Update on the Phase I Study of the Cyclin Dependent Kinase Inhibitor Dinaciclib (SCH 727965) In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Confirmation of Clinical Activity and Feasibility of Long-Term Administration
Authors: Flynn Joseph M. , Jones Jeffrey A. , Andritsos Leslie , Blum Kristie A. , Johnson Amy J. , Hessler Josh , Wiley Elizabeth , Poon Jennifer , Small Karen , Statkevich Paul , Grever Michael R. , Bannerji Rajat , Byrd John C. 
Published: October 2019

Abstract
Abstract 1396
Patients with relapsed or refractory CLL have limited treatment options, especially those with bulky lymph nodes. Dinaciclib is a potent and selective inhibitor of the cyclin dependent kinases CDK 1, 2, 5, and 9, and has potent anti-leukemic activity against CLL cells in ex vivo assays (LC50 of 240 nM). A phase 1 trial of dinaciclib administered by 2-hour i.v. infusion on days 1, 8 and 15 of a 28-day cycle was undertaken in CLL patients as an amendment to a now completed phase I solid tumor study. Thirty-three CLL subjects were enrolled in 5 dose cohorts including 16 subjects enrolled at the maximally tolerated dose of 14 mg/m2. The enrolled patients have a median age of 62 (range 43–79), 60% are Rai stage 3 or 4, 54% have bulky disease and 58% have high risk cytogenetics (del 17p13, del 11q22, or > 2 abnormalities). The median number of prior therapies are 4 (range 1–12), 88% received prior fludarabine. The starting dose of dinaciclib in CLL patients was 5 mg/m2 with subsequent cohort escalation to 7, 10, 14 and 17 mg/m2. The maximum administered dose was 17 mg/m2 where dose limiting toxicities occurred in 2 of 3 patients treated. These toxicities included a bacterial pneumonia in one patient and tumor lysis syndrome requiring temporary hemodialysis in a second patient. Expansion of the 14 mg/m2 dose level to 16 patients occurred with one additional case of TLS requiring temporary dialysis observed on Cycle 1, Day 1. In total, there were 5 cases of TLS, 3 cases of Grade 3 TLS in addition to 2 cases of TLS requiring dialysis. Common treatment related adverse events include anemia, neutropenia, thrombocytopenia, hyperglycemia, hypocalcemia, diarrhea, hypokalemia, increased AST/ALT and fatigue. Two deaths occurred on study (one each progressive disease and sepsis). The median number of treatment cycles given is 3 (range 1 – 13) with 8 patients continuing treatment for 6 cycles, 5 continuing for 9 cycles, and 4 continuing for 12 cycles. Clinical response as assessed by the 1996 NCI-WG CLL criteria (physical exam and CT evaluation) currently includes 8 partial responses out of 23 evaluable patients, including one patient proceeding to an allogeneic stem cell transplant. Ten additional patients are early in treatment (2-3 cycles administered) but are not yet evaluable for response. Responses have been observed at all dose levels studied, and include both early (at 2 cycles) and late (at 6 cycles) responses. A decrease in tumor volume has occurred in 17 patients (including responders) and additional responses may be expected with further ongoing treatment. In addition to responders, the majority of patients with proliferative disease at study entry achieved disease stabilization with acceptable toxicity while on dinaciclib treatment. Western blot assay for MCL-1 protein levels confirms pharmacodynamic activity with 10 of 10 patient samples showing a rapid decrease in MCL-1 protein levels. Further optimization of the treatment regimen will examine if less initial biochemical tumor lysis occurs with stepped up dosing of dinaciclib 10 mg/m2 in week 1 followed by 14 mg/m2 in week 2 and thereafter. Results will be updated at the meeting. Dinaciclib demonstrates promising clinical responses and feasibility of prolonged administration in heavily pre-treated CLL patients with bulky disease. These data support further study of dinaciclib in CLL and related B-cell malignancies.

Disclosures:
Off Label Use: SCH 727965 (dinaciclib) is an investigational drug. Small:Merck & Co.: Employment, Equity Ownership. Statkevich:Merck & Co.: Employment, Equity Ownership. Bannerji:Merck & Co.: Employment, Equity Ownership.