Faderl S et al. Proc ASCO 2011;Abstract 6503.

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Faderl S et al. Proc ASCO 2011;Abstract 6503. Clofarabine plus Cytarabine Compared to Cytarabine Alone in Older Patients with Relapsed or Refractory (R/R) Acute Myelogenous Leukemia (AML): Results from the Phase III CLASSIC 1 Trial Faderl S et al. Proc ASCO 2011;Abstract 6503.

R CLASSIC 1 Study Design Eligibility (N = 320) Age ≥ 55 years R/R AML At least 1 but no more than 2 prior treatments ECOG PS 0-2 n = 162 Clofarabine 40 mg/m2 IV daily x 5 plus Ara-C 1 g/m2 IV daily x 5 R Placebo IV daily x 5 plus Ara-C 1 g/m2 IV daily x 5 n = 158 Stratification: Refractory (REF): No response or first complete remission (CR1) < 6 months Relapsed (REL): CR1 ≥ 6 months Primary objective: Overall survival Secondary objectives: CR rate, overall response rate (ORR), event-free survival (EFS), disease-free survival (DFS), duration of remission (DOR), safety Faderl S et al. Proc ASCO 2011;Abstract 6503.

Overall Response Rate* 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CRi Overall Population REF REL CR ORR: p < 0.0001 CR: p = 0.0005 ORR: p = 0.0022 CR: p = 0.0353 ORR: p = 0.0019 CR: p = 0.0096 47% 49% 46% 11% 12% 13% 23% 23% 23% 5% 5% 38% 5% 35% 33% 18% 18% 18% Clo+Ara-C (n = 162) Ara-C (n = 157) Clo+Ara-C (n = 88) Ara-C (n = 83) Clo+Ara-C (n = 74) Ara-C (n = 74) * By independent response review panel Faderl S et al. Proc ASCO 2011;Abstract 6503.

Hazard ratio (Clofarabine + Ara-C vs Ara-C alone) Event-Free Survival Hazard ratio (Clofarabine + Ara-C vs Ara-C alone) p-value Overall population 0.63 0.0001 Relapsed patients 0.57 0.0022 Refractory patients 0.67 0.0131 Faderl S et al. Proc ASCO 2011;Abstract 6503.

Overall Survival Clofarabine + Ara-C (n = 162) Ara-C (n = 158) Hazard ratio p-value Median OS 6.6 months 6.4 months 1.00 0.9951 Relapsed patients NR 0.85 0.3963 Refractory patients 1.13 0.4674 NR, not reported Faderl S et al. Proc ASCO 2011;Abstract 6503.

Safety Any Grade ≥3 adverse event (AE) 98% 86% Clofarabine + Ara-C (n = 161) Ara-C (n = 155) Any Grade ≥3 adverse event (AE) 98% 86% Discontinuation of drug due to AE 11% 3% Serious AE 60% 49% Death due to AE 14% 5% Death due to treatment-related AE 6% 2% 30-day mortality 16% 60-day mortality 24% 17% Faderl S et al. Proc ASCO 2011;Abstract 6503.

Safety (continued) Clofarabine + Ara-C Ara-C Serious AEs (≥5% in either arm) Infection 38% 22% Pneumonia 8% Sepsis 5% 2% Febrile neutropenia 16% 12% Pyrexia 4% 6% ≥Grade 3 AE (noninfectious; ≥10% in either arm) 47% 34% Hypokalemia 18% 10% Thrombocytopenia 17% Anemia 13% Neutropenia 11% 9% Increased ALT/AST 21% Faderl S et al. Proc ASCO 2011;Abstract 6503.

Author Conclusions Overall survival did not differ between treatment arms. Statistically significant improvement in secondary endpoints was reported. Overall response rates and complete response rates doubled Significantly prolonged event-free survival Higher early mortality rate was reported in the clofarabine and cytarabine arm. Long-term study follow-up continues. Clofarabine in the treatment of adult patients with AML continues to be investigated in randomized cooperative group studies. Faderl S et al. Proc ASCO 2011;Abstract 6503.

Investigator Commentary: The CLASSIC 1 Study of Cytarabine with or without Clofarabine for Older Patients with Relapsed/Refractory AML This study evaluated clofarabine at 40 mg/m2 daily times 5 and high-dose cytarabine versus high-dose cytarabine alone in older patients with relapsed/refractory AML. The authors reported the CR rate to be almost doubled with clofarabine and Ara-C. The event-free survival was also much improved, but the overall survival was no different. The primary reason for that was that the induction mortality was higher. This is a theme also reported in other trials evaluating Ara-C in combination with a second agent. One point is that the clofarabine dose was probably too high. It would be interesting to have data evaluating clofarabine at a lower dose, particularly in an older patient population. It’s also not clear to me why they chose to focus on older patients, because you could make the argument that if this trial hadn’t been so restricted maybe the early mortality rate wouldn’t have been significantly increased. I believe a 67-year-old’s ability to tolerate high-dose Ara-C, even high-dose Ara-C alone, is not the same as that of a 40-year-old. I’m sure there was a rationale for the older patient population here. But in terms of the randomized trial design, the high dose of clofarabine and restricting the trial to older patients probably “put them behind the eight ball”. Susan M O’Brien, MD