GOG PROTOCOL #209 GOG 209

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1 GOG PROTOCOL #209 PROTOCOL Study Chairs Statistician Data Coordinator Randomized Phase III Trial of Doxorubicin/Cisplatin/Paclitaxel and G-CSF Versus Carboplatin/Paclitaxel in Patients with Stage III and IV or Recurrent Endometrial Cancer David Miller, MD, Gini Fleming, MD, Richard Zaino, MD, and David Cella, PhD Virginia Filiaci, MA and Helen Huang, MS (QOL) Patricia Brehm, CCRP - Stage III, stage IV or recurrent endometrial carcinoma - No prior cytotoxic chemotherapy - ER/PR assessed on primary tumor (required) -Patients with known LVEF <50% within 6 months of study entry are ineligible. * Filgrastim (G-CSF, Neupogen) 5 mcg/kg days 3-12 or Pegfilgrastin (G-CSF) 6 mg Day 3. Japanese institutions will use 2 mcg/kg/day dosing. R A N D O M I Z E GOG 209 Randomization to Regimen I requires determination of LVEF. LVEF 50% receive treatment per Regimen I. LVEF <50% crossover to Regimen II. Regimen I Doxorubicin 45 mg/m 2 IV day 1 Cisplatin 50 mg/m 2 day 1 Paclitaxel 3 hr 160 mg/m 2 day 2 G-CSF* Repeated every 21 days for 7 cycles Regimen II Paclitaxel 3 hr 175 mg/m 2 day 1 Carboplatin AUC 6 IV day 1 Repeated every 21 days for 7 cycles Activated 8/25/03 Revised 3/15/04, 5/2/05, 8/29/05, 11/21/05, 4/17/06, 10/30/06, 3/26/07 Purpose To determine if the combination of carboplatin and paclitaxel (TC) chemotherapy is therapeutically equivalent to the combination of doxorubicin, cisplatin and paclitaxel (TAP) chemotherapy with regards to survival. To determine if estrogen/progesterone receptor status provides prognostic information in patients treated with chemotherapy. To assess whether combination TC chemotherapy is superior to combination TAP chemotherapy with regards to toxicity profile, specifically neurotoxicity and infection. To measure differences in patient-reported neurotoxicity and quality of life among the regimens. Eligibility Patients must have primary Stage III, IV, or recurrent endometrial carcinoma whose potential for cure by radiation therapy or surgery alone or in combination is very poor. Pathological confirmation and Estrogen Receptor (ER)/Progesterone Receptor (PR) status of the primary tumor is mandatory. Patients may not have received prior cytotoxic chemotherapy, including chemotherapy used for radiation sensitization. Patients may have received prior hormonal therapy or therapy with biologic agents, but such therapies must be discontinued prior to entry on this study. At least four weeks should have elapsed since completion of RT involving the whole pelvis or over 50% of the spine. Patients must have adequate end-organ function. Patients must have a GOG Performance Status of 0, 1, or 2. Patients in whom both radiation and chemotherapy is planned must receive radiation prior to entry to this study. At least four weeks should have elapsed since completion of RT involving the whole pelvis or over 50% of the spine.

2 PATIENT ACCESSION DATA ENT EXCL ENT EXCL 001 RPCI SUNY-SB ALABAMA WASH U DUKE MEMORIAL ABINGTON COOPER W REED COLUMBUS WAYNE ST ANDERSON MINN MASS MT SINAI FOX CHASE MISS WCC-UNEV COLORADO OKLAHOMA UCLA VIRGINIA U WASH CHICAGO PENN MAYO HERSHEY CASE WEST CINN TAMPA NC GYNONCNET IOWA FLETCHER DALLAS YALE INDIANA GOG JAPAN W FOREST WISCONSIN IRVINE CTSU TUFTS GALVESTON RUSH WOM & INF MAGEE CENT CONN SUNY-DWN GA_CORE KENTUCKY NYU NEW MEXICO CCOP CLEV OTHERS 17 2 Regimen Number Entered Number Ineligible Number Eligible P Q Total * *Path review pending in 351; Gyn review pending in 497. TOTAL Ineligible Patients by Regimen Regimen Total Reason P Q Wrong stage Second primary Wrong cell type Wrong primary Inadequate path materials No tumor at entry Required test not done Total At this time, there are no reports of patients who were assigned to Regimen I and had to cross over to Regimen II due to pretreatment left ventricular ejection fraction <50%. There is no need at this time to inflate the sample size due to crossover.

3 ANALYSIS CLINICAL RESEARCH Patient Characteristics Regimen P Regimen Q Characteristic N % N % Age >= Ethnicity Hispanic or Latino Non-Hispanic Unknown/Not specified Race White Black/African American Asian Other Unknown Performance Status Pending Cell Type Adenosquamous Adenocarcinoma, nos Clear Cell Endometrioid Mucinous Mixed Epithelial Squamous Undifferentiated Villoglandular Serous Stage III IV Recurrent Stratification Stratum Stratum Stratum Stratus

4 Estrogen and Progesterone Receptors in Primary Tissue Regimen P Regimen Q Receptor Status N % N % Estrogen-negative Estrogen-positive Estrogen-pending Progesterone-negative Progesterone-positive Progesterone-pending Progesterone-not done Treatment Reason off therapy Regimen P N % Regimen Q N % Total Still receiving treatment Completed regimen Disease Progression Patient Refused Toxicity Death Other Adverse Events The table below summarizes the adverse effects of therapy for 491 patients considered evaluable for toxicity. All toxicity is graded according to CTCAE v2.0. Regimen P Regimen Q Adverse Effect Total Total Leukopenia Neutropenia Thrombocytopenia Anemia Other Hematologic Allergy Auditory Ventricular Function Cardiovascular Coagulation Constitutional Fatigue Fever, No Neutropenia Alopecia Rash/Desquamation Dermatologic Endocrine Gastrointestinal

5 Regimen P Regimen Q Adverse Effect Total Total Nausea Vomiting Diarrhea Anorexia Stomatitis Genitourinary/Renal Creatinine Hemorrhage Hepatic Infection/Fever Febrile Neutropenia Infection w/o Neutropenia Infection w/ Neutropenia Lymphatics Metabolic Musculoskeletal Neurologic Neuromotor Sensory neuropathy Ocular/Visual Pain Myalgia Arthralgia Pulmonary Second malignancies: Acute Leukemia (1), Melanoma (1). Deaths attributable to treatment are described in the Progression and Survival section.

6 Progression and Survival No. (%) Alive, with no evidence of disease progression Alive, following disease progression Dead Treatment... 9* Disease Treatment & Disease... 1** Other...5 Unknown...10 Pending...2 *Sepsis with neutropenia (6); aspiration (1); dehydration, anemia, neutropenia (1), renal failure (1) **Sepsis with neutropenia and pulmonary mets suspected in respiratory failure (1) ANALYSIS QUALITY OF LIFE Assessment Status The following table summarized quality of life assessments for 544 eligible patients who entered the study prior to 3/26/07. Time of Assessment Received & Valid Insufficient Answers Missed* Delinquent* Total Due No. Too Early No. Cumulative Deaths No. Prior to randomization wks post randomization wks post randomization wks post randomization * Missed: Forms missed due to patients illness, refusal, loss of contact, etc. Delinquent: Forms missed due to institutional error or missed without reasons reported. CONCLUSIONS Too early. PUBLICATIONS None.