Phase IIb Randomized Study of CPX-351 Vs. Conventional Cytarabine + Daunorubicin in Newly Diagnosed AML Patients Aged 60-75: Safety Report.

Abstract 1033 Poster Board I-55 CPX-351 is a liposomal formulation that encapsulates cytarabine and daunorubicin at a 5:1 molar ratio that is consistently synergistic and avoids antagonism across multiple leukemic and solid tumor cell lines, in vitro. In preclinical observations CPX-351 has been shown to accumulate in bone marrow where it is preferentially taken up by leukemia cells. A recently completed Phase 1 study recommended that 90-minute infusions of 101 u/m2 be given on Days 1, 3, and 5 (1 u = 1 mg cytarabine + 0.44 mg daunorubicin). The results suggested that liposomal encapsulation of this chemotherapy doublet might change the safety profile by reducing non-hematologic toxicities including alopecia, gastrointestinal toxicities (such as mucositis), and hepatic toxicity, while retaining hematopoietic cytotoxicity as evidenced by a high proportion of aplasia achieved and a significant number of complete remissions. A Phase 2 randomized study was initiated comparing CPX-351 with conventional cytarabine + daunorubicin (“7 + 3” regimen) in AML patients aged 60-75. This report summarizes safety data for the first 45 patients. Materials and Methods: Patients with de novo or therapy-related AML or AML evolved from an antecedent hematologic disorder, ECOG PS of 0-2, SCr 50% by echo or MUGA were eligible. Patients are randomized 2:1 to receive CPX-351 (100u/m2 Day 1, 3, and 5 by 90 minute infusion) or to “7 + 3” (cytarabine 100mg/m2/d for 7 days by continuous IV infusion and daunorubicin 45-60mg/m2 Day 1, 2 and 3 by IV push). Results: As of Aug. 1, 2009, 45 of the 80 patients enrolled to date have been randomized (31 to CPX-351 and 14 to “7 + 3” Control), treated and completed follow-up sufficient to capture safety data for at least the first induction course. Among this group of 45 patients one or more SAE events, as defined in the protocol, were reported in 15/31 (42%) CPX-351 patients and 5/14 (29%) Control patients. Deaths during induction were infrequently reported in both arms of the study [1 (3%) vs. 1 (7%)]. One patient in each arm of the study died of sepsis related events on Days 20 and 19, respectively. One post-induction death occurred in a patient in the CPX-351 arm who died on Day 83 of an intracranial bleed, 24 days after start of consolidation therapy. Cytopenia-related events associated with treatment of leukemia accounted for the majority of the SAEs in both arms of the study, including 11 of the 15 (73%) SAEs in the CPX-351 arm and 3 of 5 (60%) SAEs in the control arm. These SAEs consisted of fever and febrile neutropenia (13% vs.14%), sepsis (3% vs. 7%), pneumonia (3% vs. 0), major bleeding episodes (3% vs. 0) and a number of minor infections and anemia. Data for all adverse events are available for 41 patients and events occurring in 10 or more patients are presented in the table below. Skin rash was more common with CPX-351 and rigors/chills were more common with “7 + 3”. The majority of other adverse events were similar (±15%) in the two groups. | Adverse Event (all grades) | CPX-351 | 7+3 | |:--------------------------:| ------- | --- | - | | n=29 | n=12 | | Fever/Feb. Neutropenia | 23 | 79% | 9 | 75% | | Rash | 22 | 76% | 6 | 50% | | Diarrhea | 17 | 59% | 6 | 50% | | Nausea | 13 | 45% | 4 | 33% | | Stomatitis | 12 | 41% | 5 | 42% | | Fatigue | 11 | 38% | 4 | 33% | | Constipation | 10 | 34% | 4 | 33% | | Anorexia | 9 | 31% | 4 | 33% | | Rigors/Chills | 7 | 24% | 5 | 42% | | Epistaxis | 8 | 28% | 2 | 17% | Title: Most Frequent Adverse Events by Patient Discussion/Conclusion: In this study, induction mortality to date with CPX-351 is low (3%). The overall toxicity of CPX-351 appears comparable to that due to 7 + 3. As observed in the Phase 1 study of CPX-351, grade 3/4 GI adverse events were distinctly uncommon. No adverse events unique to CPX-351 were observed. CPX-351 exhibits an acceptable safety profile for use in older, newly diagnosed AML patients. Disclosures: Chiarella: Celator Pharmaceuticals: Employment. Louie: Celator Pharmaceuticals: Employment.