Schedule- and dose-dependency of CPX-351, a synergistic fixed ratio cytarabine:daunorubicin formulation, in consolidation treatment against human leukemia xenografts.
CPX-351, a liposomal formulation co-encapsulating cytarabine (Cyt) and daunorubicin (Daun), has been developed, which delivers synergistic Cyt:Daun molar ratios to bone marrow. CPX-351 has demonstrated markedly superior anti-leukemic activity over free Cyt:Daun drug cocktails in preclinical models. Given the prolonged plasma lifetime of CPX-351, we examined the relationship between therapeutic efficacy and the frequency of treatment in the consolidation setting using a bone marrow-engrafting human leukemia xenograft model. Adding a day 1,3,5 consolidation treatment course for CPX-351 therapy improved the increase in lifespan (ILS) from 116% and no cures for a single induction course, to 268% plus a 33% cure rate for an induction plus consolidation course. In contrast, free Cyt:Daun cocktail treatment provided much lower ILS values with no cures. Administering CPX-351 as consolidation therapy starting on day 42 using a day 1,3, day 1,5, or day 1,7 schedule yielded ILS values of 154%, 185%, and 108%, respectively. The increased efficacy observed for the day 1,3 and day 1,5 consolidation schedules was associated with elevated bone marrow drug accumulation for the second doses. The enhanced efficacy obtained for intermediate dosing frequency in the consolidation setting suggests that the anti-leukemic activity of synergistic drug ratios is dependent on both duration of exposure and maintenance above a therapeutic threshold.
Celator Pharmaceuticals Corporation, Vancouver, BC, Canada.
Wah-Seng
WS
Lim
Paul G
PG
Tardi
Xiaowei
X
Xie
Mannie
M
Fan
Ruby
R
Huang
Travis
T
Ciofani
Troy O
TO
Harasym
Lawrence D
LD
Mayer
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003561:Cytarabine / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000502:physiology; D003630:Daunorubicin / Q000008:administration & dosage; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes; D020714:Maximum Tolerated Dose; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D015996:Survival Rate; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004268:DNA-Binding Proteins; D004304:Dosage Forms; D008081:Liposomes; C499308:Rag2 protein, mouse; D003561:Cytarabine; D003630:Daunorubicin