The Cyclin Dependent Kinase Inhibitor SCH 727965 Demonstrates Promising Pre-Clinical and Early Clinical Activity in Chronic Lymphocytic Leukemia.

Abstract 886

Patients with chronic lymphocytic leukemia (CLL) having del(17p13.1), complex karyotype, or fludarabine-refractory disease have few therapeutic options. The cyclin-dependent kinase (CDK) inhibitor flavopiridol (Alvocidib) has been demonstrated to be very effective in genetically high-risk and fludarabine-refractory CLL cases, with a response rate of approximately 50%. We pursued pre-clinical and now early clinical studies of SCH 727965. SCH 727965 is a selective inhibitor of CDK 1, 2, 5 and 9 (IC50 of < 5nM) that shows in vitro and in vivo anti-tumor activity in a variety of pre-clinical models. Notably, SCH 727965 has an improved therapeutic index over other CDK inhibitors such as flavopiridol. A solid tumor phase I study with SCH 727965 administered by 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle has been completed, resulting in a recommended phase II dose of 12 mg/m2. Our pre-clinical studies with SCH 727965 demonstrate potent induction of apoptosis in CLL patient cells following a 2-hour incubation, with an LC50 of 240 nM. This effect is independent of prior treatment status, IgVH gene mutational status, and high-risk cytogenetic abnormalities. Importantly, minimal cytotoxicity toward normal T cells is observed. Similar to other CDK inhibitors in CLL, SCH 727965 promotes rapid down-regulation of the pro-survival gene MCL1 at both the mRNA and protein levels. Stimulation of CLL cells with CD40L mimics the lymph node microenvironment and increases resistance of CLL cells to drug-induced apoptosis (Smit et al., Blood 109:1660-68, 2007). However, co-treatment of CLL cells with SCH 727965 plus CD40L does not abrogate the apoptotic effect of SCH 727965. Based upon these promising data, a disease-specific phase I study of SCH 727965 has been initiated in previously treated CLL patients. This trial started at a dose level below the phase II dose established in the solid tumor study, due to the previous observation of hyperacute tumor lysis in CLL with other CDK inhibitors. SCH 727965 is administered by 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. Dosing cohorts are: 5 mg/m2, 7 mg/m2, 10 mg/m2, and 14 mg/m2. Further dose-escalation is allowed, depending on the frequency of dose limiting toxicities observed. To date, we have completed enrollment to cohorts 1 and 2 of the study, with ten patients enrolled. Clinical features of the patients include a median age of 58 (range 43 to 73), 60% Rai stage 3 or 4, and 60% with high-risk genomic features (del17p13, del11q22, or more than two abnormalities). These patients received a median of six (range 1 to 12) prior therapies, and 90% received prior fludarabine therapy. Biochemical evidence of tumor lysis (increased potassium, phosphate, or LDH) post-treatment has been observed in three patients. Common toxicities observed include: nausea, vomiting, diarrhea and fatigue. One patient with pre-treatment neutropenia developed fatal bacterial sepsis during cycle 1 of therapy. Three patients have discontinued therapy due to progressive disease after cycle one, including one patient who died from CLL disease. Two patients discontinued therapy with stable disease. Four patients remain on therapy; one in the lowest dose cohort has demonstrated a partial response by IWCLL 2008 criteria. The other three patients currently are early in the course of planned therapy. The clinical observation of rapid improvement in palpable adenopathy after SCH 727965 treatment is consistent with the laboratory observation of continued sensitivity of CD40L-exposed CLL cells to SCH 727965. Pharmacodynamic studies demonstrate down-modulation of MCL1 in a subset of patients. These data provide promising pre-clinical, and now early clinical, evidence of the potential therapeutic benefit of SCH 727965 in CLL. Dose escalation of SCH 727965 continues and updated results will be presented. This work was supported by the D. Warren Brown Foundation and Specialized Center of Research from the Leukemia and Lymphoma Society.