Important Safety Information
Clolar® should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. View additional Important Safety Information.

Clinical Trials

Phase 1 Trial

A phase 1, open-label, dose-escalation, noncomparative study of Clolar in heavily pretreated patients with relapsed or refractory leukemia younger than 21 years of age was conducted to define the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD).1

The starting dose of Clolar was 11.25 mg/m2/day intravenous (I.V.) infusion daily × 5 and escalated to 70 mg/m2/day I.V. infusion daily × 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 acute lymphoblastic leukemia (ALL) patients were treated with Clolar 52 mg/m2 daily × 5. In the 17 ALL patients, there were 2 complete remissions (12%) and 2 partial responses (12%) at varying doses. 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.

Phase 2 Trial

The efficacy and safety of Clolar were evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL

Patients received a fixed dose of 52 mg/m2 I.V. 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.

  • Median number of cycles was 2 (range: 1–12)
  • Median time between cycles was 28 days (range: 12–55)
Patient Profile (N=61)
Median age 12 yr
Gender, male/female 61%/39%
Prior lines of therapy (2/>2) 38%/62%
Prior transplant 30%
Refractory to immediately preceding therapy2 57%

The study was designed to determine the rate of complete remission (CR) and complete remission without total platelet recovery (CRp). Partial response (PR) was also determined. Response rates were determined by an independent Response Review Panel (IRRP).

CR was defined as:

  • no evidence of circulating blasts or extramedullary disease
  • ≤5% bone marrow blasts
  • recovery of peripheral blood counts platelet count ≥100 x 109/L
  • absolute neutrophil count (ANC) ≥1.0 x 109/L

CRp was defined as:

  • meeting all criteria of CR except for recovery of platelet counts to ≥100 x 109/L

PR was defined as:

  • complete disappearance of circulating blasts
  • ≥5% and ≤25% bone marrow blasts
  • the appearance of normal progenitor cells or M1 bone marrow that did not qualify for CR or CRp

Figure 1 summarizes the remission rates for this study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL.

Figure 1: Clolar achieves a 30% rate of CR, CRp, or PR*

*The clinical relevance of a PR in this setting is unknown.

CR (complete remission) = no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (<5% blasts), and recovery of peripheral counts (platelets ≥100 x109/L and absolute neutrophil count [ANC] ≥1.0 x 109/L).
CRp (complete remission without total platelet recovery) = meets all criteria for CR except for recovery of platelet counts to ≥100 x 109/L.
PR (partial response) = 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.

  • For the 4 patients who went on to receive a transplant, remission duration (prior to and after transplant) was 29 to 108 weeks.
  • For the 6 patients who did not receive a transplant, remission duration was 4 to 59 weeks (median 10.7 weeks).

Remission durations are based only on complete response (CR) and complete response without platelet recovery (CRp).

Ongoing Clinical Trials

As a condition of accelerated approval, FDA requires further study to demonstrate the clinical benefit of Clolar. These and other clinical trials with clofarabine are listed on www.clinicaltrials.gov

To learn more about these trials, please contact Genzyme Medical Information at 800.RX.CLOLAR (800.792.5652), or visit http://www.genzymeclinicalresearch.com.

 

Reference:

  1. Data on File
  2. Jeha S, et al. Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia. Journal of Clinical Oncology. 2006;24:1917-23.

Clolar Resources

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Prescribing Information

Prescribing Information 
Clolar prescribing information (.pdf)

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Indication

Clolar is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

Important Safety Information

Warnings and Precautions:

Clolar® should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

    Hematologic Toxicity

    • Monitor complete blood counts and platelet counts during and after Clolar therapy.
    • Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with Clolar. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia.
    • Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections.

    Infections

    The use of Clolar is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Monitor patients for signs and symptoms of infection and treat promptly.

      Hyperuricemia (Tumor Lysis)

      Administration of Clolar may result in a rapid reduction in peripheral leukemia cells. Evaluate and monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome. Provide intravenous infusion fluids throughout the five days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Administer allopurinol if hyperuricemia (tumor lysis) is expected.

        Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome

        • Evaluate and monitor patients undergoing treatment with Clolar for signs and symptoms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome and organ dysfunction.
        • Discontinue Clolar immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and consider use of steroids, diuretics, and albumin. Re-institute Clolar when the patient is stable, generally with a 25% dose reduction. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

        Hepatic Enzymes

        Hepato-biliary enzyme elevations were frequently observed in pediatric patients during treatment with Clolar. Some patients discontinued treatment due to hepatic enzyme abnormalities.

          Hepatic and Renal Impairment

          • Clolar has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution.
          • Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia.

          Use in Pregnancy

          Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Clolar.

            Nursing Mothers

            Female patients should be advised to avoid breast-feeding during treatment with Clolar.

              Incidence of Treatment Emergent Laboratory Abnormalities (All Grades)

              ParameterAny gradeGrade 3 or higher
              Anemia 83% 75%
              Leukopenia 88% 88%
              Lymphopenia 82% 82%
              Neutropenia 64% 64%
              Thrombocytopenia 81% 80%
              Elevated creatinine 50% 8%
              Elevated SGOT 74% 36%
              Elevated SGPT 81% 43%
              Elevated total bilirubin 45% 13%

              Adverse Reactions:

              Most common adverse reactions with Clolar were nausea (73%), vomiting (78%), diarrhea (56%), febrile neutropenia (55%), headache (43%), rash (38%), pruritus (43%), pyrexia (39%), fatigue (34%), palmar-plantar erythrodysesthesia syndrome (16%), anxiety (21%), flushing (19%), and mucosal inflammation (16%).

              For more information, please consult the full Prescribing Information (PDF).