Interim Analysis of EFC6663, a Multicenter Phase 2 Study of Alvocidib (flavopiridol), Demonstrates Clinical Responses Among Patients with Fludarabine Refractory CLL

Abstract 58 Background and Significance: Patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine have particularly poor outcomes with an anticipated survival of 12 to 18 months. Novel therapies are needed for this group of high risk patients. Alvocidib (flavopiridol, HMR1275) is a broad cyclin-dependent kinase(CDK) inhibitor that mediates apoptosis independent of p53 function. Previous single institution studies have shown that alvocidib has significant activity in patients with fludarabine-refractory CLL, including those with bulky lymphadenopathy or del(17p13.1). A multicenter, international phase 2 clinical trial of alvocidib was undertaken to determine the efficacy and safety among patients with fludarabine refractory CLL or prolymphocytic leukemia (B-PLL) arising from CLL. Here we report early clinical responses to alvocidib at a preplanned interim analysis after approximately 40% of the planned 165 patients completed at least 2 cycles of therapy. Methods: Eligibility included patients with CLL or B-PLL arising from CLL who have received prior alkylator therapy and were refractory to fludarabine. Cytopenias were not an exclusion criterion, but adequate renal and liver functions were required. Alvocidib was administered on a pharmacologically derived schedule, with a bolus dose of 30 mg/m2 given over 30 minutes followed by a continuous infusion of 30 mg/m2 over 4 hours. If no tumor lysis syndrome was observed with the first dose, subsequent doses were administered with a continuous infusion of 50 mg/m2 over 4 hours (i.e. total dose 80 mg/m2). Alvocidib was given once weekly for 4 weeks, followed by a 2 week break, for up to 6 cycles (24 total doses). The primary outcome measure was the objective response rate (CR+PR); secondary endpoints included a determination of toxicity using CTCAE criteria, progression free survival (PFS), overall survival (OS), duration of response, and pharmacokinetics. Responses were assessed using both NCI-96 and “hybrid” criteria, which incorporated nodal response as measured by CT scans with NCI-96 criteria. Results: At the time of analysis, 113 patients had consented and were registered (the intention-to-treat (ITT) population), 108 were treated (the as-treated (AT) population), and 68 received at least 2 cycles of therapy (the evaluable patient population). Among the ITT population, the median age was 61 years, 78% were male, 81% were Rai stage 3/4, and 65% had bulky lymphadenopathy (>5cm). The median number of prior treatments was 4 (range 1–12) and 106 patients (94%) were fludarabine refractory. Among 86 patients in the ITT population with cytogenetic data available, 30% had del(17p13.1) and 36% had del (11q22.3). Of the 40 patients treated and discontinued before completion of 2 cycles of therapy, the majority were due to adverse events (43%) and disease progression (28%). Among the evaluable patient population, 21 patients (31%) showed an objective response using NCI-96 criteria and 17 patients (25%) using the hybrid criteria. All responses were partial. Nine percent of patients progressed by NCI-96 criteria. Among the responding patients, the median duration of response was 12.2 months. The objective response (NCI-96 and hybrid criteria, respectively) in evaluable patients with del(17p13.1) (n=16) was 25% and 19%; with del(11q22.3) (n=20) was 30% and 20%; and, with bulky lymphadenopathy (n=44) was 39% and 32%. Safety analysis including the entire AT population showed the most frequent serious adverse events (SAEs, CTCAE grade ≥ 3) were infections (32%), tumor lysis syndrome (19%), diarrhea (17%), and febrile neutropenia (15%). Eight patients required hemodialysis for tumor lysis syndrome. Among the ITT population, 46 deaths have occurred, 8 within 30 days of last study treatment. Of these, 3 deaths were assessed as being related to alvocidib, with one case each of colitis, pseudomonal sepsis, and tumor lysis syndrome. Conclusions: Our data confirm that alvocidib has durable clinical activity in a minority of fludarabine-refractory CLL patients, including those with bulky lymphadenopathy and adverse cytogenetics. With careful monitoring, alvocidib could be safely administered in the context of a multinational trial. Future directions include investigating CLL settings and combinations to minimize the risk of tumor lysis syndrome and characterizing predictive biomarkers to improve patient selection and clinical benefit. Disclosures: Off Label Use: Alvocidib (flavopiridol) for the treatment of CLL. Larson:Sanofi-Aventis: Research Funding. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding.

Methodological Issues in the Assessment of Antimalarial Drug Treatment: Analysis of 13 Studies in Eight African Countries from 2001 to 2004

ABSTRACT The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).