A Pharmacokinetic Study of Oral and Intravenous Clofarabine in Patients With High Risk Myelodysplasia and Acute Leukemias - Determination of Oral Bioavailability and the Effect of Cimetidine on Clofarabine Clearance
Clofarabine is a second-generation adenosine nucleoside analog with activity in hematologic
malignancies. It has gained FDA-approval for use in children with relapsed-refractory ALL,
and early phase studies have shown activity in patients with AML and MDS. Clofarabine's
activity in acute leukemias and MDS has been established in multiple phase I and II studies,
both alone and in combination with cytosine arabinoside (araC), and in both
relapsed-refractory patients, and untreated older adults.
Pharmacokinetic investigations comparing I.V. and P.O. dosing within the same patient have
not been performed. Furthermore, the effect of OCT2 inhibition on clofarabine
pharmacokinetics in humans has not been investigated. The potential for enhanced drug
exposure and toxicity in the setting of OCT2 inhibition is of clinical importance as
clofarabine gains broader indications in hematologic oncology. In particular,
bioavailability and the OCT2 mechanism are important with prolonged drug exposure and oral
administration in older adults, who are likely to have impaired renal function and take
other drugs that interact with OCT2 such as metformin (a substrate) and trimethoprim (one of
several inhibitors). OCT2 is expressed on several solid tumor cell lines, and is thought to
play a role in tumor uptake of cationic cytotoxins. Whether OCT2 or other transporters are
expressed on leukemic blasts, or influence drug uptake has not been investigated. However,
variation in the expression of drug transporters could be one of several mechanistic
explanations for the fact that clofarabine-responsive patients accumulate intracellular
clofarabine triphosphate, whereas non-responders do not.
Single nucleotide polymorphisms have been identified in the gene encoding OCT2, which may
influence substrate uptake or inhibitor potency. Such polymorphisms may explain variation in
clofarabine pharmacokinetics and pharmacodynamics between individuals, but the potential for
this phenomenon has not previously been investigated.
Patients will receive clofarabine as induction therapy in five doses. Initially, and unless
dose escalation or de-escalation criteria are met, patients will be assigned to dose level 0
(IV Clofarabine 15mg/m2; Oral clofarabine 30mg/m2). The first three doses (on days 1, 3 and
5) will be administered followed by washout periods that extend until the next clofarabine
dose is administered. During the washout periods, frequent phlebotomy for PK sampling will
be performed in an outpatient setting at the UNC Clinical Translational Research Center
(CTRC). The duration of the induction period will be determined by time to recovery of
hematologic toxicity (platelets >50 x 109/liter, ANC >1.0x109/liter).
AML patients achieving CR, and MDS patients achieving CR, PR or hematologic improvement will
receive additional consolidation cycles of oral clofarabine daily on days 1 through 5 of
each subsequent cycle, with clofarabine dose according to assigned dose level (0: 30 mg/m2,
-1: 20 mg/m2, +1: 40 mg/m2). Consolidation cycles will begin no sooner than 28 days after
the first day of the previous clofarabine cycle. Patients will be evaluated for response
after each cycle, and will be continued on trial for up to 6 total cycles of therapy as long
as a response or lack of progression is maintained and no Grade 3-4 non-hematologic
toxicities have been observed in that patient.
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Define human intra-patient bioavailability of clofarabine; Compare the pharmacokinetics of intravenously-administered clofarabine when administered alone, with the pharmacokinetics of clofarabine when co-administered with cimetidine, an OCT2 inhibitor.
Regarding primary endpoints, each patient will generate pharmacokinetic data sufficient to compute area under the concentration versus time curve (AUC) and clearance (Cl) for each of the initial three clofarabine doses (IV, PO and IV administered after cimetidine) for each patient. These values will be used to compute the human oral bioavailability of clofarabine and compare AUC and Cl of clofarabine when given after cimetidine with AUC and Cl of clofarabine when administered alone
Matthew Foster, MD
University of North Carolina, Chapel Hill
United States: Food and Drug Administration
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