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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. CLASSIC 1 Study Design. Clofarabine 40 mg/m 2 IV

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

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  1. 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.

  2. CLASSIC 1 Study Design Clofarabine 40 mg/m2 IV daily x 5 plus Ara-C 1 g/m2 IV daily x 5 n = 162 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.

  3. Overall Response Rate* 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CRi Overall Population REF REL CR ORR: p < 0.0001CR: p = 0.0005 ORR: p = 0.0022CR: p = 0.0353 ORR: p = 0.0019CR: p = 0.0096 47% 49% 46% 11% 12% 13% 23% 23% 23% 5% 5% 5% 38% 33% 35% 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.

  4. Event-Free Survival Faderl S et al. Proc ASCO 2011;Abstract 6503.

  5. Overall Survival NR, not reported Faderl S et al. Proc ASCO 2011;Abstract 6503.

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

  7. Safety (continued) Faderl S et al. Proc ASCO 2011;Abstract 6503.

  8. 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.

  9. 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

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