Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory CLL patients with intact organ function and WBC < 200 × 109/L. Five separate dose levels (5 mg/m2, 7 mg/m2, 10 mg/m2, 14 mg/m2, and 17 mg/m2) were explored dosing on a weekly schedule × 3 with one week off (4 week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two DLTs at the 17 mg/m2 dose (TLS and pneumonia). The phase II expansion occurred at 14 mg/m2 with sixteen patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the MTD was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities, and tumor lysis syndrome. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.

No 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.

Purpose: To assess Mobetron soft docking sensitivity thresholds by measuring dosimetric changes resulting from incremental displacements of isolated docking parameters. Methods: The Mobetron device uses a sensitive optical system to establish alignment of the collimator with a treatment cone. To assess the limits of this sensitivity, we isolated each docking parameter (transverse, tilt, and vertical) and varied each incrementally within the docking display range. Transverse displacements ranged in 1mm increments from 0.0cm to 0.4cm. Profiles were taken at dmax for each energy (6MeV, 9MeV and 12MeV) along the direction of displacement. Angular displacements ranged in 0.1° increments from 0.0° to 0.4°. Baseline corrected profiles were assessed with a point‐by‐point symmetry analysis and a max‐min flatness metric (90%‐1cm). Vertical displacements ranged from 0.0cm to 0.4cm in 1mm increments. Output factors were compared by % difference from baseline and PDDs were measured at each vertical displacement to assess changes in dmax and R50 values. Results: For 1mm lateral displacements, symmetry/flatness deviations for the 10cm cone were +0.48%/+0.38% at 6MeV, +0.95%/+1.04% at 9MeV, and +1.77%/+1.96% at 12MeV. Profiles in the direction orthogonal to gantry motion measured +0.99%/+1.29% symmetry/flatness changes at 4mm displacement. For 0.10 angular displacements, symmetry/flatness deviations for the 10cm cone were +0.07%/+0.05% at 6MeV +0.23%/+0.33% at 9MeV, and +0.34%/+0.59% at 12MeV. The 3cm and 6cm cones were less sensitive to transverse and angular displacements. At 4mm vertical displacement, the 3cm cone differed from baseline by 3.02%, 2.30%, and 2.42% (6MeV, 9MeV, and 12MeV respectively). Maximum combined deviation from baseline in quadrature for one extra docking light (half sensitivity) in each displacement vector was >2%. Conclusion: For transverse and vertical displacements, the docking sensitivity range is adequate to ensure flatness and symmetry differences <1.0%. However, for angular displacements, all energies with the 10cm cone deviated at or beyond this threshold.

Purpose: To develop a TG‐142 compliant QA process for 7 Varian TrueBeam linear accelerators (linacs) with enhanced beam conformance and dosimetrically matched beam models. To ensure consistent performance of all 7 linacs, the QA process should include a common set of baseline values for use in routine QA on all linacs. Methods: The TG 142 report provides recommended tests, tolerances and frequencies for quality assurance of medical accelerators. Based on the guidance provided in the report, measurement tests were developed to evaluate each of the applicable parameters listed for daily, monthly and annual QA. These tests were then performed on each of our 7 new linacs as they came on line at our institution. Results: The tolerance values specified in TG‐142 for each QA test are either absolute tolerances (i.e. ±2mm) or require a comparison to a baseline value. The results of our QA tests were first used to ensure that all 7 linacs were operating within the suggested tolerance values provided in TG −142 for those tests with absolute tolerances and that the performance of the linacs was adequately matched. The QA test results were then used to develop a set of common baseline values for those QA tests that require comparison to a baseline value at routine monthly and annual QA. The procedures and baseline values were incorporated into a spreadsheets for use in monthly and annual QA. Conclusion: We have developed a set of procedures for daily, monthly and annual QA of our linacs that are consistent with the TG‐142 report. A common set of baseline values was developed for routine QA tests. The use of this common set of baseline values for comparison at monthly and annual QA will ensure consistent performance of all 7 linacs.