Preoperative Pemetrexed and Carboplatin for Select Stage IB, II, and III Non-Squamous Non-Small-Cell Lung Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT00906282
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 46
• Locations: 12
• Arm: 1
• Duration (Months): 75
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this multi-center Phase II trial is to examine the impact of pemetrexed/carboplatin in the preoperative treatment of patients with select stage IB, II,and III non-squamous NSCLC. Because patients with non-squamous type NSCLC have been shown to have better survival rates than patients with squamous tumors when given pemetrexed with a platinum agent, only patients with non-squamous NSCLC (adenocarcinoma, large cell, and undifferentiated), not including squamous histology, will be allowed to participate in this study. If this novel regimen proves to be safe and active in this setting, it will provide rationale for further investigation in a larger, prospective, randomized trial.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Drug: Pemetrexed; Drug: Carboplatin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Preoperative Pemetrexed and Carboplatin in Patients With Select Stage IB, II, and III Non-Squamous Non-Small-Cell Lung Cancer
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pemetrexed/Carboplatin 4 cycles of preoperative treatment (1 Cycle = 21 days): Pemetrexed: 500 mg/m2 intravenously (IV) for 10 minutes on Day 1 each cycle; Carboplatin: AUC 6.0 by IV on Day 1 each cycle.	Drug: Pemetrexed; 500 mg/m2 IV over 10 minutes on Day 1 of every 3-week treatment cycle for a total of 4 cycles (12 weeks).; Other Names: Alimta ; Drug: Carboplatin; AUC 6.0 IV on Day 1 of every 3-week treatment cycle for a total of 4 cycles (12 weeks).; Other Names: 41575-94-4

Outcome Measures

Primary Outcome Measures

1. 3-Year Overall Survival Rate [36 months]

   The percentage of patients who were alive at 3 years from time of first study treatment until date of death from any cause. Overall survival is shown for the Intent-to-Treat population.

Secondary Outcome Measures

1. Objective Tumor Response [At 6 and 12 weeks]

   Objective Tumor Response defined as the percent of patients who completed up to 4 cycles of pre-operative chemotherapy and achieved a complete response (CR) or partial response (PR) assessed by Response Evaluation in Solid Tumors (RECIST) 1.0. Patients with stable disease (SD) or response to treatment were deemed surgical candidates. [CR=disappearance of all target tumors; PR= ≥30% decrease in the sum of the longest diameters of target tumors. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.]

2. Pathologic Response Rate [weeks 15 -18]

   Percent of patients having a pathological complete or partial response (pCR or pPR) at surgery. pCR defined as complete removal of all tumor. pPR defined as residual viable tumor demonstrated in the resected specimen.

3. Rate of Residual Disease as an Assessment of Pathological Partial Response (pPR) [At 15-18 weeks]

   pPR was further assessed by the amount of residual tumor measured at surgery: microscopic residual disease = less than 1 centimeter (<1 cm); macroscopic residual disease = 1 centimeter or greater (≥1 cm).

4. Complete Resection Rate [At weeks 15-18]

   The percent of patients who had surgical resection listed by procedure type: lobectomy or pneumonectomy, or resection of adjacent chest wall or mediastinal structures when appropriate. Surgery followed standard guidelines for resection of non-small-cell lung cancer (NSCLC).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologically-confirmed NSCLC (adenocarcinoma, large cell, and undifferentiated). Patients with squamous histology are not eligible.

2. Life expectancy of at least 12 weeks.

3. Patients with the following stages of NSCLC:

• T2 N0 tumors: Limited to tumors >=4 cm.

• T1-2 N1 tumors.

• T3 N0-1 tumors (excluding superior sulcus tumors): Including tumors involving the chest wall, proximal airway, or mediastinal pleura where preoperative radiotherapy is not planned.

• T1-2 N2 tumors: For patients with N2 disease involving one zone (Upper zone (R), AP zone (L), subcarinal zone, or lower zone) and nodes <=2cm in diameter.

• T4 N0-1 tumors (excluding superior sulcus tumors): T4 lesions other than malignant effusions where radiotherapy is not planned.

1. Patients with clinical N2 involvement must have histologic confirmation by mediastinoscopy (or alternate biopsy procedure).

2. Tumors should be considered potentially resectable.

3. No evidence of extrathoracic metastatic disease.

4. Patients must have measurable disease by RECIST criteria.

5. Patients must be candidates (medically) for chemotherapy followed by surgical resection.

6. Adequate recovery from recent surgery. At least 1 week must have elapsed from the time of a minor surgery; at least 3 weeks must have elapsed from the time of a major surgery.

7. Laboratory values as follows:

• Absolute neutrophil count (ANC) >=1500/μL

• Hemoglobin (Hgb) >=10 g/dL

• Platelets >=100,000/uL

• AST/SGOT and ALT/SGPT within normal limits (WNL)

• Total bilirubin within normal limits (WNL)

• Calculated creatinine clearance >=45 mL/min

1. ECOG Performance Status grade 0 or 1.

2. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Alimta.

3. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.

4. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.

5. Patient must be accessible for treatment and follow-up.

6. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

Exclusion Criteria:

1. Patients with the following stages are excluded:

• T1 N0;

• T2 N0, with primary tumor <4 cm;

• T1-2 N2, with multiple zones of N2 involvement;

• T3-4 N2;

• Any N3;

• Any TxNxM1 disease; or

• Any stage where surgery and/or chemoradiotherapy is the preferred initial approach in management, as deemed by the treating physician.

1. Squamous or predominant squamous mixed histologies.

2. Mixed small-cell and non-small cell histologies.

3. Pulmonary carcinoid tumors.

4. Presence of third space fluid which cannot be controlled by drainage.

5. Use of erythropoietin as a hematopoietic growth factor is not allowed.

6. Cardiac disease, including: congestive heart failure (CHF) > Class II per New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, cardiac arrhythmia, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

7. Women who are pregnant (positive pregnancy test) or lactating.

8. Use of any non-approved or investigational agent within 30 days of administration of the first dose of study drug.

9. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

10. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

11. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

12. History of hypersensitivity to active or inactive excipients of any component of treatment.

13. Inability to comply with study and/or follow-up procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Fort Myers	Florida	United States	33901
2	Medical Oncology Associates of Augusta	Augusta	Georgia	United States	30901
3	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
4	Baptist Hospital East	Louisville	Kentucky	United States	40207
5	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
6	National Capital Clinical Research Consortium	Bethesda	Maryland	United States	20817
7	Nebraska Methodist Cancer Center	Omaha	Nebraska	United States	68114
8	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
9	South Carolina Oncology Associates, PA	Columbia	South Carolina	United States	29210
10	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee	United States	37404
11	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37023
12	Virginia Cancer Institute	Richmond	Virginia	United States	23235

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Eli Lilly and Company

Investigators

• Study Chair: David R Spigel, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT00906282
• Other Study ID Numbers: SCRI LUN 186
• First Posted: May 21, 2009
• Last Update Posted: Feb 24, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by SCRI Development Innovations, LLC: neoadjuvant NSCLC; NSCLC; pemetrexed
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carboplatin; Pemetrexed

Study Results

Participant Flow

Recruitment Details	Between Aug 2009 and Jul 2013, 46 patients with potentially resectable non-squamous NSCLC were enrolled from 10 participating sites in the U.S.
Pre-assignment Detail	Patients (pts) received up to 4 cycles (12 weeks) of preoperative chemotherapy and were restaged after 6 and 12 weeks. Pts with progressive disease or intolerable toxicity came off study; pts who remained surgical candidates had resection at weeks 15-18. Following resection pts received no further planned protocol treatment.

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks of preoperative chemotherapy: Pemetrexed: 500 mg/m2 intravenously (IV) for 10 minutes on Day 1 each cycle; Carboplatin: AUC 6.0 by IV over 30-60 minutes on Day 1 each cycle Weeks 15-18: Patients deemed surgical candidates will have resection.
Period Title: Preoperative Chemotherapy
STARTED	46
COMPLETED	27
NOT COMPLETED	19
Period Title: Preoperative Chemotherapy
STARTED	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks (4 cycles) of preoperative treatment given on Day 1 of each 21-day cycle: Pemetrexed: 500 mg/m2 intravenously (IV) over 10 minutes Carboplatin: AUC 6.0, IV infused over 30-60 minutes At weeks 15-18, surgical candidates will have resection.
Overall Participants	46
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Gender (Count of Participants)
Female	28 60.9%
Male	18 39.1%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	42 91.3%
African-American	4 8.7%
Region of Enrollment (participants) [Number]
United States	46 100%
Clinical Stage of Cancer (participants) [Number]
Stage 1B	5 10.9%
Stage IIA/II/B	17 37%
Stage IIIA	23 50%
Stage IIIB	1 2.2%

Outcome Measures

1. Primary Outcome

Title	3-Year Overall Survival Rate
Description	The percentage of patients who were alive at 3 years from time of first study treatment until date of death from any cause. Overall survival is shown for the Intent-to-Treat population.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks of preoperative chemotherapy: Pemetrexed: 500 mg/m2 intravenously (IV) for 10 minutes on Day 1 each cycle; Carboplatin: AUC 6.0 by IV over 30-60 minutes on Day 1 each cycle Weeks 15-18: Patients deemed surgical candidates will have resection.
Measure Participants	46
Number (95% Confidence Interval) [percentage of participants]	45 97.8%

2. Secondary Outcome

Title	Objective Tumor Response
Description	Objective Tumor Response defined as the percent of patients who completed up to 4 cycles of pre-operative chemotherapy and achieved a complete response (CR) or partial response (PR) assessed by Response Evaluation in Solid Tumors (RECIST) 1.0. Patients with stable disease (SD) or response to treatment were deemed surgical candidates. [CR=disappearance of all target tumors; PR= ≥30% decrease in the sum of the longest diameters of target tumors. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.]
Time Frame	At 6 and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks of preoperative chemotherapy: Pemetrexed: 500 mg/m2 intravenously (IV) for 10 minutes on Day 1 each cycle; Carboplatin: AUC 6.0 by IV over 30-60 minutes on Day 1 each cycle Weeks 15-18: Patients deemed surgical candidates will have resection.
Measure Participants	46
PR	41 89.1%
SD	48 104.3%

3. Secondary Outcome

Title	Pathologic Response Rate
Description	Percent of patients having a pathological complete or partial response (pCR or pPR) at surgery. pCR defined as complete removal of all tumor. pPR defined as residual viable tumor demonstrated in the resected specimen.
Time Frame	weeks 15 -18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks of preoperative chemotherapy: Pemetrexed: 500 mg/m2 intravenously (IV) for 10 minutes on Day 1 each cycle; Carboplatin: AUC 6.0 by IV over 30-60 minutes on Day 1 each cycle Weeks 15-18: Patients deemed surgical candidates will have resection.
Measure Participants	27
pPR	100 217.4%
pCR	0 0%

4. Secondary Outcome

Title	Rate of Residual Disease as an Assessment of Pathological Partial Response (pPR)
Description	pPR was further assessed by the amount of residual tumor measured at surgery: microscopic residual disease = less than 1 centimeter (<1 cm); macroscopic residual disease = 1 centimeter or greater (≥1 cm).
Time Frame	At 15-18 weeks

Outcome Measure Data

Analysis Population Description

The amount of residual tumor measured in centimeters (cm).

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks of preoperative chemotherapy: Pemetrexed: 500 mg/m2 intravenously (IV) for 10 minutes on Day 1 each cycle; Carboplatin: AUC 6.0 by IV over 30-60 minutes on Day 1 each cycle Weeks 15-18: Patients deemed surgical candidates will have resection.
Measure Participants	27
Median (Full Range) [centimeters]	2.5

5. Secondary Outcome

Title	Complete Resection Rate
Description	The percent of patients who had surgical resection listed by procedure type: lobectomy or pneumonectomy, or resection of adjacent chest wall or mediastinal structures when appropriate. Surgery followed standard guidelines for resection of non-small-cell lung cancer (NSCLC).
Time Frame	At weeks 15-18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed/Carboplatin/Surgery
Arm/Group Description	Up to 12 weeks (4 cycles) of preoperative treatment on Day 1 of each 21-day cycle: Pemetrexed: 500 mg/m2 intravenously (IV) over 10 minutes Carboplatin: AUC 6.0, IV infused over 30-60 minutes At weeks 15-18, surgical candidates will have resection.
Measure Participants	27
Lobectomy	70
Wedge Resection	15
Pneumonectomy	11
Bilobectomy	4

Adverse Events

Time Frame	Every 3 weeks up to 12 weeks during preoperative treatment, then every 3 months post surgery for years 1-2, and every 6 months thru years 3-5..
Arm/Group Title	Pemetrexed/Carboplatin
Arm/Group Description	All patients who received at least 1 dose of study treatment were included in the safety analysis.
All Cause Mortality
	Pemetrexed/Carboplatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pemetrexed/Carboplatin
	Affected / at Risk (%)	# Events
Total	18/46 (39.1%)
Blood and lymphatic system disorders
Thrombocytopenia	2/46 (4.3%)
Neutropenia	2/46 (4.3%)
Anemia	2/46 (4.3%)
Leukopenia	1/46 (2.2%)
Cardiac disorders
Atrial Fibrillation	1/46 (2.2%)
Infections and infestations
Anorectal cellulitis	1/46 (2.2%)
Gastroenteritis	1/46 (2.2%)
Pneumonia	1/46 (2.2%)
Investigations
Neutrophil count decreased	1/46 (2.2%)
Platelet count	1/46 (2.2%)
Platelet count decreased	1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/46 (2.2%)
Haemothorax	1/46 (2.2%)
Pleural effusion	1/46 (2.2%)
Pulmonary embolism	1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	Pemetrexed/Carboplatin
	Affected / at Risk (%)	# Events
Total	46/46 (100%)
Blood and lymphatic system disorders
Anaemia	24/46 (52.2%)
Thrombocytopenia	22/46 (47.8%)
Leukopenia	17/46 (37%)
Neutropenia	18/46 (39.1%)
Lymphopenia	4/46 (8.7%)
Gastrointestinal disorders
Nausea	29/46 (63%)
Constipation	25/46 (54.3%)
Vomiting	15/46 (32.6%)
Diarrhoea	10/46 (21.7%)
Stomatitis	4/46 (8.7%)
Dyspepsia	3/46 (6.5%)
General disorders
Fatigue	36/46 (78.3%)
Oedema Peripheral	5/46 (10.9%)
Pyrexia	6/46 (13%)
Mucosal Inflammation	5/46 (10.9%)
Asthenia	3/46 (6.5%)
Chest pain	3/46 (6.5%)
Chills	3/46 (6.5%)
Infections and infestations
Upper respiratory tract infection	3/46 (6.5%)
Urinary tract infection	3/46 (6.5%)
Investigations
Haemoglobin	9/46 (19.6%)
Platelet count decreased	4/46 (8.7%)
Platelet count	8/46 (17.4%)
Neutrophil count	8/46 (17.4%)
Neutrophil count decreased	5/46 (10.9%)
Weight decreased	6/46 (13%)
White blood cell count	5/46 (10.9%)
Haemoglobin decreased	4/46 (8.7%)
Blood creatinine decreased	3/46 (6.5%)
White blood cell count decreased	3/46 (6.5%)
Blood glucose increased	3/46 (6.5%)
Metabolism and nutrition disorders
Hyperglycaemia	8/46 (17.4%)
Dehydration	9/46 (19.6%)
Decreased appetite	8/46 (17.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/46 (8.7%)
Back pain	3/46 (6.5%)
Nervous system disorders
Dysgeusia	7/46 (15.2%)
Headache	5/46 (10.9%)
Dizziness	3/46 (6.5%)
Psychiatric disorders
Insomnia	5/46 (10.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	14/46 (30.4%)
Cough	9/46 (19.6%)
Epistaxis	5/46 (10.9%)
Dyspnoea Exertional	3/46 (6.5%)
Haemoptysis	3/46 (6.5%)
Skin and subcutaneous tissue disorders
Rash	5/46 (10.9%)
Alopecia	5/46 (10.9%)
Pruritis	4/46 (8.7%)
Vascular disorders
Hypotension	5/46 (10.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.