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Mechanism of Action
Clofarabine is sequentially metabolized intracellularly to the 5'-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5'-triphosphate metabolite. Clofarabine has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death.
Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro.
The population pharmacokinetics of Clolar were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m² dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steadystate were 28.8 L/h/m² and 172 L/m², respectively. The terminal half-life was 5.2 hours.
No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females.
No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population.
Based on 24-hour urine collections in the pediatric studies, 49-60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). The pathways of non-hepatic elimination remain unknown.
In vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP substrates. However, no in vivo drug interaction studies have been conducted.
An in vitro transporter study suggested that clofarabine is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hOCT2. Although the clinical implications of this finding have not been determined, signs of Clolar toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.
Seventy-eight (78) pediatric patients with ALL were exposed to Clolar. Seventy (70) of the patients received the recommended pediatric dose of Clolar 52 mg/m² daily for 5 days as an intravenous (IV) infusion.
Dose Escalation Study in Pediatric Patients with Hematologic Malignancies
The safety and efficacy of Clolar were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study. The starting dose of Clolar was 11.25 mg/m²/day IV infusion daily x 5 and escalated to 70 mg/m²/day IV infusion daily x 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clolar 52 mg/m² daily for 5 days. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) at varying doses. Doselimiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m². As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m²/day for 5 days.
Single-Arm Study in Pediatric ALL
Clolar was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study.
All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African-American, 2% were Asian and 5% were Other race.
The overall remission (OR) rate (Complete Remission [CR] + CR in the absence of total platelet recovery [CRp]) was evaluated. CR was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow ( ≤ 5% blasts), and recovery of peripheral counts [platelets ≥ 100 x 109/L and absolute neutrophil count (ANC) ≥ 1.0 x 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥ 100 x 109/L. Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow ( ≥ 5% and ≤ 25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. Duration of remission was also evaluated. Transplantation rate was not a study endpoint.
Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).
Table 3 summarizes results for the pediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 530 mg (range 29-2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1-12). The median time between cycles was 28 days with a range of 12 to 55 days.
Table 3: Results in Single-A rm Pediatric ALL
|N = 61|
|CR % [95% CI]||11.5 (4.7, 22.2)|
|CRp % [95% CI]||8.2 (2.7, 18.1)|
|Median Duration of CR plus CRp (range in weeks)1||10.7 (4.3 to 58.6)|
|CR = Complete response
CRp = Complete response without platelet recovery
1 Does not include 4 patients who were transplanted (duration of response, including response after transplant, in these 4 patients was 28.6 to 107.7 weeks).
Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown.
Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp. Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp.
Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy.
Last reviewed on RxList: 2/1/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Clolar Information
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