterward, reporting occurred if the PI became aware of the SAE and at minimum, if the SAE was believed to be possibly related to crizotinib. Death was reported irrespective of any intervening treatment. The overall reporting period for SAEs for the final analysis was 25 Sep 2013 (date first patient consented) to 20 Jul 2015.
 
Arm/Group Title Crizotinib
Hide Arm/Group Description Single-arm trial whereby all consented, enrolled, eligible patients receive crizotinib
All-Cause Mortality
Crizotinib
Affected / at Risk (%)
Total   --/-- 
Hide Serious Adverse Events
Crizotinib
Affected / at Risk (%)
Total   30/127 (23.62%) 
Cardiac disorders   
Acute myocardial infarction  1  1/127 (0.79%) 
Gastrointestinal disorders   
Abdominal pain  1  1/127 (0.79%) 
General disorders   
Disease Progression  1  4/127 (3.15%) 
Pyrexia  1  1/127 (0.79%) 
Hepatobiliary disorders   
Hepatic cyst  1  1/127 (0.79%) 
Hepatic function abnormal  1  1/127 (0.79%) 
Infections and infestations   
Pneumonia  1  7/127 (5.51%) 
Appendicitis  1  1/127 (0.79%) 
Bronchiolitis  1  1/127 (0.79%) 
Bronchopulmonary aspergillosis  1  1/127 (0.79%) 
Cellulitis  1  1/127 (0.79%) 
Empyema  1  1/127 (0.79%) 
Lung infection  1  1/127 (0.79%) 
Oesophageal infection  1  1/127 (0.79%) 
Urinary tract infection  1  1/127 (0.79%) 
Investigations   
Alanine aminotransferase increased  1  1/127 (0.79%) 
Aspartate aminotransferase increased  1  1/127 (0.79%) 
Hepatic enzyme increased  1  1/127 (0.79%) 
Metabolism and nutrition disorders   
Decreased appetite  1  1/127 (0.79%) 
Malnutrition  1  1/127 (0.79%) 
Musculoskeletal and connective tissue disorders   
Spinal osteoarthritis  1  1/127 (0.79%) 
Nervous system disorders   
Headache  1  1/127 (0.79%) 
Ruptured cerebral aneurysm  1  1/127 (0.79%) 
Seizure  1  1/127 (0.79%) 
Renal and urinary disorders   
Renal cyst  1  2/127 (1.57%) 
Respiratory, thoracic and mediastinal disorders   
Pleural effusion  1  3/127 (2.36%) 
Respiratory failure  1  3/127 (2.36%) 
Pneumothorax  1  1/127 (0.79%) 
Vascular disorders   
Deep vein thrombosis  1  1/127 (0.79%) 
Embolism  1  1/127 (0.79%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (18.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Crizotinib
Affected / at Risk (%)
Total   126/127 (99.21%) 
Blood and lymphatic system disorders   
Neutropenia  1  12/127 (9.45%) 
Anaemia  1  11/127 (8.66%) 
Leukopenia  1  7/127 (5.51%) 
Cardiac disorders   
Sinus bradycardia  1  11/127 (8.66%) 
Eye disorders   
Vision blurred  1  22/127 (17.32%) 
Visual impairment  1  21/127 (16.54%) 
Diplopia  1  7/127 (5.51%) 
Photopsia  1  7/127 (5.51%) 
Gastrointestinal disorders   
Diarrhoea  1  58/127 (45.67%) 
Nausea  1  56/127 (44.09%) 
Vomiting  1  47/127 (37.01%) 
Constipation  1  44/127 (34.65%) 
Abdominal pain upper  1  10/127 (7.87%) 
Abdominal pain  1  8/127 (6.30%) 
Stomatitis  1  8/127 (6.30%) 
Abdominal distention  1  7/127 (5.51%) 
General disorders   
Oedema peripheral  1  24/127 (18.90%) 
Fatigue  1  19/127 (14.96%) 
Pyrexia  1  17/127 (13.39%) 
Chest pain  1  8/127 (6.30%) 
Infections and infestations   
Nasopharyngitis  1  17/127 (13.39%) 
Upper respiratory tract infection  1  12/127 (9.45%) 
Pneumonia  1  8/127 (6.30%) 
Urinary tract infection  1  7/127 (5.51%) 
Investigations   
Alanine aminotransferase increased  1  65/127 (51.18%) 
Aspartate aminotransferase increased  1  57/127 (44.88%) 
Neutrophil count decreased  1  23/127 (18.11%) 
White blood cell count decreased  1  19/127 (14.96%) 
Blood creatinine increased  1  17/127 (13.39%) 
Gamma-glutamyltransferase increased  1  10/127 (7.87%) 
Blood alkaline phosphate increased  1  7/127 (5.51%) 
Metabolism and nutrition disorders   
Decreased appetite  1  22/127 (17.32%) 
Hypoproteinaemia  1  8/127 (6.30%) 
Hypoalbuminaemia  1  7/127 (5.51%) 
Musculoskeletal and connective tissue disorders   
Back pain  1  11/127 (8.66%) 
Pain in extremity  1  8/127 (6.30%) 
Nervous system disorders   
Dysgeusia  1  22/127 (17.32%) 
Dizziness  1  18/127 (14.17%) 
Headache  1  14/127 (11.02%) 
Psychiatric disorders   
Insomnia  1  7/127 (5.51%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  18/127 (14.17%) 
Dyspnoea  1  7/127 (5.51%) 
Skin and subcutaneous tissue disorders   
Rash  1  15/127 (11.81%) 
Pruritis  1  9/127 (7.09%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (18.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
PI will provide publication/disclosures at least 30 days before submission for publication; PI agrees to delay this for a period not to exceed an added 60 days if action is required to protect IP rights, & will remove, on request, any previously undisclosed Confidential Info (other than the Study results) before disclosure. Multi-centre study: PI agrees 1st publication will be joint & cover all sites; but may publish separately if this isn't submitted by12 mos of completion of study at all sites
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Director Clinical and Operational Science
Organization: OxOnc Development
Phone: 6093157013
EMail: Allison.Kemner@oxfordoncology.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01945021    
Other Study ID Numbers: OO 12-01
First Submitted: September 5, 2013
First Posted: September 18, 2013
Results First Submitted: July 28, 2016
Results First Posted: August 1, 2016
Last Update Posted: May 5, 2020