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A Study of Thymidylate Synthase Expression in Patients With Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT00887549
Recruitment Status : Completed
First Posted : April 24, 2009
Results First Posted : August 30, 2011
Last Update Posted : June 19, 2012
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non-Small Cell Lung Cancer
Interventions Drug: pemetrexed
Drug: cisplatin
Enrollment 70
Recruitment Details  
Pre-assignment Details The trial consists of induction therapy (up to 4 cycles of pemetrexed-cisplatin treatment) and maintenance therapy (pemetrexed only). Only participants who do not develop disease progression during induction therapy are eligible to receive maintenance therapy.
Arm/Group Title Pemetrexed
Hide Arm/Group Description Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
Period Title: Induction Therapy
Started 70
Completed 43
Not Completed 27
Reason Not Completed
Adverse Event             8
Physician Decision             1
Progressive Disease             13
Death due to Study Disease             4
Death due to Study Drug Toxicity             1
Period Title: Maintenance Therapy
Started 43
Completed 0
Not Completed 43
Reason Not Completed
Adverse Event             16
Physician Decision             1
Progressive Disease             25
Death due to adverse event             1
Arm/Group Title Pemetrexed
Hide Arm/Group Description Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
Overall Number of Baseline Participants 70
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 70 participants
63.0  (9.42)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 70 participants
Female
32
  45.7%
Male
38
  54.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 70 participants
Caucasian 69
Asian 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 70 participants
Ireland 4
United Kingdom 66
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 70 participants
0- Fully active 24
1- Ambulatory, Restricted Strenuous Activity 46
[1]
Measure Description: Classifies patients according to their functional impairment. Scores range from 0 (Fully Active) to 5 (Death).
Pathological Diagnosis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 70 participants
Adenocarcinoma, not otherwise specified (NOS) 34
Adenocarcinoma, acinar 1
Adenocarcinoma, poorly differentiated 20
Bronchioalveolar Carcinoma 6
Carcinoma, Non-Small Cell, Lung (NSCL), (NOS) 3
Carcinoma, NSC, Poorly Differentiated, Lung 5
Carcinoma, undifferentiated 1
Past and Current Tobacco Usage  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 70 participants
Never used tobacco products 6
Ever used tobacco products 64
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS is time from first dose to first observation of disease progression/death (any cause). PFS is reported for participants with thymidylate synthase (TS) scores. For participants not known to have died by the data cut-off date and who do not have progressive disease, PFS will be censored at date of last objective progression-free disease assessment. For participants who receive systemic anticancer therapy after study drug discontinuation and prior to disease progression/death, PFS will be censored at date of last objective progression-free disease assessment prior to chemotherapy.
Time Frame Baseline to measured progressive disease with follow-up every 6 weeks until progression of disease (up to 18 months after the last participant commenced induction therapy)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Population for the efficacy assessment includes all treated participants with a valid TS expression assessment. Six participants were censored for PFS.
Arm/Group Title Pemetrexed
Hide Arm/Group Description:
Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
Overall Number of Participants Analyzed 60
Median (95% Confidence Interval)
Unit of Measure: months
5.5
(3.9 to 6.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pemetrexed
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Cox
Comments The Cox model, based upon participant level data, included PFS as dependent variable and TS score in the nucleus as independent variable.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.015
Confidence Interval (2-Sided) 95%
1.008 to 1.021
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With Tumor Response (Tumor Response Rate)
Hide Description Tumor response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response=disappearance of all target lesions; Partial Response=30% decrease in sum of longest diameter of target lesions; Progressive Disease=20% increase in sum of longest diameter of target lesions; Stable Disease=small changes that do not meet above criteria. Percentage of participants with tumor response was determined by the number of participants with PR or CR (confirmed or not) divided by the total number of treated participants multiplied by 100.
Time Frame Baseline to disease progression (up to 20 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants.
Arm/Group Title Pemetrexed
Hide Arm/Group Description:
Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
Overall Number of Participants Analyzed 70
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
30
(19.62 to 42.13)
3.Secondary Outcome
Title Percentage of Participants With Concordance Between Local and Central Histological Diagnosis
Hide Description A centralized pathology review on all enrolled participants was performed to confirm the histological diagnosis performed at the site. Upon review of the local diagnosis obtained at the respective site, the central reviewer established whether or not there was an agreement between the local and central diagnosis. The percentage of participants with concordance was defined as the number of participants for which there was an agreement divided by the number of treated participants (concordance rate) multiplied by 100.
Time Frame Baseline
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants.
Arm/Group Title Pemetrexed
Hide Arm/Group Description:
Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
Overall Number of Participants Analyzed 70
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
78.6
(67.1 to 87.5)
4.Secondary Outcome
Title Percentage of Participants Surviving at 18 Months (Overall Survival Rate)
Hide Description The percentage of participants surviving at 18 months was defined as the number of treated participants who had not died prior to 18 months from the date of their first dose divided by the total number of treated participants multiplied by 100. For participants who are alive, overall survival was censored at the last contact.
Time Frame Baseline to date of death (up to 24.5 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants. Nineteen participants were censored for overall survival.
Arm/Group Title Pemetrexed
Hide Arm/Group Description:
Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
Overall Number of Participants Analyzed 70
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
37.1
(25.89 to 49.52)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Pemetrexed
Hide Arm/Group Description Induction Therapy: pemetrexed 500 milligrams per square meter (mg/m^2) and cisplatin 75 mg/m^2, intravenous, day 1 of each 21 day cycle for the first 4 cycles; Maintenance Therapy: pemetrexed 500 milligrams per square meter (mg/m^2), intravenous, day 1 of each 21 day cycle until progression or unacceptable toxicity occurs
All-Cause Mortality
Pemetrexed
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Pemetrexed
Affected / at Risk (%) # Events
Total   41/70 (58.57%)    
Blood and lymphatic system disorders   
Anaemia  1  1/70 (1.43%)  2
Febrile neutropenia  1  1/70 (1.43%)  1
Neutropenia  1  3/70 (4.29%)  3
Thrombocytopenia  1  1/70 (1.43%)  1
Cardiac disorders   
Atrial fibrillation  1  2/70 (2.86%)  2
Atrial flutter  1  1/70 (1.43%)  1
Pericardial effusion  1  2/70 (2.86%)  2
Pericarditis  1  1/70 (1.43%)  1
Tachycardia  1  1/70 (1.43%)  1
Ear and labyrinth disorders   
Tinnitus  1  1/70 (1.43%)  1
Eye disorders   
Ocular hyperaemia  1  1/70 (1.43%)  1
Gastrointestinal disorders   
Abdominal pain  1  1/70 (1.43%)  1
Abdominal pain upper  1  1/70 (1.43%)  1
Constipation  1  1/70 (1.43%)  1
Diarrhoea  1  5/70 (7.14%)  5
Nausea  1  7/70 (10.00%)  7
Vomiting  1  7/70 (10.00%)  7
General disorders   
Chest discomfort  1  1/70 (1.43%)  1
Fatigue  1  4/70 (5.71%)  4
Non-cardiac chest pain  1  5/70 (7.14%)  5
Oedema peripheral  1  2/70 (2.86%)  3
Pyrexia  1  3/70 (4.29%)  3
Hepatobiliary disorders   
Cholecystitis  1  1/70 (1.43%)  1
Infections and infestations   
Catheter site infection  1  1/70 (1.43%)  1
Cellulitis  1  4/70 (5.71%)  4
Lower respiratory tract infection  1  6/70 (8.57%)  6
Lung infection  1  1/70 (1.43%)  1
Neutropenic sepsis  1  2/70 (2.86%)  2
Oral candidiasis  1  2/70 (2.86%)  2
Penile infection  1  1/70 (1.43%)  1
Pneumonia  1  3/70 (4.29%)  3
Urinary tract infection  1  1/70 (1.43%)  1
Injury, poisoning and procedural complications   
Fall  1  1/70 (1.43%)  1
Vena cava injury  1  1/70 (1.43%)  1
Investigations   
Blood creatinine increased  1  1/70 (1.43%)  1
Blood urea increased  1  1/70 (1.43%)  1
Gamma-glutamyltransferase increased  1  1/70 (1.43%)  1
Haemoglobin decreased  1  3/70 (4.29%)  3
Lymphocyte count decreased  1  1/70 (1.43%)  1
Neutrophil count decreased  1  2/70 (2.86%)  3
Platelet count decreased  1  2/70 (2.86%)  2
White blood cell count decreased  1  1/70 (1.43%)  1
Metabolism and nutrition disorders   
Dehydration  1  3/70 (4.29%)  3
Hypocalcaemia  1  2/70 (2.86%)  2
Hypokalaemia  1  1/70 (1.43%)  1
Hypophagia  1  1/70 (1.43%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia  1  1/70 (1.43%)  1
Back pain  1  1/70 (1.43%)  1
Joint swelling  1  1/70 (1.43%)  1
Musculoskeletal pain  1  1/70 (1.43%)  1
Pain in extremity  1  2/70 (2.86%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Intracranial tumour haemorrhage  1  1/70 (1.43%)  1
Lymphangiosis carcinomatosa  1  1/70 (1.43%)  1
Metastases to central nervous system  1  1/70 (1.43%)  1
Metastases to spine  1  1/70 (1.43%)  1
Nervous system disorders   
Cerebrovascular accident  1  1/70 (1.43%)  1
Dizziness  1  1/70 (1.43%)  1
Presyncope  1  1/70 (1.43%)  1
Syncope  1  1/70 (1.43%)  1
Psychiatric disorders   
Confusional state  1  2/70 (2.86%)  2
Renal and urinary disorders   
Haematuria  1  1/70 (1.43%)  1
Incontinence  1  1/70 (1.43%)  1
Renal failure acute  1  2/70 (2.86%)  2
Respiratory, thoracic and mediastinal disorders   
Cough  1  1/70 (1.43%)  1
Dyspnoea  1  4/70 (5.71%)  4
Pleural effusion  1  1/70 (1.43%)  1
Pulmonary embolism  1  4/70 (5.71%)  4
Skin and subcutaneous tissue disorders   
Hyperhidrosis  1  1/70 (1.43%)  1
Vascular disorders   
Deep vein thrombosis  1  1/70 (1.43%)  1
Raynaud's phenomenon  1  1/70 (1.43%)  1
Superior vena cava syndrome  1  1/70 (1.43%)  1
Vena cava thrombosis  1  1/70 (1.43%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pemetrexed
Affected / at Risk (%) # Events
Total   67/70 (95.71%)    
Blood and lymphatic system disorders   
Anaemia  1  15/70 (21.43%)  15
Neutropenia  1  7/70 (10.00%)  10
Ear and labyrinth disorders   
Tinnitus  1  5/70 (7.14%)  5
Eye disorders   
Lacrimation increased  1  15/70 (21.43%)  15
Gastrointestinal disorders   
Abdominal pain  1  5/70 (7.14%)  5
Constipation  1  23/70 (32.86%)  28
Diarrhoea  1  19/70 (27.14%)  23
Dry mouth  1  5/70 (7.14%)  5
Dyspepsia  1  10/70 (14.29%)  12
Nausea  1  33/70 (47.14%)  53
Stomatitis  1  4/70 (5.71%)  4
Vomiting  1  25/70 (35.71%)  34
General disorders   
Chest pain  1  4/70 (5.71%)  4
Fatigue  1  39/70 (55.71%)  43
Mucosal inflammation  1  5/70 (7.14%)  5
Oedema peripheral  1  10/70 (14.29%)  11
Infections and infestations   
Cellulitis  1  5/70 (7.14%)  6
Lower respiratory tract infection  1  13/70 (18.57%)  16
Oral candidiasis  1  6/70 (8.57%)  7
Urinary tract infection  1  4/70 (5.71%)  5
Investigations   
Alanine aminotransferase increased  1  8/70 (11.43%)  8
Aspartate aminotransferase increased  1  6/70 (8.57%)  6
Blood creatinine increased  1  11/70 (15.71%)  11
Creatinine renal clearance decreased  1  5/70 (7.14%)  5
Gamma-glutamyltransferase increased  1  4/70 (5.71%)  4
Haemoglobin decreased  1  10/70 (14.29%)  13
Neutrophil count decreased  1  6/70 (8.57%)  9
Weight decreased  1  6/70 (8.57%)  6
Metabolism and nutrition disorders   
Decreased appetite  1  22/70 (31.43%)  23
Hypokalaemia  1  4/70 (5.71%)  5
Musculoskeletal and connective tissue disorders   
Joint swelling  1  5/70 (7.14%)  5
Musculoskeletal chest pain  1  5/70 (7.14%)  5
Musculoskeletal pain  1  5/70 (7.14%)  5
Nervous system disorders   
Dizziness  1  4/70 (5.71%)  4
Dysgeusia  1  12/70 (17.14%)  12
Headache  1  13/70 (18.57%)  14
Lethargy  1  9/70 (12.86%)  9
Neuropathy peripheral  1  6/70 (8.57%)  7
Tremor  1  4/70 (5.71%)  4
Psychiatric disorders   
Anxiety  1  4/70 (5.71%)  4
Insomnia  1  5/70 (7.14%)  5
Respiratory, thoracic and mediastinal disorders   
Cough  1  13/70 (18.57%)  14
Dyspnoea  1  8/70 (11.43%)  8
Epistaxis  1  5/70 (7.14%)  7
Haemoptysis  1  4/70 (5.71%)  4
Oropharyngeal pain  1  4/70 (5.71%)  4
Rhinorrhoea  1  4/70 (5.71%)  4
Skin and subcutaneous tissue disorders   
Alopecia  1  11/70 (15.71%)  11
Rash  1  15/70 (21.43%)  15
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
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.
Results Point of Contact
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT00887549     History of Changes
Other Study ID Numbers: 13069
H3E-BP-JMIK ( Other Identifier: Eli Lilly and Company )
First Submitted: April 23, 2009
First Posted: April 24, 2009
Results First Submitted: July 29, 2011
Results First Posted: August 30, 2011
Last Update Posted: June 19, 2012