STUDY PROTOCOL. Fabio Ciceri M.D. Istituto Scientifico H. San Raffaele Dept. of of Oncology, Haematology/Transplant Unit I Milan

Transcription

1 STUDY PROTOCOL Clinical phase II trial to evaluate the safety and efficacy of treosulfan combined with cytarabine and fludarabine prior to autologous haematopoietic stem cell transplantation in elderly patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome Principal investigators Massimo Bernardi M.D. Dept. of Oncology, Haematology/Transplant Unit Fabio Ciceri M.D. Co-investigators Michela Tassara M.D. Alessandro Crotta M.D. Jacopo Peccatori M.D. Project-No.: FLAT-Auto Ethics Approval: Date of the Protocol: Version 01: June, 2007 Study title:

2 Clinical phase II trial to evaluate the safety and efficacy of treosulfan combined with cytarabine and fludarabine prior to autologous haematopoietic stem cell transplantation in elderly patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome Valutazione della tossicità e dell efficacia del treosulfano in combinazione con citarabina e fludarabina come condizionamento pre-autotrapianto di cellule staminali ematopoietiche, nei pazienti anziani affetti da Leucemia Mieloide Acuta o Sindrome Mielodisplastica. Protocollo clinico di fase II. Version: 01-07, October 2007 Clinical Investigators: Herewith I confirm that I read the study protocol carefully and declare my consent with it. I will treat and examine the patients in accordance with the study protocol, the national applicable laws, the international guidelines on good clinical practice (ICH-GCP) and the Declaration of Helsinki.

3 STUDY TITLE Short Title CO-ORDINATING INVESTIGATORS Clinical phase II trial to evaluate the safety and efficacy of treosulfan combined with cytarabine and fludarabine prior to autologous haematopoietic stem cell transplantation in elderly patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome. Treosulfan-cytarabine-fludarabine combination before autologous transplantation Massimo Bernardi M.D. Michela Tassara M.D. Alessandro Crotta M.D. Jacopo Peccatori M.D. Fabio Ciceri M.D. STATISTICAL ANALYSIS Roberto Crocchiolo M.D. STUDY OBJECTIVES Primary objective: -Evaluation of disease free survival Secondary objectives: -Evaluation of engraftment of autotransplant -Evaluation of incidence of CTC grade 3 and 4 adverse events within day +90 -Evaluation of non-relapse mortality within day +90 -Evaluation of non-relapse mortality at +1 year and + 2 years -Evaluation of overall survival -Evaluation of relapse incidence End of total follow up for OS, DFS, RI, NRM = 2 years after transplantation of the last patient included.

4 INCLUSION CRITERIA 1. Patients with de novo or secondary acute myeloid leukemia or with Int 2 or High risk myelodysplastic syndrome, according to IPSS. 2. Patients unable or unfit to receive an hematopoietic stem cell transplantation from an HLA-identical related or unrelated, or HLA-haploidentical related donor. 3. Hematologic complete remission after 1 or 2 cycles of induction standard chemotherapy. 4. Successful collection of autologous peripheral blood hematopoietic stem cells: 5.0x10e6 /kg patient BW. 5. Age 65 years. 6. Performance Status 0-2 ECOG, % Karnofsky. 7. Written informed consent. EXCLUSION CRITERIA 1. Diagnosis of AML M3. 2. Second concomitant malignancies 3. Severe concomitant illnesses/medical conditions (e.g. impaired respiratory and/or cardiac function) 4. Known and manifested malignant involvement of the CNS 5. Active infectious disease 6. HIV- positivity or active hepatitis infection 7. Impaired liver function (bilirubin > 1.5 x upper normal limit; transaminases > 3.0 x upper normal limit) 8. Impaired renal function (creatinine-clearance < 60 ml/min; serum creatinine > 1.5 x upper normal limit). 9. Pleural effusion or ascites > 1.0 L 10. Known hypersensitivity to treosulfan and/or cytarabine and/or fludarabine 11. Participation in another experimental drug trial within 4 weeks before day Non-cooperative behaviour or non-compliance 13. Psychiatric diseases or conditions that might impair the ability to give informed consent STUDY MEDICATION FLAT: Fludarabine i.v. 30 mg/m²/d day -6 to -2 Cytarabine i.v. 2 g/m²/d day -6 to -2 Treosulfan i.v. 10 g/m²/d day -6 to -4 Autologous stem-cell transplantation i.v.: day 0 (source: peripheral blood) PEG Filgrastim s.c. 6 mg day +3

5 STUDY SCHEDULE Pre-Study phase I -Assessment at diagnosis before start of induction chemotherapy. -Administration of induction chemotherapy (1 to 2 cycles). -Evaluation of response to induction chemotherapy: Patients in partial remission (PR) after cycle 1 receive a second cycle -Patients in CR after 1 or 2 cycles proceed to Pre-Study phase II Pre-Study phase II -Administration of consolidation chemotherapy (1 cycle). -Leukapheresis of PBSC at recovery after consolidation chemotherapy. -Patients in CR and with successful PBSC collection proceed to Study period I. Study Period I -Initial assessment (within 2 weeks before start of conditioning). -From day -6 to N > 1000: daily blood and neutrophil count. -From day -6 to +28: daily evaluation of adverse events. -From day +29 to +90: weekly assessment for OS, DFS, RI, NRM and adverse events Study period II (Follow-up for OS, DFS, RI, NRM) -Monthly assessment starting at month 3 until + 1 year after transplantation. -Quarterly assessment starting at + 1 year after transplantation until end of follow-up. -End of follow up: 2 years after transplantation of the last patient included Analysis study period I Primary and secondary study endpoints will be analysed 28 and 90 days after transplantation of the last patient included. Analysis study period II Time-dependent variables (OS, DFS, RI, NRM) will be finally analysed 2 years after transplantation of the last patient included. STATISTICS / DESIGN Design: Monocentre, non-randomised, non-controlled, open-label clinical phase II protocol Number of patients: 15 Timelines: Anticipated start: January 2008 Recruitment period: 2 years Total duration: 4 years

6