S0124: Cisplatin Combined With Irinotecan or Etoposide For Extensive-Stage Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known whether cisplatin combined with irinotecan is more effective than cisplatin combined with etoposide in treating extensive-stage small cell lung cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of cisplatin combined with either irinotecan or etoposide in treating patients who have extensive-stage small cell lung cancer.

Detailed Description
-----------------
OBJECTIVES: Compare the survival of patients with extensive stage small cell lung cancer treated with cisplatin and irinotecan vs cisplatin and etoposide. Compare the objective response rate and progression-free survival of patients treated with these regimens. Compare the toxic effects of these regimens in these patients. Determine the association between UGT1A1 polymorphisms and irinotecan-associated toxic effects in these patients. Determine the association between ERCC-1 and XRCC-1 polymorphisms and non-response of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of metastatic sites (single vs multiple), lactic dehydrogenase (no greater than upper limit of normal (ULN) vs greater than ULN), and weight loss in the past 6 months (5% or less vs more than 5%). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive irinotecan IV over 90 minutes on days 1, 8, and 15 and cisplatin IV over 30-60 minutes on day 1. Courses repeat every 4 weeks. Arm II: Patients receive etoposide IV over 30-60 minutes on days 1-3 and cisplatin IV over 30-60 minutes on day 1. Courses repeat every 3 weeks. Treatment in both arms continues for 4 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 620 patients (310 per treatment arm) will be accrued for this study within 4 years.

Official Title
-----------------
Randomized Phase III Trial of Cisplatin and Irinotecan (NSC-616348) Versus Cisplatin and Etoposide in Patients With Extensive Stage Small Cell Lung Cancer (E-SCLC)

Conditions
-----------------
Lung Cancer

Intervention / Treatment
-----------------
* Drug: cisplatin
* Drug: etoposide
* Drug: irinotecan hydrochloride


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed extensive stage small cell lung cancer (SCLC) Measurable or evaluable disease by CT scan, MRI, x-ray, physical exam, or nuclear exam Brain metastases allowed if previously treated with radiotherapy and/or surgery and are neurologically stable (i.e., no progressing symptoms and off steroids and anticonvulsants) PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-1 Life expectancy Not specified Hematopoietic WBC at least 3,000/mm^3 Absolute granulocyte count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin no greater than 1.5 times upper limit of normal (ULN) AST or ALT no greater than 2.5 times ULN Renal Creatinine normal Creatinine clearance at least 50 mL/min Other Not pregnant or nursing Fertile patients must use effective contraception No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix HIV negative No concurrent AIDS-related illness PRIOR CONCURRENT THERAPY: Biologic therapy No prior biologic therapy for SCLC No filgrastim (G-CSF) within 24 hours of chemotherapy Chemotherapy No prior systemic chemotherapy for SCLC Endocrine therapy See Disease Characteristics Radiotherapy See Disease Characteristics At least 21 days since prior brain radiotherapy and recovered No other prior radiotherapy for SCLC Surgery See Disease Characteristics At least 21 days since prior thoracic or other major surgery and recovered Other No concurrent enzyme inducing antiepileptic drugs (phenytoin, phenobarbital, oxcarboxepine, or carbamazepine)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: cisplatin<br>* Arm 1: 60 mg/m2 IV (over 30-60 min) on Day 1, Q 4 weeks x 4 Cycles Arm 2: 80 mg/m2 IV (over 30-60 min) on Day 1, Q 4 weeks x 4 Cycles<br>Drug: irinotecan hydrochloride<br>* 60 mg/m2 IV (over 90 min)on Days 1, 8 & 15. Q 4 weeks x 4 Cycles<br>|
| Active Comparator: 2<br> | Drug: cisplatin<br>* Arm 1: 60 mg/m2 IV (over 30-60 min) on Day 1, Q 4 weeks x 4 Cycles Arm 2: 80 mg/m2 IV (over 30-60 min) on Day 1, Q 4 weeks x 4 Cycles<br>Drug: etoposide<br>* 100 mg/m2 IV (over 30-60 min) on Days 1 , 2 & 3. Q 3 weeks x 4 Cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the duration between the date of randomization( enrollment) and the date of death due to any cause. Patients last known to be alive were censored at the date of last contact. | Weekly while on treatment, then every 3 months for first year, then every 6 months unitl a maximum of 3 years from enrollment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-Free Survival was defined as the duration from the date of randomization (enrollment) until the date of documentation of progression as defined by RECIST (a 20% increase over nadir in the sum of longest diameters of target lesions, clear progression of a non-target lesion in the opinion of the treating investigator, appearance of new lesions, or symptomatic deterioration) or death due to any cause. Patients last known to be alive and without evidence of progression were censored at the date of last contact. | Every 6 weeks until disease progression or a maximum of 3 years from the date of enrollment. | 
| Confirmed and Unconfirmed Complete and Partial Responses. | Patients underwent chest CT/MRI every 6 weeks while on treatment and tumor response was evaluated by RECIST in the subset of patients with at least one target lesion at baseline. A target lesion was defined as a lesion with a longest diameter of at least 2 cm ( or at least 1 cm if by spiral CT). A complete response (CR) was defined as the disappearance of all disease, including non-target lesions. A partial response (PR) was defined as a 30% or greater decrease in the sum of the longest diameters. Confirmation of a CR or PR was defined as a second determination of CR or PR at least 4 weeks after the first determination. | Every 6 weeks while on protocol treatment for a maximum of 12 weeks | 
| Number of Patients With a Given Type and Grade of Adverse Event. | Only adverse events that are possibly, probably or definitely related to study drug are reported. Only patients who received protocol treatment and were assessed for adverse events are included. | Every 4 weeks while subject on protocol treatment for a maximum of 12 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
extensive stage small cell lung cancer