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A Study of Pemetrexed and Cisplatin, in Non Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT01000480
Recruitment Status : Completed
First Posted : October 23, 2009
Results First Posted : January 1, 2014
Last Update Posted : April 2, 2014
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non Small Cell Lung Cancer
Interventions Drug: Pemetrexed
Drug: Cisplatin
Radiation: Thoracic Radiotherapy
Enrollment 90
Recruitment Details  
Pre-assignment Details Study treatment had 2 phases and follow-up. Induction phase: 2 cycles of pemetrexed-cisplatin. Then, if eligible, the concurrent phase: 2 more cycles of pemetrexed-cisplatin and thoracic radiotherapy. Follow-up period: Started when treatment discontinued or completed, and lasted up to 2 years after first dose of pemetrexed.
Arm/Group Title Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Hide Arm/Group Description

Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.

Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity >Grade 2 (Common Terminology Criteria for Adverse Events).

Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.

Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label.

Period Title: Induction Phase
Started 90
Received at Least 1 Dose of Either Drug 90
Death (Any Cause) or Disease Progression 8 [1]
Completed 83
Not Completed 7
Reason Not Completed
Adverse Event             2
Lost to Follow-up             1
Physician Decision             1
Entry Criteria Not Met             3
[1]
Participants who died (any cause) or had disease progression considered to have completed phase.
Period Title: Concurrent Therapy Phase
Started 75 [1]
Death (Any Cause) or Disease Progression 1 [2]
Completed 65
Not Completed 10
Reason Not Completed
Adverse Event             4
Protocol Violation             2
Withdrawal by Subject             3
Physician Decision             1
[1]
Eight participants (pts) who completed Induction Phase, not eligible for Concurrent Therapy Phase.
[2]
Pts who died (any cause) or had disease progression considered to have completed the phase.
Period Title: Follow-Up Period
Started 88 [1]
Completed 88
Not Completed 0
[1]
One pt lost to follow-up during induction, 1 pt died in concurrent therapy, both not enter follow-up
Arm/Group Title Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Hide Arm/Group Description

Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.

Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity >Grade 2 (Common Terminology Criteria for Adverse Events).

Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.

Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label.

Overall Number of Baseline Participants 90
Hide Baseline Analysis Population Description
Intent-to-treat population: participants who received at least 1 dose of study drug (pemetrexed or cisplatin).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 90 participants
61.7  (8.15)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants
Female
39
  43.3%
Male
51
  56.7%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
White Number Analyzed 90 participants
90
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 90 participants
France 9
Spain 17
Germany 42
Italy 22
Stage of Disease   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 90 participants
Stage IIIA 32
Stage IIIB 56
Stage IV 2
[1]
Measure Description: Classification based on American Joint Committee on Cancer (AJCC) Staging System for lung cancer (sixth edition, 2002). Disease stage means how big the tumor is and how far it has spread. Stages range from 0 (not spread) to IV (spread throughout the body). Stage IIIA is a locally advanced cancer that spread to lymph nodes within the chest area. Stage IIIB is a locally advanced cancer that spread to nearby tissue or far away lymph nodes, or has fluid, containing cancer cells, built up between the layers lining the lungs.
Eastern Cooperative Oncology Group (ECOG) performance status (PS)   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 90 participants
ECOG PS=0 59
ECOG PS=1 31
ECOG PS=2 0
[1]
Measure Description: ECOG PS classified participants according to their functional impairment. Scores ranged from 0 (Fully Active) to 5 (Death). 0=Fully Active; 1=Ambulatory, Restricted Strenuous Activity; 2=Ambulatory, No Work Activities; 3=Partially Confined to Bed, Limited Self Care; 4=Completely Disabled; and 5=Death.
Initial pathological diagnosis   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 90 participants
Adenocarcinoma (lung) 81
Carcinoma (large cell, lung) 7
Carcinoma (non-small cell, lung, NOS) 1
Carcinoma (non-small cell, poorly differentiated) 1
[1]
Measure Description: The number of participants with an initial pathological diagnosis of Adenocarcinoma (lung), Carcinoma (large cell, lung), Carcinoma [non-small cell, lung, not otherwise specified (NOS)], Carcinoma (non-small cell, lung, poorly differentiated).
Current Tobacco Use  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 90 participants
Never used tobacco 7
Former user of tobacco 55
Current use of tobacco 28
1.Primary Outcome
Title 1 Year Progression Free Survival
Hide Description Progression free survival (PFS) was defined as the time from study enrollment to the first observation of progressive disease (PD) or death from any cause. For participants not known to have died as of the data cut-off date and who did not have objective PD, PFS was censored at the date of the last objective progression-free disease assessment. For participants who received subsequent systemic anticancer therapy (after discontinuation from the study drug) prior to objectively determined PD or death, PFS was censored at the date of the last objective progression-free disease assessment prior to start of postdiscontinuation chemotherapy. If a participant did not have a complete baseline disease assessment, then PFS was censored at the enrollment date, regardless whether or not objectively determined PD or death had been observed for the participant.
Time Frame Date of first dose to date of objectively determined PD or death [every cycle up to 4 cycles and then every 3 months up to 1 year (1 cycle=21 days)]
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: participants who received at least 1 dose of either study drug (pemetrexed or cisplatin). The number of participants censored was 35.
Arm/Group Title Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Hide Arm/Group Description:

Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.

Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity >Grade 2 (Common Terminology Criteria for Adverse Events).

Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.

Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label.

Overall Number of Participants Analyzed 90
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
53.7
(44.8 to 62.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Comments Null hypothesis (H0): 1-year PFS ≤45% and the alternative hypothesis (H1): 1-year PFS ≥60%, at a 2-sided alpha level of 5%, assuming that PFS time followed an exponential distribution.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0645
Comments P-value for H0 which compared the investigational regimen to historical data.
Method maximum likelihood estimate
Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival
Hide Description Overall survival (OS) was the duration from enrollment to death due to any cause. Participants who were alive were censored at the last contact.
Time Frame Date of first dose to date of death (up to 35.4 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: participants who received at least 1 dose of study drug (pemetrexed or cisplatin). The number of participants censored was 45.
Arm/Group Title Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Hide Arm/Group Description:

Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.

Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity >Grade 2 (Common Terminology Criteria for Adverse Events).

Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.

Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label.

Overall Number of Participants Analyzed 90
Median (95% Confidence Interval)
Unit of Measure: months
26.2 [1] 
(16.7 to NA)
[1]
The upper 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.
3.Secondary Outcome
Title Number of Participants With an Objective Tumor Response
Hide Description Participants with confirmed complete response (CR), confirmed partial response (PR), stable disease (SD), or progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria, as well as participants with a not evaluable/tumor response unknown. CR: disappearance of all tumor lesions. PR: either a) at least a 30% decrease in sum of longest diameter (LD) of target lesions taking as a reference baseline sum LDs, or b) complete disappearance of target lesions, with persistence (not worsening) of 1 or more nontarget lesions. In either case, no new lesions appeared. SD: small changes that did not meet above criteria. PD: at least a 20% increase in sum of LD of target lesions taking as reference smallest sum LD recorded since treatment started or appearance of 1 or more new lesions. Participants who discontinued study treatment (for reasons other than progression) before entering concurrent phase were considered to have non-evaluable response.
Time Frame Date of first dose through end of follow-up [up to 30 weeks (1 cycle=21 days)]
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: Participants who received at least 1 dose of study drug (pemetrexed or cisplatin).
Arm/Group Title Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Hide Arm/Group Description:

Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.

Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity >Grade 2 (Common Terminology Criteria for Adverse Events).

Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.

Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label.

Overall Number of Participants Analyzed 90
Measure Type: Number
Unit of Measure: participants
Complete Response 9
Partial Response 45
Stable Disease 16
Disease Progression 12
Not evaluable/Response unknown 8
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Hide Arm/Group Description

Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.

Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity >Grade 2 (Common Terminology Criteria for Adverse Events).

Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.

Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label.

All-Cause Mortality
Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Affected / at Risk (%)
Total   --/--    
Hide Serious Adverse Events
Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Affected / at Risk (%) # Events
Total   23/90 (25.56%)    
Blood and lymphatic system disorders   
Leukopenia  1  1/90 (1.11%)  1
Ear and labyrinth disorders   
Hypoacusis  1  1/90 (1.11%)  1
Gastrointestinal disorders   
Constipation  1  1/90 (1.11%)  1
Enteritis  1 [1]  1/90 (1.11%)  1
Gastritis erosive  1  1/90 (1.11%)  1
Nausea  1  1/90 (1.11%)  1
General disorders   
Asthenia  1  1/90 (1.11%)  1
General physical health deterioration  1  2/90 (2.22%)  2
Pyrexia  1  1/90 (1.11%)  1
Infections and infestations   
Device related infection  1  1/90 (1.11%)  1
Pneumonia  1  1/90 (1.11%)  1
Septic shock  1 [1]  1/90 (1.11%)  1
Injury, poisoning and procedural complications   
Radiation oesophagitis  1  8/90 (8.89%)  9
Metabolism and nutrition disorders   
Dehydration  1  2/90 (2.22%)  2
Hyponatraemia  1  1/90 (1.11%)  1
Nervous system disorders   
Cerebrovascular accident  1  1/90 (1.11%)  1
Paraesthesia  1  1/90 (1.11%)  1
Syncope  1  1/90 (1.11%)  1
Renal and urinary disorders   
Renal impairment  1  1/90 (1.11%)  1
Urinary retention  1  1/90 (1.11%)  1
Respiratory, thoracic and mediastinal disorders   
Pulmonary embolism  1  4/90 (4.44%)  4
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
[1]
Event resulted in death
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pemetrexed, Cisplatin, and Thoracic Radiotherapy
Affected / at Risk (%) # Events
Total   85/90 (94.44%)    
Blood and lymphatic system disorders   
Anaemia  1  7/90 (7.78%)  8
Leukopenia  1  12/90 (13.33%)  13
Lymphopenia  1  6/90 (6.67%)  11
Neutropenia  1  17/90 (18.89%)  22
Thrombocytopenia  1  5/90 (5.56%)  5
Ear and labyrinth disorders   
Vertigo  1  6/90 (6.67%)  6
Eye disorders   
Conjunctivitis  1  6/90 (6.67%)  6
Gastrointestinal disorders   
Constipation  1  22/90 (24.44%)  26
Diarrhoea  1  8/90 (8.89%)  8
Dyspepsia  1  7/90 (7.78%)  7
Dysphagia  1  27/90 (30.00%)  27
Nausea  1  43/90 (47.78%)  67
Oesophagitis  1  23/90 (25.56%)  25
Stomatitis  1  10/90 (11.11%)  12
Vomiting  1  11/90 (12.22%)  15
General disorders   
Asthenia  1  18/90 (20.00%)  23
Chest pain  1  5/90 (5.56%)  8
Fatigue  1  14/90 (15.56%)  16
Pyrexia  1  8/90 (8.89%)  10
Injury, poisoning and procedural complications   
Radiation oesophagitis  1  10/90 (11.11%)  10
Radiation skin injury  1  10/90 (11.11%)  10
Investigations   
Haemoglobin decreased  1  7/90 (7.78%)  7
Neutrophil count decreased  1  5/90 (5.56%)  6
White blood cell count decreased  1  5/90 (5.56%)  7
Metabolism and nutrition disorders   
Decreased appetite  1  8/90 (8.89%)  11
Musculoskeletal and connective tissue disorders   
Back pain  1  6/90 (6.67%)  6
Nervous system disorders   
Dizziness  1  7/90 (7.78%)  7
Dysgeusia  1  7/90 (7.78%)  9
Respiratory, thoracic and mediastinal disorders   
Cough  1  14/90 (15.56%)  14
Dyspnoea  1  13/90 (14.44%)  14
Skin and subcutaneous tissue disorders   
Rash  1  6/90 (6.67%)  6
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
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
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Layout table for additonal information
Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01000480    
Other Study ID Numbers: 13099
H3E-EW-S128 ( Other Identifier: Eli Lilly and Company )
First Submitted: October 21, 2009
First Posted: October 23, 2009
Results First Submitted: November 12, 2013
Results First Posted: January 1, 2014
Last Update Posted: April 2, 2014