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• W2375706089 abstract "Abstract Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults. While the breadth of therapies for this incurable disorder has increased recently, patients afflicted with high risk disease have few and predominantly unsatisfactory options. Cyclin-dependent kinase (CDKs) inhibitors, such as Flavopiridol, have demonstrated clinical activity in CLL, though have been associated with significant therapy associated tumor lysis (TLS). Dinaciclib is a selective inhibitor of CDKs 1, 2, 5, and 9 that exhibits activity in CLL, including high risk subtypes. We performed a phase 1 dose escalation trial in relapsed and refractory CLL in order to determine the recommended phase 2 dose and maximum administered dose of dinaciclib. Patients received treatment as a 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. The initial starting dose, determined based on preclinical data, was 5 mg/m2. Other dosing cohorts of 7 mg/m2, 10 mg/m2, 14 mg/m2 and 17mg/m2 were included in the dose escalation schema. An expansion cohort of patients utilizing an intra-patient dose escalation of 7mg/m2 on day 1, 10mg/m2 on day 8 and 14mg/m2 on day 15 during cycle 1 and 14mg/m2 on days 1, 8, and 15 of each subsequent cycle was further employed. Patients continued on treatment until there was disease progression, unacceptable toxicity or subject’s refusal to continue. In total, 52 patients have been enrolled on this trial. The median age is 62.4 years (range 43-79), with 46% of patients ≥65 years. The majority of patients have advanced Rai stage (65%) and/or bulky disease (69%) and 46% with del(17p13.1). The median number of prior therapies is 4 (range 1-12) with 92% having received prior fludarabine and 31% having received prior flavopiridol. One episode of a dose limiting toxicity (DLT) was noted at 7mg/m2 (sepsis/death) and two at dose level of 17mg/m2 (hyperacute tumor lysis syndrome and pneumonia). One further DLT of TLS occurred at the recommended phase II dose level of 14mg/m2 during cohort expansion for a total of 18 patients treated at 14mg/m2. The most common serious adverse events included leucopenia, anemia, thrombocytopenia and metabolic evidence of tumor lysis, which occurred in 15% of patients. Clinical response was assessed utilizing the 1996 NCI-WG CLL criteria. The overall response rate of evaluable patients was 58% (28 of 48), while 57% patients with del(17p13.1) and 63% with del(11q22) achieved at least a partial response. The median progression free survival was 481 days (95% CI, 253 – 481). For responders, the median treatment duration was 214.5 days (range, 79 – 470 days). In conclusion, Dinaciclib is clinically active in this population of relapsed and refractory CLL. Importantly, patients with high risk disease, such as del(17p13.1) demonstrated impressive overall responses. Utilizing a dose escalation treatment model, Dinaciclib is well tolerated, safe and associated with typical toxicities which are readily managed. The use of this agent in combination with other efficacious agents, especially in the high risk CLL population is warranted. Disclosures: Jones:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Small:Merck: Employment. Im:Merck: Employment. Zhou:Merck: Employment." @default.
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• W2375706089 date "2013-11-15" @default.
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• W2375706089 title "Dinaciclib (SCH 727965) Is a Novel Cyclin-Dependent Kinase (CDK) Inhibitor That Exhibits Activity In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia (CLL)" @default.
• W2375706089 doi "https://doi.org/10.1182/blood.v122.21.871.871" @default.
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