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Clolar

On December 28, 2004, the FDA granted accelerated approval for clofarabine (Clolar™, made by Genzyme Corporation), a purine nucleoside antimetabolite given by intravenous infusion for treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.

The approval of this indication is based on the induction of complete responses. Clinical studies demonstrating increased survival or other clinical benefit have not been conducted. Approval was granted under accelerated approval regulations that require the applicant to conduct and complete additional clinical studies to confirm clinical benefit.

Efficacy and safety were demonstrated in a single multicenter trial that enrolled 49 patients. Most patients had received two to four prior regimens and 15/49 (31 percent) had undergone at least one transplant. The median age was 12 years.

Clofarabine was given at a dose of 52 mg/m2, intravenously, over two hours daily for five days, repeated every two to six weeks following recovery or return to baseline organ function. The study endpoints were the rate of complete response (CR) and the rate of complete response without platelet recovery (CRp). The former was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow, and recovery of peripheral platelet and absolute neutrophil counts; the latter was defined as meeting all criteria for CR except for platelet count recovery. Response rates were determined by an Independent Response Review Panel (IRRP).

Six patients (12 percent) achieved a CR and four patients (8 percent) achieved a CRp, and five patients (10 percent) achieved a PR. Of the 15 responding patients, six had post-clofarabine bone marrow transplantation. Hence, response durations could not be determined. In the patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days.

The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, febrile neutropenia, hepatobiliary toxicity, infections, and renal toxicity. Clofarabine can produce systemic inflammatory response syndrome/capillary leak syndrome (SIRS), manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure. Cardiac toxicity was characterized as left ventricular systolic dysfunction; tachycardia may also occur.

Dacogen

On May 2, 2006, the FDA approved decitabine for injection (Dacogen®, made by MGI Pharma, Inc.) for the treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Safety and efficacy were demonstrated in an open-label, multicenter, randomized, controlled trial in 170 adult patients with all five French-American-British (FAB) subtypes of MDS and with International Prognostic Scoring System scores of high risk, intermediate-2 and intermediate-1.

Eighty-nine patients were randomized to decitabine plus supportive care and 81 were randomized to supportive care. Patients randomized to the decitabine arm received the drug intravenously at a dose of 15 mg/m2 over a three-hour period every eight hours for three consecutive days. This treatment cycle was repeated every six weeks, depending on the patient's clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors.

Responses were classified using the MDS International Working Group criteria. Patients were required to be red blood cell and platelet transfusion independent during the period of response. The overall response rate (CR+PR) in the intent-to-treat population was 17 percent in the decitabine-treated group and 0 percent in the supportive care group (p<0.001).

In the decitabine-treated group the median duration of response was 288 days and the median time to response was 93 days. All but one of the decitabine-treated patients who responded did so by the fourth cycle. Decitabine treatment did not significantly delay the median time to acute myelogenous leukemia or death.

A total of 164 patients were accrued to two additional open-label, single-arm, multicenter studies of decitabine in patients with any of the FAB subtypes of MDS. The overall response rates in these two studies were 26 percent (N=66) and 24 percent (N=98).

The major toxicity of decitabine was myelosuppression as manifested by neutropenia, thrombocytopenia, anemia, and febrile neutropenia. Other common adverse events included nausea, vomiting, diarrhea, constipation, fever, edema, hyperglycemia, hypomagnesemia, hypokalemia, arthralgias, back pain, cough, headache, insomnia, rash, petechiae, and pallor.

No age- or gender- related differences in safety were detected. Patients with hepatic or renal dysfunction were not studied. Insufficient numbers of nonwhite patients were enrolled in these clinical trials to draw any conclusions.

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