Avenue E. Mounier 83/11 1200 Brussels Belgium Tel: +32 2 774 1611 Email: [email protected] www.eortc.org Summary Attachment for EudraCT Name of Individual study Table Referring to Part of the Dossier (For National Authority Use Sponsor/Company: Only) EORTC Name of the Volume: finished product Name of Active Page Ingredients: Clofarabine Cytarabine Idarubicin Title of the Study Clofarabine in combination with a standard remissioninduction regimen (AraC and idarubicin) in patients 18-60 years old with previously untreated intermediate and bad risk acute myelogenous leukemia (AML) or high risk myelodysplasia (MDS) : a phase I-II study of the EORTC-LG and GIMEMA (AML-14A trial) Investigators & Study Centers Number of Country City patients Belgium 4 101.Hopital Jules Bordet (BE) Brussels 1 109.A.Z. St Jan (BE) Brugge 3 Italy 28 3931.Tor Vergata Roma (IT) Roma 12 733.La Sapienza Ematologia (IT) Roma 16 Netherlands 43 304.RU Nijmegen (NL) Nijmegen 24 310.Univ Med Ctr Leiden (NL) Leiden 13 22.J Bosch 'S Hertogenb (NL) 's-Hertogenbosch 6 Grand Total 75 ST-006-AF-01 Page 1 of 4 Template version 2 Short Study Report for Health Authorities EORTC Name of Individual study Table Referring to Part of the Dossier (For National Authority Use Sponsor/Company: Only) EORTC Name of the Volume: finished product Name of Active Page Ingredients: Clofarabine Cytarabine Idarubicin Publication Willemze R, Suciu S, Muus P, Halkes CJ, Meloni G, Meert L, Karrasch M, Rapion J, (reference) Vignetti M, Amadori S, de Witte T, Marie JP.Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial). Hematol (2014) 93: 965. doi:10.1007/s00277-014- 2056-6 Dominik Selleslag, Stefan Suciu, Giovanna Meloni, Petra Muus, Constantijn J.M. Halkes, Adriano Venditti, Safaa M. Ramadan, Hans Pruijt, Liv Meert, Marco Vignetti, Jean-Pierre Marie, Sébastian Wittnebel, Theo de Witte, Sergio Amadori, Roelof Willemze, Frédéric Baron. Low-dose clofarabine in combination with a standard remission induction in patients aged 18-60 years with previously untreated intermediate and bad-risk acute myeloid leukemia or high-risk myelodysplastic syndrome: combined phase I/II results of the EORTC/GIMEMA AML-14A trial. Haematologica February 2017 102: e47-e51; doi:10.3324/haematol.2016.153130 Objective(s) The main objective of the phase I part of the study was to determine the recommended/maximum tolerated dose of two routes of administration of clofarabine when administered in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin). The main objective of the phase II part of the trial was to explore the anti-leukemic activity of the phase I selected dosage schedules of clofarabine (10 mg/m2/day) given either as a 1-hour i.v. infusion (Arm A) or as a push injection (Arm B) over 10 minutes Methodology Open label randomized 2-arm multicenter trial with a sequential phase I-II design. Phase I was based on a 3+3 design. Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT), defined as treatment-related adverse events: • Non-hematological grade III-V toxicity (CTCAE 3.0) occurring during 8 weeks (except grade III events resolving to grade < II within 4 weeks or alopecia, nausea, vomiting rapidly controlled with appropriate measures) after the start of the remission induction. • Hematological toxicity defined as bone marrow hypoplasia leading to neutrophil or platelet recovery (neutrophils > 0.5 x 109/l and platelets >50 x 109/l) later than 8 weeks after start of last remission induction. After the maximum tolerated dose was reached in the phase I of the trial, additional patients were randomized in the phase II part of the trial using a 1-sample Fleming design Stratification factors for randomization: institution, presence of poor prognostic features (WBC at diagnosis ≥ 100x109/l and/or presence of very high risk cytogenetic/molecular features: -5/5q-, -7/7q-, presence of complex abnormalities (> 3 abnormalities), 3q, t(6;9), t(9;22) or FLT3-ITD+) ST-006-AF-01 Page 2 of 4 Template version 2 Short Study Report for Health Authorities EORTC Name of Individual study Table Referring to Part of the Dossier (For National Authority Use Sponsor/Company: Only) EORTC Name of the Volume: finished product Name of Active Page Ingredients: Clofarabine Cytarabine Idarubicin Number of patients The statistical considerations were the following: P0 was 65%; P1 was 85%; beta error Number planed was 0.05 (actual one 0.07) and alpha error was 0.15 (actual one 0.12). Thus, for each (Statistical design) of the arms A and B, the regimen was considered as active and feasible if ≥ 23/30 Number analyzed (76.7%) patients achieved a CR/CRi. A total of 30 patients were required in each arm (24 patients in addition to the 6 from the phase 1 of the trial using the same dosage of clofarabine) Diagnosis and Inclusion criteria included (1) age 18-60 years, (2) primary or secondary (including main criteria for AML occurring after MDS) intermediate or high-risk AML (AML was defined inclusion according to the WHO criteria) or MDS with 10-19% blast cells in the bone marrow (BM), (3) previously untreated disease (debulking treatment with hydroxyurea for ≤ 14 days was allowed), (4) WHO Performance Status grade 0-2, and (5) adequate renal (serum creatinine ≤ upper normal limit) and hepatic (AST/ALT/alkaline phosphatase level <2.5 x upper normal limit) functions. Main exclusion criteria included (1) good-risk AML (i.e. AML-M3 with t(15;17), or AML with t(8;21) or inv(16)) and a white blood cell count (WBC) at diagnosis of <100 x109/L), (2) blast crisis chronic myeloid leukemia or AML supervening a myeloproliferative disorder, (3) central nervous system leukemia, (4) evidence of severe concurrent cardiac, pulmonary, and neurological disorder, and (5) uncontrolled infection Treatment Clofarabine was administered at 10 mg/m2 on days 2, 4, 6, 8 and 10 either as a 1-hour Test product, dose infusion (Arm A) or as a push injection (Arm B). and mode of Ara-C was administered at 100 mg/m2/day on days 1–10 as a continuous infusion, administration while idarubicin was given at 10 mg/m2/day on days 1, 3, and 5 as a 5 minutes i.v. (batch number if injection. applicable) A second identical course of induction chemotherapy was given in case of a partial response (PR). One cycle of consolidation chemotherapy consisting of Ara-C (500 mg/m2 every 12 hours as a 2-hour i.v. infusion on days 1-6) and idarubicin (10 mg/m2/day on days 4, 5 and 6) was administered in patients in both arms who achieved a CR/incomplete CR (CRi), if they had a WHO PS 0-3 and did not have uncontrolled infections, renal and liver abnormalities (defined as bilirubin and creatinine values > 3 upper limit of normal values,) or severe heart disease. Duration of Recommended post-consolidation treatment: allogeneic hematopoietic cell treatment transplantation (HCT) for patients with a HLA-identical related donor or for patients with very high-risk cytogenetics who had an HLA-compatible related or unrelated donor, or an autologous HCT in patients who were not candidate for allogeneic HCT (according to the EORTC/GIMEMA AML-12) Reference therapy, dose and mode of administration (batch number if applicable) ST-006-AF-01 Page 3 of 4 Template version 2 Short Study Report for Health Authorities EORTC Name of Individual study Table Referring to Part of the Dossier (For National Authority Use Sponsor/Company: Only) EORTC Name of the Volume: finished product Name of Active Page Ingredients: Clofarabine Cytarabine Idarubicin Criteria for evaluation Efficacy For the combined phase I-II part of the trial, the primary endpoint was the CR/CRi rate after 1 or 2 induction cycles, where Clofarabine was administered at 10 mg/m2 (dosage considered to be safe in the phase I part, and recommended for the phase II part of this study). recommended from the phase I part). The aim was to determine whether, in each treatment group, the true CR/CRi rate was > 65% or not. Secondary endpoints included toxicity, overall survival (OS) from inclusion, OS from CR/CRi, disease-free survival (DFS) from CR/CRi, and incidences of relapse and of death in CR/CRi Safety Toxicities were graded with CTCAE version 3.0 scoring system (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf) Statistical methods The duration of OS was calculated from the date of randomization until death. DFS was calculated as the time from CR/CRi until the first relapse or death. The Kaplan- Meier method was used to estimate time-to-event outcomes. One-year OS and DFS rates and medians were presented with 95% confidence intervals (CI) based on the Brookmeyer and Crowley method. Summary of Results Efficacy Results A total of 64 patients was randomized. Among the 62 patients who met the inclusion criteria, 5 had high-risk MDS. Median age was 50 yrs (range 20-60). Among the 64 randomized patients, 62 were considered as eligible (31 in each arm). Median age was 50 yrs (range 20-60). In each arm, after induction, 26 out of 31 patients reached CR/CRi (83.9%, 95% CI: 66.3-94.6%; 75.2% CI: 73.2-91.4%). For both treatment groups, and for both estimated CIs (classical 95% CI, and the 75.2% corresponding to the 1-sided alpha=12.4%) these contain the targeted P1=85% CR/CRi rate, and the lower CI boundary was higher than the inacceptable CR/CRi of P0=65%.