Background: Pgp expression in AML increases with age and correlates with inferior therapeutic response and survival. Zosuquidar is a potent and highly specific Pgp inhibitor with minimal pharmacokinetic (PK) interaction with conventional xenobiotic antineoplastics. Prolonged Pgp blockade is believed necessary to optimize antineoplastic sensitization in resistant cells in vitro. We previously reported that 72-hour CIV Zosuquidar at 700 mg/d resulted in rapid and sustained Pgp inhibition during the entire period of anthracycline administration in Pgp+ AML (Lancet, et al. ASH 2006).

Methods: We report interim results from a Phase I/II trial of 72-hr CIV zosuquidar in older adults with newly diagnosed Pgp+ AML. Primary objective: to determine the response (CR + CRp) rate in Pgp+ patients. Eligibility included ages 55–75, ECOG PS 0-2, adequate end-organ function, and Pgp+ by functional assay. Zosuquidar was initiated 4 hrs prior to the first doses of DNR (45 mg/m2/d x 3d) and ARA-C (100 mg/m2/d CIV x 7d) and continued for 72 hrs. Reinduction with the same dosing schedule was permitted in patients with significant cytoreduction without aplasia. Patients who achieved a CR/CRp received up to 2 cycles of consolidation with the same agents using an abbreviated schedule.

Results: 67 patients with Pgp+ AML were enrolled on the study; 80 patients were included in the safety analysis. Sixty-two of the 67 Pgp+ patients received Zosuquidar at 700 mg/day, while 5 received 800 mg/day (during phase I). Median age was 66; M/F was 46/21; cytogenetics: adverse (19), intermediate (29), and unknown/not done (19); de novo/secondary AML: 36/31. Mean percentage of planned Zosuquidar actually administered was 94%. CR/CRp was achieved in 32 of 66 (48%) evaluable Pgp+ patients (CR=25, CRp=7). Fifteen of 31 (48%) patients with secondary AML, and 6 of 19 (32%) with adverse-risk cytogenetics achieved CR/CRp. Eight of 14 (57%) patients age ≥ 70 responded. Induction-related death (< 30 days) occurred in 10% of patients. Other common toxicities included infection/febrile neutropenia (89%), tremor (42%), hallucinations (11%), nausea (52%), and diarrhea (51%). Median times to neutrophil (≥ 1000/μL) and platelet (≥ 100,000/μL) recovery were 34 and 33 days, respectively. With a median followup of 7.5 months, the median overall survival was 8.9 months and the median relapse-free survival was 9.3 months.

Conclusions: CIV Zosuquidar 700 mg/d with DNR and ARA-C is well tolerated, with signs of clinical benefit in poor-risk older patients with Pgp+ AML, warranting continued study of this combination. Accrual to the current trial is ongoing.

Topics:
cytarabine, daunorubicin, intravenous infusion, continuous, leukemia, myelocytic, acute, older adult, p-glycoprotein, c-reactive protein, cyclic amp receptor protein, epley maneuver, leukemia, secondary acute

Disclosure:Employment: PSM is employed by Kanisa Pharm. Ownership Interests: PSM, AFL, and BIS own stock options in Kanisa Pharm, a start-up company, the stock of which is not publicly traded. Research Funding: JEL, JG, SL, LDC, MST, IG, DM, and MRB receive research funding in support of the clinical trial. Membership Information: AFL and BIS are members of the advisory board for Kanisa Pharm.

2007, The American Society of Hematology
2007
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