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
Condition: Lymphoma, Mantle-cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Hairy Cell; Waldenstrom Macroglobulinemia; Multiple Myeloma
MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Waldenstrom Macroglobulinemia; Leukemia, Hairy Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM),
           and other lymphoid malignancies are all incurable lymphoid malignancies that mainly
           affect persons in their late 60s and early 70s. Conventional chemotherapy can achieve
           high rates of clinical response, but relapse following these responses is almost
           universal. Patients with lymphoid malignancies relapse because their tumor cells become
           resistant to chemotherapy; therefore, new types of drugs are needed for better treatment
           responses.

        -  The investigational drug ON 01910.Na has been shown to be active against MCL and CLL
           cells, but further research is needed to determine the most safe and effective dose for
           this drug.

      Objectives:

        -  To determine the maximum tolerated dose (the highest dose that does not cause
           unacceptable side effects) of ON 01910.Na in patients with cancers of the lymphoid
           cells.

        -  To study the effects that ON 01910.Na has on cancers of the lymphoid cells.

      Eligibility:

        -  Patients 18 years of age and older who have been diagnosed with cancer of the lymphoid
           cells, and who have not been able to take or have not benefitted from existing treatment
           options.

      Design:

        -  Evaluations before the treatment period:

        -  Full medical history and physical examination, and pregnancy test for women.

        -  Blood and urine tests.

        -  Disease evaluation with computerized tomography (CT) scan, magnetic resonance imaging
           (MRI), electrocardiogram; bone marrow and lymph node biopsies; and skeletal x-rays, if
           clinically indicated.

        -  Treatment with ON 01910.Na:

        -  Different research subjects will receive increasing doses of ON 01910.Na to determine
           which dose is considered safe.

        -  To reduce the risk of one rare serious side effect of treatment for myeloid
           malignancies, patients will take allopurinol 12 hours before and 7 days after each drug
           infusion, one 300 mg pill each day.

        -  Cycles 1 2: Patients will be admitted to the clinical center for 2 days at the beginning
           of each cycle. Each cycle involves intravenous infusion of ON 01910.Na continuously for
           a period of 48 hours, followed by 12 days of observation. Researchers will try to
           maintain the schedule of 2 days of infusion every 14 days, but the interval between
           doses may be extended if patients experience delayed recovery blood counts.

        -  Cycles 3 4: Patients who are doing well and choose to continue may receive an additional
           two cycles (2 days of inpatient infusion followed by 12 days of outpatient observation).
           At the end of cycle 4, researchers will determine if the disease is responding to
           therapy. Patients who experience side effects may continue to take ON 01910.Na at a
           lower dose or may stop receiving the drug.

        -  Patients who respond well to four cycles of ON 01910.Na may be eligible for additional
           cycles of ON 01910.Na.

        -  Patients who need to start another medication to treat their disease will stop taking ON
           01910.Na, and the researchers will perform a final study visit 2 weeks after the last
           dose of ON 01910.Na. After that, participation in the study will be complete.
    

Detailed description: 
      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).
    

Intervention name(s): ON01910 Na
Intervention type(s): Drug
Intervention MeSH terms: ON 01910
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Small Lymphocytic Lymphoma (SLL); Prolymphocytic Lymphoma (PLL); Hairy Cell Leukemia (HCL); Mantle Cell Lymphoma; MCL; Chronic Lymphocytic Leukemia; CLL; Multiple Myeloma; MM