Early Evidence of Anti-Lymphoma Activity of the Cyclin Dependent Kinase Inhibitor Dinaciclib (SCH 727965) In Heavily Pre-Treated Low Grade Lymphoma and Diffuse Large Cell Lymphoma Patients

Dinaciclib (SCH 727965) is a potent and selective inhibitor of the cyclin dependent kinases CDKs 1, 2, 5, and 9, with in vitro activity against lymphoma.

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 solid tumor patients with 12 mg/m² established as the recommended phase 2 dose (RPTD). The RPTD was explored in expansion cohorts of up to 10 patients each with low grade lymphomas (primarily follicular lymphoma (FL)), and intermediate/high grade lymphomas (diffuse large B-cell lymphoma (DLBCL)). Sixteen patients have been treated with dinaciclib, including 7 with FL, 1 with mantle cell lymphoma (MCL) and 1 with marginal zone lymphoma (MZL) in the low grade group and 7 with DLBCL in the intermediate/high grade group. Patient median age was 66 (range 43–82) and the median number of prior therapies was 2.5 (range 1–8). All patients received prior rituximab and 4 patients had previously received flavopiridol. All patients were treated with dinaciclib at the 12 mg/m² dose. Dose de-escalation to 10 mg/m² was required in 2 patients during treatment. The median number of cycles administered was 3 (range 1–9) with 3 patients continuing treatment for 3 cycles, 4 for 6 cycles, and 1 for 9 cycles. Of the 16 lymphoma patients treated, 2 remain on treatment.

Responses were assessed using the revised Cheson criteria for lymphoma (J Clin Oncol 25: 579-86, 2007). One partial response in a patient with DLBCL was observed with an 85% decrease in tumor mass. This patient, previously treated with R-CHOP from May-August 2008 and R-ICE from December 2008-March 2009, was able to continue on to autologous stem cell transplantation for potential curative salvage. Activity not meeting criteria for partial response was seen in 2 patients with FL (decreased tumor mass of 27% and 39%, respectively) and one patient with MCL (8% decrease in tumor mass).

Treatment-related adverse events occurring in ≥ 25% of pts included anemia, cytokine release syndrome, nausea, vomiting, diarrhea, fatigue, leucopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common CTCAE v3.0 treatment-related grade 3 and 4 toxicities, occurring in 3 or more patients, were leukopenia, lymphopenia, and neutropenia. Cytokine release syndrome was observed in 4 patients, was manageable with dexamethasone and did not prevent continued treatment on protocol.

Dinaciclib demonstrates clinical responses in heavily pre-treated lymphoma patients supporting further study in lymphoma and other hematologic malignancies. Updated information with longer follow-up will be presented.

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