Phase III Comparison of Thoracic Radiotherapy Regimens in Patients with Limited Small Cell Lung Cancer also Receiving Cisplatin and Etoposide

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1 Phase III Comparison of Thoracic Radiotherapy Regimens in Patients with Limited Small Cell Lung Cancer also Receiving Cisplatin and Etoposide Activated: March 15, 2008 Study Chairpersons: J. Bogart Total Accrual as of 11/25/2009: 73 G. Masters Projected Accrual : 670 Statisticians: H. Pang Current Protocol Update: #01, December 15, 2008 L. Hodgson Data Coordinator: S. Sutherland SCHEMA (1 cycle = 21 days) Patients will receive 4 cycles of chemotherapy on all arms Prophylactic cranial irradiation (PCI) should be offered to all patients with a complete or near complete response Part II: Based on the results of Part I, the experimental arm with the higher rate of toxic events will be discontinued and patients will be randomized as follows: Prophylactic cranial irradiation (PCI) should be offered to all patients with a complete or near complete response.

2 Objectives Primary To determine whether administering high dose thoracic radiotherapy, 70 Gy (2 Gy once-daily over 7 weeks) or 61.2 Gy (1.8 Gy once daily for 16 days followed by 1.8 Gy twice daily for 9 days), will improve median and 2-year survival compared with 45 Gy (1.5 Gy twice daily over 3 weeks) in patients with limited stage small cell lung cancer. Secondary 1. To compare treatment related toxic effects of thoracic radiotherapy regimens in patients with limited stage small cell lung cancer. 2. To compare response rates, failure-free survival and toxicity of thoracic radiotherapy regimens in patients with limited stage small cell lung cancer. 3. To compare rates of local relapse, distant metastases and brain metastases with these regimens. 4. To compare patients quality of life between these treatment regimens in terms of their physical symptoms, physical functioning and psychological state. 5. To describe the patterns of use of thoracic intensity modulated radiation therapy (IMRT) in patients with limited stage small cell lung cancer. 6. To examine blood-based biomarkers of response and resistance to cisplatin and etoposide. Eligibility Criteria Histologically or cytologically documented small cell lung cancer of limited stage Measurable disease No prior chemotherapy or radiotherapy for SCLC No prior mediastinal or thoracic radiotherapy Patients with complete surgical resection of disease are not eligible ECOG Performance Status 0-2 Non-pregnant and non-nursing Age 18 years Required Initial Laboratory Values Granulocytes Platelets AST( SGOT) Total Bilirubin Serum Creatinine OR Calculated CrCI Administrative Comments 1,500/µl 100,000/µl < 2 x ULN <1.5 x ULN <1.5 x ULN 70 ml/min CALGB was activated on March 15, As of November 25, 2009, there were 73 patients enrolled. This study is being monitored according to the NCI guidelines for slow accruing studies. After 30 patients enrolled in each experiment arms, an interim endpoint will be utilized to select between the two experimental treatment arms, Arm B and Arm C. No formal analyses were performed at this time. There was adverse event data for 53 patients. Accrual Accrual by Institution For Period 3/15/2008 through 11/25/2009 Main/At-Large Member Affiliate Total BATI CCHLTH CHAPEL CHICAGO GRENVIL MARYLAND MIAMI MO/EFCC MVCC NCRF NHOH OSUMC RPCI SECCC SYRACUSE WASH-BARN WFUSM CALGB Total: CTSU 43 Total Accrual 73 Accrual by Month Total Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Total Adverse Events

3 Hematologic Adverse Events Blood/Bone Marrow Hemoglobin A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 B 5 ( 25%) 0 ( 0%) 0 ( 0%) 20 C 3 ( 19%) 0 ( 0%) 0 ( 0%) 16 Leukocytes (total WBC) A 4 ( 24%) 8 ( 47%) 0 ( 0%) 17 B 6 ( 30%) 7 ( 35%) 0 ( 0%) 20 C 5 ( 31%) 8 ( 50%) 0 ( 0%) 16 Lymphopenia A 3 ( 18%) 3 ( 18%) 0 ( 0%) 17 B 0 ( 0%) 2 ( 10%) 0 ( 0%) 20 C 2 ( 13%) 3 ( 19%) 0 ( 0%) 16 Neutrophils/granulocytes (ANC/AGC) A 5 ( 29%) 9 ( 53%) 0 ( 0%) 17 B 4 ( 20%) 10 ( 50%) 0 ( 0%) 20 C 4 ( 25%) 8 ( 50%) 0 ( 0%) 16 Platelets A 1 ( 6%) 4 ( 24%) 0 ( 0%) 17 C 0 ( 0%) 3 ( 19%) 0 ( 0%) 16 SUMMARY Maximum Hematologic AE A 5 ( 29%) 9 ( 53%) 0 ( 0%) 17 B 3 ( 15%) 13 ( 65%) 0 ( 0%) 20 C 3 ( 19%) 12 ( 75%) 0 ( 0%) 16 Non-Hematologic Adverse Events Allergy/Immunology Allergic reaction/hypersensitivity Auditory/Ear Hearing: patients without baseline audiogram Tinnitus Cardiac Arrhythmia Supraventricular and nodal arrhythmia A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Cardiac General Hypotension

4 Left ventricular diastolic dysfunction Coagulation INR (International Normalized Ratio of prothr ) Constitutional Symptoms A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Fatigue (asthenia, lethargy, malaise) A 3 ( 18%) 0 ( 0%) 0 ( 0%) 17 B 3 ( 15%) 1 ( 5%) 0 ( 0%) 20 C 3 ( 19%) 0 ( 0%) 0 ( 0%) 16 Fever (in the absence of neutropenia ) A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Insomnia A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Weight loss Gastrointestinal Infection Anorexia A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Dehydration A 2 ( 12%) 1 ( 6%) 0 ( 0%) 17 B 4 ( 20%) 0 ( 0%) 0 ( 0%) 20 C 5 ( 31%) 0 ( 0%) 0 ( 0%) 16 Dysphagia (difficulty swallowing) A 3 ( 18%) 0 ( 0%) 0 ( 0%) 17 B 4 ( 20%) 0 ( 0%) 0 ( 0%) 20 Esophagitis A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 B 1 ( 5%) 1 ( 5%) 0 ( 0%) 20 Nausea A 2 ( 12%) 0 ( 0%) 0 ( 0%) 17 B 3 ( 15%) 0 ( 0%) 0 ( 0%) 20 C 4 ( 25%) 0 ( 0%) 0 ( 0%) 16 Vomiting A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 B 5 ( 25%) 0 ( 0%) 0 ( 0%) 20

5 Febrile neutropenia (fever of unknown origin ) Infection (documented clinically or microbiologic) A 4 ( 24%) 0 ( 0%) 0 ( 0%) 17 A 1 ( 6%) 1 ( 6%) 0 ( 0%) 17 B 0 ( 0%) 2 ( 10%) 0 ( 0%) 20 Infection - Other (Specify ) Infection with normal ANC or Grade 1 or 2 neu Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminas ) AST, SGOT (serum glutamic oxaloacetic transami ) Albumin, serum-low (hypoalbuminemia) A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 B 2 ( 10%) 0 ( 0%) 0 ( 0%) 20 Calcium serum-low (hypocalcemia) B 2 ( 10%) 0 ( 0%) 0 ( 0%) 20 Glucose serum-high (hyperglycemia) Phosphate serum-low (hypophosphatemia) A 0 ( 0%) 1 ( 6%) 0 ( 0%) 17 Potassium serum-low (hypokalemia) A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Potassium, serum-low (hypokalemia)

6 Sodium serum-low (hyponatremia) A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 C 0 ( 0%) 1 ( 6%) 0 ( 0%) 16 Sodium, serum-low (hyponatremia) Musculoskeletal/Soft Tissue Muscle weakness, generalized or specific area Neurology Pain Dizziness Neuropathy: sensory Syncope (fainting) A 1 ( 6%) 0 ( 0%) 0 ( 0%) 17 Pain A 3 ( 18%) 0 ( 0%) 0 ( 0%) 17 Pulmonary/Upper B 4 ( 20%) 0 ( 0%) 0 ( 0%) 20 Dyspnea (shortness of breath) Renal/Genitourinary Vascular C 2 ( 13%) 1 ( 6%) 0 ( 0%) 16 Renal failure Thrombosis/embolism (vascular access-related) Thrombosis/thrombus/embolism A 2 ( 12%) 0 ( 0%) 0 ( 0%) 17 SUMMARY C 1 ( 6%) 1 ( 6%) 0 ( 0%) 16

7 Maximum Non-Hematologic AE A 6 ( 35%) 3 ( 18%) 0 ( 0%) 17 B 10 ( 50%) 4 ( 20%) 0 ( 0%) 20 C 8 ( 50%) 3 ( 19%) 0 ( 0%) 16 SUMMARY Maximum Overall AE A 7 ( 41%) 9 ( 53%) 0 ( 0%) 17 B 5 ( 25%) 14 ( 70%) 0 ( 0%) 20 C 2 ( 13%) 13 ( 81%) 0 ( 0%) 16