Gruppo Italiano Terapie Innovative nei Linfomi (G.I.T.I.L.) Dr. Andrea Gallamini S.C. Ematologia Az. Ospedaliera S. Croce e Carle, Cuneo

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1 Sponsor Principal Investigator Protocol Coordinators Coordinating Centre Writing committee CRO Gruppo Italiano Terapie Innovative nei Linfomi (G.I.T.I.L.) Dr. Andrea Gallamini S.C. Ematologia Az. Ospedaliera S. Croce e Carle, Cuneo Dr. Alessandro Rambaldi Dr. Andrea Gallamini S.C. Ematologia Azienda Ospedaliera S. Croce e Carle Via M. Coppino, Cuneo AIL Phone FAX gallamini.a@ospedale.cuneo.it Andrea Gallamini, Alessandro Rambaldi, Corrado Tarella Massimo Gianni, Alberto Biggi, Stephan Chuvie, Anna Di Russo, Roberto Marchioli Operations Office: Laboratory of Clinical Epidemiology of NEGRISUD Institute Multicentre clinical study with early treatment intensification in patients with high risk Hodgkin lymphoma, identified as FDG-PET positive after two conventional ABVD courses (HD 0607 study) Menton, April 9, 2010 NIH registration code: NCT

2 Interim PET in ABVD-treated HL patients Gallamini, A. et al. J Clin Oncol; 25:

3 2-y PFS according to PET results (164 pts)

4 PET response-adapted clinical trials in advanced-stage HL 1. Positron Emission Tomography (PET)-Adapted Chemotherapy In Advanced Hodgkin Lymphoma (GITIL HD 0607) Fludeoxyglucose F 18-PET/CT Imaging in Assessing Response to Chemotherapy in Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Hodgkin Lymphoma (RATHL) 3. High-Dose Chemotherapy and Stem Cell Transplantation, in Patients PET-2 Positive, After 2 Courses of ABVD (IIL HD 0802) and Comparison of RT Versus no RT in PET-2 Negative Patients (IIL HD 0801) HD18 for Advanced Stages in Hodgkins LymphomaHD18 for Advanced Stages in Hodgkins Lymphoma. (GHSG HD 18) 5. Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma.(SWOG/CALGB USA Intergroup Trial)

5 PET response-adapted clinical trials in advanced-stage HL 1. Positron Emission Tomography (PET)-Adapted Chemotherapy In Advanced Hodgkin Lymphoma (GITIL HD 0607) Fludeoxyglucose F 18-PET/CT Imaging in Assessing Response to Chemotherapy in Patients With Newly Diagnosed Stage II, Stage III, or Stage IV 1. Hodgkin Positron Lymphoma Emission (RATHL) Tomography (PET)-Adapted 3. High-Dose Chemotherapy and Stem Cell Transplantation, in Patients PET-2 Positive, (GITIL After HD 2 Courses 0607). of ABVD (IIL HD 0802) and Comparison of RT Versus no RT PET-2 Negative Patients (IIL HD 0801) HD18 for Advanced Stages in Hodgkins LymphomaHD18 for Advanced Stages in Hodgkins Lymphoma. (GHSG HD 18) 5. Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma.(SWOG/CALGB USA Intergroup Trial) Chemotherapy In Advanced Hodgkin Lymphoma (HL)

6 Endpoints Primary endpoint Secondary endpoints 3-year progression free survival (PFS) of the entire cohort of patients. - 3-year event free survival (EFS) of all the registered patients, whatever the treatment assigned. Events are deaths from any cause, disease progression, secondary cancer, late serious treatment-related events. - Feasibility of the program for the entire population of advanced-stage HL patients admitted to GITIL institutions

7 Inclusion criteria Inclusion criteria Exclusion criteria Patients with advanced classical Hodgkin Lymphoma according to the WHO classification Aged Not previously treated Stages IIB to IV B All IPS prognostic groups Patients who have signed an informed consent form Patients aged more than 60. Concomitant or previously treated neoplastic disorder less than 5 year before the diagnosis of Hodgkin s lymphoma. Psychiatric disorders Uncontrolled infectious disease Impaired cardiac (EF < 50%), renal (creatinine clearance < 60 ml/m)hiv, HBV DNA, HCV RNA positive markers Pregnancy and lactation Patients with uncompensated diabetes mellitus and fasting glucose levels over 200 mg/dl

8 Geographic distribution of participating Centers NIH registration code: NCT CMNS centers active centers 3 center waiting for for approval by by CE CE

9 HD IIB-IV B stage R ABVD x 2 CT-PET + - GITIL GITIL HD0607 HD0607 Protocol Protocol ABVD x 4 BEACOPP-esc. x 4 BEACOPP-bas. x 4 R-BEACOPP-esc. x 4 CT-PET R-BEACOPP-bas. x 4 Allo-SC available (n/y) (Biopsy +) IGEV x 4 + ASCT CT-PET + - R No Consolidation Rx therapy Consolidation Rx therapy Double ASCT ASCT + Allo-RIC CT-PET Assess response on completion of treatment CT-PET Follow up until death

10 Central panel for PET reviewing PET-centre of the GITIL Institution (X) PET-2 (positive or minimally positive) & PET-0 Reviewer 1 Reviewer 2 Reviewer 3 Reviewer 4 Reviewer 5 Reviewer 6 Reviewer 7 Within three days Pos./ neg. Pos./ neg. Pos./ neg. Pos./ neg. Pos./ neg. Pos./ neg. Pos./ neg. First three incoming replies: PET-2 positive or negative INFN Website Clinical Centre GITIL (X) CRO

11 PET center uploads PET- 0 & PET-2 (positive or minimally positive) on the dedicated WEBsite of INFN of Turin & SMS every 6h PET review panel 72h First 3 replies CMNS Center Center of of scientific scientific and and administrative coordination Clinical Center RANDOMIZING

12 Patient enrolment ( )

13 First 100 enrolled patients ( ) (100)ENROLLED (2) MISSING (98)INITIAL THERAPY (ABVD x 2) (96)COMPLETED ABVD x 2 (1) Ongoing (1) OUT -PD (96)INTERIM STAGING CT-PET 2 (23) PET-2 Pos (73) PET-2 Neg

14 Interim-PET positive patients ( ) (23) PET-2 Pos (11) esc. BEACOPP (12) esc. R-BEACOPP (3) End of Study (2) Refusal (1) PD (11) Ongoing (9) PET 3 (after 4 esc BEACOPP) (1) PET-3 Pos (8) PET-3 Neg (1) DHAP (8) [R] BEACOPP bs (4) FINAL RESTAGING

15 Interim-PET negative patients ( ) (73) PET-2 Neg (12)MISSING (61) ABVD x 4 (14) Ongoing (45) CT-PET 3 (2) End of Study (2) Refusal (5) PET-3 Pos (40) PET-3 Neg (4) MISSING (1) HDS Therapy (11) RX NO (12) RX YES (17)Bulky No (5) MISSING (33) FINAL RESTAGING

16 Concordance rate among six reviewers (N=47: ) Mean U.F. F.F. A.B. U.G. F.C M.G U.F CONCORDANCE F.F A.B Almost perfect U.G Substantial F.C Moderate M.G k Cohen coefficient

17 2nd Investigator meeting: Capri,