NCCTG Status Report for Study N April 2008

Transcription

1 Phase II Randomized Study of Pemetrexed With Sorafenib Versus Pemetrexed lone as Second-line Therapy in Patients With dvanced Non-Small Cell Lung Cancer Purpose of - Primary Study: 1) To compare the progression-free survival in patients who receive pemetrexed and sorafenib (experimental) versus pemetrexed alone (standard) in patients with advanced non-small cell lung cancer (second-line). - Secondary endpoints 1) To compare the overall survival, tumor response rate, duration of response, and toxicity rates between pemetrexed and sorafenib (experimental) versus pemetrexed alone (standard) in patients with advanced non-small cell lung cancer (second line). - Translational 1) To evaluate the intracellular content of pemetrexed polyglutamates as a measure of activity of pemetrexed transport and activation enzymes. 2) To evaluate polymorphisms and gene expression in pemetrexed patients. 3) To evaluate predictive markers of hypertension (e.g. pharmacogenetics, VEGF- and svegfr-1, and DM) in relation to clinical toxicity and outcomes. 4) s part of ongoing research for NCCTG lung studies, we are banking paraffin-embedded tissue blocks/slides and blood samples for future evaluation of pharmacogenetic and/or proteomic markers. Study Chairs: lex. djei M.D. Kendrith M. Rowland Jr. M.D. QC Specialist: Rachael Meyers Statistician: Nathan R. Foster M.S. Nurse Resource: Wanda L. DeKrey R.N., OCN Status: 09/07/2007 ctivated Projected Number of Patients: 104 Excluded: None Final ccrual: N Stratification ECOG PS: 0 vs. 1 Factors: Schema: Randomize Pemetrexed + Sorafenib Pemetrexed Treating Schedule: rm gent Dose Route Days Freq Pemetrexed* 500mg/m2 IV in 100ml NS over 10 1 Every 21 days minutes N Page 1 of 5

2 rm gent Dose Route Days Freq Sorafenib 400mg (2 tablets) Oral twice a day 1-21 Every 21 days B Pemetrexed* 500mg/m2 IV in 100ml NS over 10 1 Every 21 days minutes rms and B: Delay the first dose of pemetrexed until the patient has taken folic acid for at least 5 of the 7 days immediately preceding the first dose of pemetrexed and until the vitamin B12 injection has been administered. *Creatinine clearance must be >=45mL/min before any pemetrexed is given using the Cockcroft-Gault formula (see Section 3.15 of the protocol). Study Design: This randomized phase II study is designed to compare the progression-free survival (PFS) of pemetrexed and sorafenib (experimental arm) versus pemetrexed alone (standard treatment arm) as second line treatment among patients with advanced NSCLC (Stage IIIB with pleural effusions or IV) using a one-stage design. Patients will be randomized between pemetrexed alone and the combination of pemetrexed with sorafenib in a 1:1 fashion. The first 6 patients enrolled on rm (pemetrexed + sorafenib) will be assessed for tolerability of this regimen, will be included in all efficacy analyses, if there is not need to reduce the dose of sorafenib. If, however, the sorafenib dose does need to be reduced based on the evaluation of the first 6 patients on arm, these first 6 patients will not be included in the efficacy analyses. Forty-seven evaluable patients will be accrued to each arm of this study. total of 94 patients (47 on each arm) will provide 82% power to compare the overall PFS for rm versus rm B using a one-sided log rank test with alpha=.05 with uniform enrollment for 15 months and a 3- month follow-up period. This sample size calculation assumes the 6-month PFS for rm is 20% and the 6-month PFS for rm B is 42%. The assumption of 42% PFS at 6 months is derived from the recently conducted phase III trial (38) where the median PFS for second-line treatment for advanced NSCLC using pemetrexed alone was approximately 3 months which provides a 3-month PFS estimate of approximately 50% at 3 months. ccrual: s of February 4th, this study has accrued a total of 14 patients, 7 to rm and 7 to rm B. This study is temporarily suspended to review the tolerability of the rm treatment. See the accrual table for further information. Patient Characteristics: See the baseline characteristics table for information on the patient characteristics by arm. vailable Information: ll patients are eligible so far. N Page 2 of 5

3 dverse Events: Four and three patients are evaluable for adverse events for rms and B, respectively. Two of the arm patients have experienced grade 4 adverse events, both of which were hematologic (leukopenia and neutropenia). No rm B patients have experienced any grade 4 or higher adverse events. There was one additional rm patient that died cycle 3, but this grade 5 sudden death was unlikely related to the study treatment. This event is not listed in the dverse Event table. See the adverse event table for further details. Study Status: This study is temporarily suspended to review the cycle 1 adverse events for rm. ccrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months nn rbor Cedar Rapids Dayton Fargo Green Bay Mayo Metro MN Montana N Indiana Rapid City Sioux City Upstate Carol Total Membership ccrual Baseline Characteristics Table: Characteristics rm Gender f 5 4 m 2 3 Performance Score Race White 6 6 Black or frican merican 0 1 merican Indian or laska Native 1 0 rm B N Page 3 of 5

4 Grade 4/5 and Most Frequent dverse Event Table: rm Evaluable Patients: 4 rm B Evaluable Patients: 3 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology LEUKOPENI THROMBOCYTOPENI NEMI NEUTROPENI Cardiovascular HYPERTENSION Constitutional Symptoms FTIGUE WEIGHT LOSS Dermatology/Skin RSH Gastrointestinal NOREXI NUSE DEHYDRTION CONSTIPTION STOMTITIS VOMITING MUCOSITIS-RT PHRYNX MS FS Metabolic/Laboratory HYPOPHOSPHTEMI LIPSE N Page 4 of 5

5 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Neurology NEURO-SENSORY Pain PIN-HEDCHE RTHRLGI Pulmonary DYSPNE Maximum Grade dverse Event B N Page 5 of 5