Non Small Cell Lung Cancer
Conditions
Keywords
neoadjuvant NSCLC, NSCLC, pemetrexed
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.
Interventions
DRUGPemetrexed
500 mg/m2 IV over 10 minutes on Day 1 of every 3-week treatment cycle for a total of 4 cycles (12 weeks).
DRUGCarboplatin
AUC 6.0 IV on Day 1 of every 3-week treatment cycle for a total of 4 cycles (12 weeks).
Sponsors
Eli Lilly and Company
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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. 4. Patients with clinical N2 involvement must have histologic confirmation by mediastinoscopy (or alternate biopsy procedure). 5. Tumors should be considered potentially resectable. 6. No evidence of extrathoracic metastatic disease. 7. Patients must have measurable disease by RECIST criteria. 8. Patients must be candidates (medically) for chemotherapy followed by surgical resection. 9. 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. 10. 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 11. ECOG Performance Status grade 0 or 1. 12. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Alimta. 13. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol. 14. 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. 15. Patient must be accessible for treatment and follow-up. 16. 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. 2. Squamous or predominant squamous mixed histologies. 3. Mixed small-cell and non-small cell histologies. 4. Pulmonary carcinoid tumors. 5. Presence of third space fluid which cannot be controlled by drainage. 6. Use of erythropoietin as a hematopoietic growth factor is not allowed. 7. 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. 8. Women who are pregnant (positive pregnancy test) or lactating. 9. Use of any non-approved or investigational agent within 30 days of administration of the first dose of study drug. 10. Patients may not receive any other investigational or anti-cancer treatments while participating in this study. 11. 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. 12. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study. 13. History of hypersensitivity to active or inactive excipients of any component of treatment. 14. Inability to comply with study and/or follow-up procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. \[CR=disappearance of all target tumors; PR= ≥30% decrease in the sum of the longest diameters of target tumors. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.\] |
| 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. |
| 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). |
| 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). |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed/Carboplatin/Surgery 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. | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Preoperative Chemotherapy | Not surgical candidates, off study | 10 |
| Preoperative Chemotherapy | Progressive disease | 6 |
| Preoperative Chemotherapy | Toxicity | 1 |
| Preoperative Chemotherapy | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Pemetrexed/Carboplatin/Surgery |
|---|---|
| Age, Continuous | 65 years |
| Clinical Stage of Cancer Stage 1B | 5 participants |
| Clinical Stage of Cancer Stage IIA/II/B | 17 participants |
| Clinical Stage of Cancer Stage IIIA | 23 participants |
| Clinical Stage of Cancer Stage IIIB | 1 participants |
| Gender Female | 28 Participants |
| Gender Male | 18 Participants |
| Race/Ethnicity, Customized African-American | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 42 Participants |
| Region of Enrollment United States | 46 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 46 / 46 |
| serious Total, serious adverse events | 18 / 46 |
Outcome results
Primary
3-Year Overall Survival Rate
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed/Carboplatin/Surgery | 3-Year Overall Survival Rate | 45 percentage of participants |
Secondary
Complete Resection Rate
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed/Carboplatin/Surgery | Complete Resection Rate | Wedge Resection | 15 percentage of patients |
| Pemetrexed/Carboplatin/Surgery | Complete Resection Rate | Lobectomy | 70 percentage of patients |
| Pemetrexed/Carboplatin/Surgery | Complete Resection Rate | Pneumonectomy | 11 percentage of patients |
| Pemetrexed/Carboplatin/Surgery | Complete Resection Rate | Bilobectomy | 4 percentage of patients |
Secondary
Objective Tumor Response
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed/Carboplatin/Surgery | Objective Tumor Response | PR | 41 percentage of participants |
| Pemetrexed/Carboplatin/Surgery | Objective Tumor Response | SD | 48 percentage of participants |
Secondary
Pathologic Response Rate
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed/Carboplatin/Surgery | Pathologic Response Rate | pPR | 100 percentage of participants |
| Pemetrexed/Carboplatin/Surgery | Pathologic Response Rate | pCR | 0 percentage of participants |
Secondary
Rate of Residual Disease as an Assessment of Pathological Partial Response (pPR)
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
Population: The amount of residual tumor measured in centimeters (cm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin/Surgery | Rate of Residual Disease as an Assessment of Pathological Partial Response (pPR) | 2.5 centimeters |