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- W2271812310 abstract "7005 Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Clinical activity is observed in ovarian cancer and AML. Voreloxin combined with cytarabine (Ara-C) show supra-additive activity preclinically. Interim results from a phase Ib/II study in relapsed or refractory AML are reported. Methods: Dose-escalation in relapsed/refractory AML patients (pts) with ≤ 3 prior induction regimens; phase II expansion in first-relapse pts (CR1 ≥ 3 months) at MTD. Voreloxin given d1 and d4, combined with: A) continuous infusion 400 mg/m 2 /d x 5d Ara-C (CIV), or B) bolus 1 g/m 2 /d IV x 5d Ara-C. Voreloxin starting dose: A) 10 mg/m 2 /dose; B) 70 mg/m 2 /dose. Treatment: induction, reinduction if needed, and up to 2 courses for consolidation. DLT, PK, and PD were assessed in cycle 1. Pts’ PBMC were evaluated for induction of DNA damage response markers. Ex vivo sensitivity of pt BMA to voreloxin and Ara-C were evaluated by CellTiter-Glo proliferation assay. Results: 52 pts treated to date (A: 41 pts, dose-escalation; 5 pts Phase 2; B: 6 pts dose-escalation). A) MTD is 80 mg/m 2 /dose voreloxin. Infections are the most common G3 or higher toxicity. Voreloxin PK were dose proportional to 50 mg/m 2 , then plateaued. Evaluation of PBMC pre- and posttreatment suggests modulation of pDNA-PKcs and pChk2 may reflect response. Ex vivo BMA assay results suggest that voreloxin is the primary contributor to the majority of CRs observed. Phase Ib: 9 CRs + CRp were observed in multiply relapsed or 1° refractory pts. B) 70 mg/m 2 /dose voreloxin, no DLT; too early to evaluate activity. Conclusions: Voreloxin in combination with CIV Ara-C is generally well-tolerated, with CR in relapsed/refractory pts. Enrollment continues: A) phase II; B) phase Ib. Ex vivo activity assay results suggest that voreloxin is the primary contributor to the majority of CR. Induction of pDNA-PKcs and pChk2 in PBMCs from treated pts may reflect response. [Table: see text]" @default.
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- W2271812310 date "2009-05-20" @default.
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- W2271812310 title "Phase Ib/II pharmacokinetic/pharmacodynamic (PK/PD) study of combination voreloxin and cytarabine in relapsed or refractory AML patients" @default.
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