Molecular Profiling in Lung Cancer Patients

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00191308
• Collaborator: (none)
• Enrollment: 30
• Locations: 3
• Arm: 1
• Duration (Months): 67
• Patients Per Site: 10
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The main purpose of this study of pemetrexed combined with cisplatin used as neoadjuvant chemotherapy (2 or 3 cycles) in participants with operable non-small cell lung cancer (NSCLC) is to look at various genes present in participants' blood and tumor tissue to see if there is any link between the levels or changes in the genes and how participants with lung cancer respond to pemetrexed and cisplatin treatment.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer; Carcinoma	Drug: pemetrexed; Drug: cisplatin; Procedure: Radical Non-Small Cell Lung Cancer (NSCLC) surgery	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Molecular Profiling and Safety Study of Operable Lung Cancer Patients Treated With Alimta Combined With Cisplatin as Neoadjuvant Chemotherapy
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pemetrexed + Cisplatin Pemetrexed: 500 milligrams per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs	Drug: pemetrexed; 500 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs; Other Names: LY231514 Alimta ; Drug: cisplatin; 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs; Procedure: Radical Non-Small Cell Lung Cancer (NSCLC) surgery; All participants proceeded to surgery within 4-8 weeks from the last dose of pemetrexed.

Outcome Measures

Primary Outcome Measures

1. High/Low Expression of Selected Molecular Markers in Tumor Tissues and Hypermethylated Genes in Peripheral Blood [Baseline, Cycle 2, and surgery (4-8 weeks after last dose of pemetrexed)]

   Molecular markers assessed by immunohistochemistry: thymidylate synthase, glycinamide ribonucleotide formyl transferase (GARFT), epidermal growth factor receptor (EGFR); and by polymerase chain reaction: dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthetase (FPGS), reduced folate carrier, alpha folate receptor, Excision Repair Cross-Complementation Group 1 (ERCC1), folylpolyglutamate hydrolase (FPGH). Hypermethylated genes assessed by methylation-specific polymerase chain reaction. Due to small sample size, tumor-tissue analyses were not done.

Secondary Outcome Measures

1. Percentage of Participants With Objective Tumor Response (Response Rate) [Treatment start to disease progression or surgery (4-8 weeks after last dose of pemetrexed)]

   Tumor response to treatment using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR)=disappearance of all target lesions; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD)=20% increase in sum of longest diameter of target lesions; Stable Disease (SD)=small changes that do not meet above criteria. Response rate was estimated as the total number of CR or PR, divided by the total number of participants treated.

2. Duration of Response [Time of response to disease progression (up to 44.4 months)]

   The duration of response was defined as the time from complete response (CR) or partial response (PR) to disease progression. Complete Response (CR)=disappearance of all target lesions; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD)=20% increase in sum of longest diameter of target lesions.

3. Disease Free Survival (DFS) [Treatment start to disease progression or death from any cause (up to 45.5 months)]

   DFS was the time from date of first dose to first observation of progressive disease (PD) or death due to any cause. PD=20% increase in sum of longest diameter of target lesions. If a participant was not known to have died or have PD, DFS was censored at the date of the last objective progression-free disease assessment.

4. Overall Survival (OS) [Treatment start to death from any cause (up to 47.6 months)]

   OS was defined as the time from treatment start to death from any cause. For participants who were alive, OS was censored at the last contact date.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• pathologic documentation of non-small cell lung cancer (NSCLC)

• tumor must be accessible by bronchoscopy for tumor tissue sample collection

• patients must have lung cancer with clinical stage IB, II, IIIA

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• patients must not have received prior systemic chemotherapy or radiation therapy for NSCLC (prior resection of lung is allowed provided at least 5 years have elapsed between prior surgery and enrolment)

Exclusion Criteria:

• bronchoalveolar carcinoma or stage IIIA tumor involving the superior sulcus (Pancoast tumors)

• pregnant or breast feeding patients

• patients who have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry

• patients with history or presence of other malignancy except in situ carcinoma of the skin or prior malignancy treated more than 5 years before without recurrence (excluding melanoma, breast cancer and hypernephroma)

• unwillingness to take folic acid or vitamin B12 supplementation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bystra Slaska		Poland	43-360
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Poznan		Poland	60-569
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Warsaw		Poland	02-781

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/ GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00191308
• Other Study ID Numbers: 9356; H3E-PL-S051
• First Posted: Sep 19, 2005
• Last Update Posted: Oct 21, 2011
• Last Verified: Oct 1, 2011

• Additional relevant MeSH terms: Lung Neoplasms; Pemetrexed

Study Results

Participant Flow

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Period Title: Overall Study
STARTED	30
COMPLETED	29
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Overall Participants	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.94 (8.214)
Sex: Female, Male (Count of Participants)
Female	1 3.3%
Male	29 96.7%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	30 100%
Region of Enrollment (participants) [Number]
Poland	30 100%
Basis for Diagnosis (participants) [Number]
Histopathological	30 100%
Cytological	0 0%
Initial Pathological Diagnosis (participants) [Number]
Adenocarcinoma of Lung	2 6.7%
Mixed Cell Carcinoma of Lung	0 0%
Squamous Cell Carcinoma of Lung	20 66.7%
Large Cell Carcinoma of Lung	0 0%
Bronchoalveolar Carcinoma	0 0%
Other	8 26.7%
Stage of Disease at Study Entry (participants) [Number]
Stage IB	18 60%
Stage IIA	2 6.7%
Stage IIB	10 33.3%

Outcome Measures

1. Primary Outcome

Title	High/Low Expression of Selected Molecular Markers in Tumor Tissues and Hypermethylated Genes in Peripheral Blood
Description	Molecular markers assessed by immunohistochemistry: thymidylate synthase, glycinamide ribonucleotide formyl transferase (GARFT), epidermal growth factor receptor (EGFR); and by polymerase chain reaction: dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthetase (FPGS), reduced folate carrier, alpha folate receptor, Excision Repair Cross-Complementation Group 1 (ERCC1), folylpolyglutamate hydrolase (FPGH). Hypermethylated genes assessed by methylation-specific polymerase chain reaction. Due to small sample size, tumor-tissue analyses were not done.
Time Frame	Baseline, Cycle 2, and surgery (4-8 weeks after last dose of pemetrexed)

Outcome Measure Data

Analysis Population Description

Due to lack of eligible participants, enrollment was stopped early when 30 participants were enrolled. Tumor samples were collected in only 19 of these 30 participants. Results obtained from analyses of a small number of available samples were considered to be of little scientific and medical relevance, and tumor-tissue analyses were not conducted.

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Measure Participants	0

2. Secondary Outcome

Title	Percentage of Participants With Objective Tumor Response (Response Rate)
Description	Tumor response to treatment using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR)=disappearance of all target lesions; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD)=20% increase in sum of longest diameter of target lesions; Stable Disease (SD)=small changes that do not meet above criteria. Response rate was estimated as the total number of CR or PR, divided by the total number of participants treated.
Time Frame	Treatment start to disease progression or surgery (4-8 weeks after last dose of pemetrexed)

Outcome Measure Data

Analysis Population Description

Tumor response rate and 95% confidence interval (CI) of best CR or PR were evaluated on all qualified enrolled participants treated with at least 1 dose of study medication. Criteria=histological or cytological diagnosis of non-small cell lung cancer (NSCLC) IB-IIIA; presence of measurable disease; no previous NSCLC chemotherapy and radiotherapy.

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Measure Participants	29
Number (95% Confidence Interval) [percentage of participants]	34.5 115%

3. Secondary Outcome

Title	Duration of Response
Description	The duration of response was defined as the time from complete response (CR) or partial response (PR) to disease progression. Complete Response (CR)=disappearance of all target lesions; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD)=20% increase in sum of longest diameter of target lesions.
Time Frame	Time of response to disease progression (up to 44.4 months)

Outcome Measure Data

Analysis Population Description

Duration of response was analyzed on responders treated with at least 1 dose of study medication. Criteria=histological or cytological diagnosis of non-small cell lung cancer (NSCLC) IB-IIIA; presence of measurable disease; no previous NSCLC chemotherapy and radiotherapy; responder.

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Measure Participants	10
Median (95% Confidence Interval) [months]	42.5

4. Secondary Outcome

Title	Disease Free Survival (DFS)
Description	DFS was the time from date of first dose to first observation of progressive disease (PD) or death due to any cause. PD=20% increase in sum of longest diameter of target lesions. If a participant was not known to have died or have PD, DFS was censored at the date of the last objective progression-free disease assessment.
Time Frame	Treatment start to disease progression or death from any cause (up to 45.5 months)

Outcome Measure Data

Analysis Population Description

DFS was evaluated on all qualified enrolled patients who received at least 1 dose of study medication. Criteria=histological or cytological diagnosis of non-small cell lung cancer (NSCLC) IB-IIIA; presence of measurable disease; no previous NSCLC chemotherapy and radiotherapy.

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Measure Participants	29
Median (95% Confidence Interval) [months]	43.7

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from treatment start to death from any cause. For participants who were alive, OS was censored at the last contact date.
Time Frame	Treatment start to death from any cause (up to 47.6 months)

Outcome Measure Data

Analysis Population Description

OS was evaluated on all qualified enrolled patients who received at least 1 dose of study medication.

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
Measure Participants	29
Median (95% Confidence Interval) [months]	NA

Adverse Events

Arm/Group Title	Pemetrexed + Cisplatin
Arm/Group Description	Pemetrexed: 500 milligram per square meter (mg/m^2) intravenous (IV) every 21 days (q 21 days) for 3 cycles unless disease progression occurs. Cisplatin: 75 mg/m^2 IV q 21 days for 3 cycles unless disease progression occurs.
All Cause Mortality
	Pemetrexed + Cisplatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pemetrexed + Cisplatin
	Affected / at Risk (%)	# Events
Total	4/30 (13.3%)
Gastrointestinal disorders
Gastric ulcer	1/30 (3.3%)	1
Injury, poisoning and procedural complications
Post procedural haemorrhage	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopleural fistula	2/30 (6.7%)	2
Other (Not Including Serious) Adverse Events
	Pemetrexed + Cisplatin
	Affected / at Risk (%)	# Events
Total	19/30 (63.3%)
Investigations
Alanine aminotransferase increased	4/30 (13.3%)	4
Aspartate aminotransferase increased	4/30 (13.3%)	4
Weight increased	4/30 (13.3%)	4
Metabolism and nutrition disorders
Hyperkalaemia	3/30 (10%)	3
Hypernatraemia	2/30 (6.7%)	2
Skin and subcutaneous tissue disorders
Rash	2/30 (6.7%)	2

Limitations/Caveats

Trial enrollment was terminated early due to lack of eligible participants.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.