PK Study of Oral and IV Clofarabine in High Risk Myelodysplasia+Acute Leukemias
This is a non-blinded, non-randomized pharmacokinetic study to determine the oral bioavailability of clofarabine, and the effect of cimetidine on clofarabine pharmacokinetics in patients with poor-risk acute leukemias and myelodysplastic syndrome (MDS).
Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Chronic Myelomonocytic Leukemia
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||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|
- 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. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
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
- Examine safety of orally-administered clofarabine; Examine the safety of a combined intravenous and oral clofarabine regimen [ Time Frame: 5 Years ] [ Designated as safety issue: Yes ]
Regarding secondary objectives, safety will be evaluated by grading and reporting all adverse experiences during protocol therapy.
The DLT rate of ≤ 20% is considered to be acceptable.
- Examine efficacy of orally-administered clofarabine [ Time Frame: 5 years ] [ Designated as safety issue: No ]Response to therapy will be determined at the time of hematologic reconstitution (platelets >50 x 109/liter, ANC >1.0x109/liter for MDS patients or platelets >100 x 109/liter, ANC >1.0x109/liter for leukemia patients) or day 28, whichever is sooner by complete blood count with differential and bone marrow aspirate, biopsy and cytogenetics.
- Explore the influence of OCT2-encoding single nucleotide polymorphisms on clofarabine pharmacokinetics and pharmacodynamics [ Time Frame: 5 years ] [ Designated as safety issue: No ]The effect of previously-described OCT2 polymorphisms on clofarabine pharmacokinetics will be investigated in an exploratory study. If specific OCT2-encoding single nucleotide polymorphisms are detected in study subjects, the geometric mean AUC and Cl of clofarabine in such patients will be compared with the geometric mean AUC and Cl in patients with wild-type OCT2.
|Study Start Date:||September 2010|
|Estimated Study Completion Date:||July 2015|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
- Clolar (intravenous clofarabine)
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01169012
|United States, North Carolina|
|University of North Carolina at Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599|
|Principal Investigator:||Matthew Foster, MD||University of North Carolina, Chapel Hill|