A Pilot Study of the Safety and Activity of Escalating Doses of ON 01910.Na in Patients With Relapsed Mantle Cell Lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukemia, and Related Lymphoid Malignancies

Mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and the related lymphoid malignancies included in this protocol are all incurable lymphoid malignancies that mainly affect persons in their late 60s and early 70s. Conventional chemotherapy can be effective at achieving high rates of clinical response, but relapse following these responses is almost universal. Response rates in the relapsed setting are inferior due to acquired resistance of the tumor cells, and new therapies with novel mechanisms of action are needed. Our aim in this study is to specifically address the needs of these patients for whom few effective treatments are available. Patients with lymphoid malignancies relapse due to acquired resistance of tumor cells to chemotherapy agents and innovative targeted therapies which overcome these mechanisms of resistance are needed. One such investigational drug, ON 01910.Na, is a potent and selective inhibitor of the cell cycle and leads to reduction in cyclin D1 expression. In vitro, ON01910.Na shows activity against CLL and MCL cell lines with resultant cellular death. The overexpression of cyclin D1 in these related lymphoid malignancies provides a rationale for its use in selected patients with these conditions. We therefore propose this non-randomized, pilot, dose-escalating Phase I study of ON 01910.Na in patients with MCL, CLL, MM and related lymphoid malignancies who have relapsed after or are refractory to standard therapy. The primary objective is to determine the toxicity profile (including the maximum tolerated dose and recommended phase II dose) of ON 01910.Na when administered the first 2 (or amended later to 3) days of a 2-week cycle in escalating doses in patients with MCL, CLL, MM and related lymphoid malignancies. The first cohort was dosed at 1200mg/m2/day times 2 days. The second cohort was dosed at 1500mg/m2/day for 2 days. Three subjects were enrolled into the third cohort at 1800mg/m2/day times 2 days. One subject completed the 1800mg/m2/ day times 2 days dosing scheme. Two subjects stopped study drug after the first dose due to progressive disease. The 3 subjects who received 1800mg/m2/day times 2 days will compose cohort 3. New safety data from the drug manufacturer lead to Amendment L, which changed the dosing from 48 hours to 72 hours. On November 18, 2010, the IRB approved Amendment L, which changed the dosing for the new cohorts 4 and 5 to 1800mg/day times 3 days, and 2100mg/day times 3 days, respectively. Secondary objectives include, the biological effects of ON 01910.Na (for example cyclin D1 expression) on cell-cycle pathways of cells obtained from blood, lymph nodes or bone marrow, the toxicity profile of ON 01910.Na with subsequent dosing after 2 cycles of therapy, early indications of biologic activity after 4 cycles of therapy, evaluation of the pharmacokinetics of ON 01910.Na at the RPTD level, and indications of biologic activity during extended access (after 4 cycles (day 56)). The primary endpoint will be the toxicity profile at each dose level through day 28 (cycle 2 day 14). Secondary endpoints include the reduction in lymph nodes, quantification of circulating lymphoma cells, assessment of extranodal disease sites, and/or measurement of the malignant monoclonal proteins in the serum or urine after 4 cycles of therapy (day 56).