Study Data

Phase 1 trial in pediatrics

Based on activity demonstrated in a phase 1 study of clofarabine in adult patients with acute leukemia¹, 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) ².

The starting dose of Clolar was 11.25 mg/m²/day intravenous (IV) infusion daily × 5 and escalated to 70 mg/m²/day IV 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 (12.5%) and 2 partial remissions (12.5%) 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 in pediatrics

A single dose, single arm, open label study of Clolar was conducted in relapsed/refractory pediatric patients with ALL to determine the rate of complete remission (CR), complete remission without total platelet recovery (CRp), and partial response (PR), as determined by an unblinded Independent Response Review Panel (IRRP).

• CR was defined as no circulating blasts or extramedullary disease, <5% bone marrow blasts, recovery of peripheral blood counts (platelet count >100 x 10⁹/L and 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 no circulating blasts, ≥5% and ≤25% bone marrow blasts, and the appearance of normal progenitor cells or M1 bone marrow that did not qualify for CR or CRp.

Phase 2 trial results

Results from this phase 2 trial demonstrated a nearly 31% response rate (CR+CRp+PR) in a heavily pretreated population; fifteen of 49 (30.6%) patients achieved a response with Clolar as a single agent, either CR, CRp, or PR.

Responses were seen in patients with both pre-B and T-cell immunophenotypes of ALL.

Duration of response

Six of those 15 patients were able to undergo post-treatment bone marrow transplantation (transplantation rate was not a study endpoint so that duration of response could not be determined). In the 9 responding patients who were not transplanted, response durations ranged from 7 to 160+ days.

Patients were heavily pretreated

All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 46/49 (93.8%), had received 2 to 4 prior regimens and 15/49 (30.6%) of the patients had undergone at least 1 prior transplant. The table below lists additional characteristics of the study group.

Phase 2 trial dosing

All patients received a dose of 52 mg/m² daily by intravenous infusion for 5 consecutive days. Treatment cycles were repeated every 2 to 6 weeks for up to 12 cycles depending on recurrence of leukemia or recovery of normal hematopoiesis (ANC ≥0.75 x 10⁹/L) and organ function. Dosage calculations were based on the patient’s body surface area (BSA) determined from the actual height and weight obtained before each cycle. There was no dose modification during the remission induction phase of treatment (maximum of 2 cycles). Doses could be reduced and/or delayed during the post-induction phase. There was no dose escalation.

Phase 2 trial medications

Routine prophylactic use of growth factors was not permitted during the study. Prophylactic use of antibiotics, antifungals, and antivirals was recommended. The study was amended to require treatment with steroids before and after clofarabine administration on Days 1 to 3 of Cycle 1 in an effort to reduce the development of rash, hand-foot syndrome, and vomiting, as well as symptoms of cytokine release following infusion with clofarabine.

References

1. Kantarjian H, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol 2003;21:1167–73.
2. Jeha S, Gandhi V, Chan K, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004;103:784–9.

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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 Considerations

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome, and organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered.

The most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting (grade 3: 8%; grade 4: 1%), nausea (grade 3: 15%; grade 4: 1%), and diarrhea (grade 3: 10%); hematologic effects, including anemia (grade 3: 70%; grade 4: 18%), leukopenia (grade 4: 99%), thrombocytopenia (grade 3: 36%; grade 4: 64%), neutropenia (grade 3: 3%; grade 4: 7%), and febrile neutropenia (grade 3: 53%; grade 4: 3%); and infection (grade 3: 56%; grade 4: 18%).

Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Left ventricular systolic dysfunction was also noted. Since Clolar is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of Clolar administration. In addition, since the liver is a known target organ for Clolar toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided.

Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been observed in patients treated with Clolar. 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.

Pericardial effusion was a frequent finding in these patients on post-treatment studies. Careful hematologic monitoring during therapy is important. Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. Severe hepatotoxic events have been reported in an ongoing, phase 1/2 clinical trial investigating Clolar in combination with etoposide and cyclophosphamide in pediatric patients with relapsed or refractory acute leukemia. This study found that patients who had previously received a hematopoietic stem cell transplant may be at higher risk for hepatotoxicity.

Patients receiving Clolar may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breastfeeding while receiving treatment with Clolar.

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