Ignite Creation Date:
2025-12-26 @ 10:44 PM
Ignite Modification Date:
2025-12-26 @ 10:44 PM
Study NCT ID:
NCT01169012
Status:
COMPLETED
Last Update Posted:
2017-08-22
First Post:
2010-07-22
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
PK Study of Oral and IV Clofarabine in High Risk Myelodysplasia+Acute Leukemias
Sponsor:
UNC Lineberger Comprehensive Cancer Center
Organization:
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2017-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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).
Detailed Description:
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.
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.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 10-0256 | OTHER | UNC OHRE | View |