NCCTG Status Report for Study N May 2010

Transcription

1 Phase I/II Trial of Imatinib Mesylate; (Gleevec; STI-571) in Treatment of Recurrent Oligodendroglioma and Mixed Oligoastrocytoma Purpose of - Objectives Study: 1) Study 1: To identify the MTD of imatinib in the study population currently on EIC therapy. 2) Study 2: To assess the efficacy of imatinib in the study population as measured by progression-free survival, response, and overall survival. 3) Study 3: To acquire pilot data on a patient group not traditionally eligible for this study population (those having greater than 2 prior chemotherapy regimens or 2 prior chemotherapy regimens for recurrent/progressive disease). - Studies 1, 2, and 3 1) To examine the toxicity and safety of imatinib in the study population. 2) To perform a preliminary correlative study of 1p/19q alterations, apdfgr gene amplification and levels of related downstream signaling elements in tumor tissue with clinical study endpoints. 3) To perform a descriptive correlative analysis of steady state pharmacokinetic data regarding imatinib and active metabolites with the study endpoints. * Study Endpoints 1) Study 1: The primary endpoint of this study is dose limiting toxicity for patients receiving EICs. 2) Studies 2 and 3: Primary endpoint for these studies is progression-free survival at 6 months. Secondary endpoints include: (1) confirmed response; (2) percentage of patients progression-free at 12 & 18 months after start of treatment; (3) progression-free survival; (4) overall time to death; and (5) quality of life. Study Chairs: Kurt. Jaeckle M.D. Patrick J. Flynn M.D. QC Specialist: Carla R. Hilton Statistician: S. Keith nderson MS Nurse Resource: Wanda L. DeKrey R.N., OCN Status: 06/20/2003 ctivated Projected Number of Patients: 93 Excluded: 1 Final ccrual: N Stratification None Factors: Schema: Study 1: Register C) EIC patients: Imatinib Study 2: Register ) EIC patients: Imatinib N Page 1 of 8

2 Treating Schedule: NCCTG Status Report for Study N May 2010 B) Non-EIC patients: Imatinib Study 3: Register D) EIC patients having >2 prior chemotherapy regimens or 2 prior chemotherapy regimens for recurrent/progressive disease: Imatinib E) Non-EIC patients having >2 prior chemotherapy regimens or 2 prior chemotherapy regimens for recurrent/progressive disease: Imatinib gent Dose Route Days Freq Imatinib* To be determined PO Twice daily Every 28 days (continuous without B Imatinib 300 mg PO Twice daily Every 28 days (continous without C Imatinib Call Random Center for assigned dose level PO Divided and administered twice daily per Cohort Dose Level Every 28 days (continuous without D Imatinib To be determined P.O. Twice daily Every 28 days (continuous without E Imatinib Imatinib 300 mg P.O. Twice daily Every 28 days (continuous without * Study 2: will not open until a dose level has been established in Study 1 ( C) Study Design: This study consists of three clinical trials in patients with oligodendroglioma or mixed oligoastrocytoma. Study 1 is a phase I trial designed to establish the maximum tolerated dose (MTD) of imatinib when given to patients who are receiving enzyme-inducing anticonvulsants (EICs). Study 2 is a single-stage phase II trial designed to assess (a) the ability of imatinib to extend progression-free survival in oligodendroglioma and mixed oligoastrocytoma, as measured by 6-month progression-free survival from study registration, (b) the toxicities associated with this agent, and (c) associations between clinical variables, 1p/19q alterations, and various parameters related to alpha-pdfgr gene amplification. Study 2 has one planned interim analysis after the 23rd eligible patient has been followed for 6 months. Study 3 is a pilot study designed to obtain data with respect to survival, progression-free survival, response rate, and toxicity associated with Imatinib in patients with >2 prior chemotherapy regimens (any combination adjuvant + recurrence) or 2 regimens given for recurrent/progressive disease. Studies 2 and 3 will initially open to patients not on EICS and will open to patients on EICs after the conclusion of Study 1. N Page 2 of 8

3 ccrual: The study opened to NCCTG on June 20th, s of March 23, 2010, 33 patients have been enrolled to Study 2 ( B) (with one major treatment violation), Study 1 ( C) has enrolled 11 patients, and Study 3 ( E) has enrolled 11 patients. ccrual by membership is summarized in the ccrual Table below. Patient Characteristics: vailable baseline information is summarized in the Baseline Characteristics Table below. The 33 patients on study 2 are 19 males and 14 females (42%) ranging in age from 22 to 83 years old (median age=46). The 11 patients on study 1 are 10 males and 1 female (9%), ranging in age from 34 to 65 years old (median age=45). The 11 patients on study 3 are 7 males and 4 females (36%), ranging in age from 22 to 59 years old (median age=46). vailable Information: s of 3/23/2010, in study 2, 32 patients are evaluable and 23 patients have died. In study 1, 11 patients are evaluable and 8 patients have died. nd in study 3, 11 patients are evaluable and 7 patients have died. dverse Events: With dverse Event information available for 32 patients in study 2, 11 patients in study 1, and 11 patients in study 3 (see dverse Event Table below), two grade-5 events have been reported; one of which was considered possibly related to treatment (thrombosis). Twenty two grade-4 adverse events have been seen in 11 patients, all in study 2. One patient had hemorrhage and seizure; another had thrombosis, seizure, and vomiting; a third patient had seizure, hyponatremia, neuro-motor, and hemorrhage; personality change was observed in a fourth patient; a fifth patient experienced fatigue; a sixth patient had dyspnea, hyperuricemia, thrombocytopenia and speech impairment; a seventh patient experienced depression; an eighth patient experienced neuro-motor; a ninth patient experienced leukopenia, neutropenia, and fatigue; the tenth patient experienced neutropenia; the last patient experienced hyperglycemia. In study 1 there were 2 clinically relevant dose limiting toxicities in the first 6 patients ( one in each cohort of 3 patients). One patient had a grade 3 hemorrhage and the other had a grade 3 low consciousness. n addendum was approved to accrue up to an additional 6 patients in cohorts of 3. The three additional patients accrued to cohort 3 did not experience any grade 3 or higher adverse events. Study Status: Study 2 ( B) and Study 3 ( E) are currently open to patients not taking enzyme inducing anti-convulsants (EICs). Study 1 ( C) is open to patients receiving EICs. In study 2 ( B) there was sufficient evidence to continue accrual past the interim analysis. N Page 3 of 8

4 dditional Information: Jaeckle K, nderson K, Wu W, Egorin M, Galanis E, Brown PD, Sarkaria J, Colesas D, Buckner J. Pharmacokinetic nalysis of Imatinib in Patients with Recurrent naplastic Oligodendroglioma: North Central Cancer Treatment Group (NCCTG) N0272. (Society for Neuro-oncology, 2007) ccrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months Bismarck Carle Des Moines Florida Geisinger Lehigh Mayo Metro MN Mo Valley Montana Sioux Falls Toledo Wichita Total Membership ccrual Baseline Characteristics Table: Characteristics B C D ge Group < > Corticosteroid Therapy Missing Yes No Extent Recurrence Resection None Biopsy Subtotal Resection Gross Total Resection Extent Resection None Biopsy E N Page 4 of 8

5 Characteristics B C D E Subtotal Resection Gender f m Histologic Grade History Brain Missing Yes No Primary Histology Type Oligo O Prior Nitrosoureas Missing Yes No Recurrent Histology Type Oligo O Missing Recurrent Tumor Grade Missing Grade 4/5 and Most Frequent dverse Event Table: B Evaluable Patients: 32 C Evaluable Patients: 11 E Evaluable Patients: 11 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology NEUTROPENI B C N Page 5 of 8

6 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % E LEUKOPENI B C E NEMI B THROMBOCYTOPENI B E Cardiovascular THROMBOSIS B EDEM B C Constitutional Symptoms FTIGUE B C E CONSTITUTIONL SYMPT B Dermatology/Skin RSH B Gastrointestinal NOREXI B NUSE B C E STOMTITIS B DYSPEPSI B VOMITING B C N Page 6 of 8

7 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % E DIRRHE-NO COLOSTOM B E Hemorrhage HEMORRHGE B C Hepatic SGOT (ST) B C LK PHOS B Metabolic/Laboratory HYPOCLCEMI B E HYPONTREMI B HYPERURICEMI B HYPOPHOSPHTEMI B C E HYPERGLYCEMI B C E Neurology INSOMNI B SEIZURE B E SPEECH B LOW CONSCIOUSNESS B C N Page 7 of 8

8 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % DEPRESSION B E PERSONLITY CHNGE B NEURO-MOTOR B E Pulmonary DYSPNE B Renal /Genitourinary CRETININE B Maximum Grade dverse Event B C E N Page 8 of 8