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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

Primary Purpose

Lymphoma, Mantle-cell, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Hairy Cell

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ON01910 Na
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma, Mantle-cell focused on measuring Small Lymphocytic Lymphoma (SLL), Prolymphocytic Lymphoma (PLL), Hairy Cell Leukemia (HCL), Mantle Cell Lymphoma, MCL, Chronic Lymphocytic Leukemia, CLL, Multiple Myeloma, MM

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

  • INCLUSION CRITERIA:

    1. Histologically documented or cytologically confirmed diagnosis of Mantle Cell Lymphoma (MCL) and refractory to, or relapsed after, greater than or equal to 1 prior lines of antineoplastic therapy (including an anthracycline or mitoxantrone and rituximab, each in one or more lines).

      OR

      Histologically documented or cytologically confirmed diagnosis of Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), or Prolymphocytic Lymphoma (PLL) and refractory to, or relapsed after, greater than or equal to 1 prior lines of antineoplastic therapy (including either a nucleoside analogue or an alkylating agent or a combination thereof. Must have relapsed after, failed or opted not to receive rituximab or alemtuzumab. Not a candidate for or opted not to participate in bone marrow transplantation.

      OR

      Histologically documented or cytologically confirmed diagnosis of Multiple Myeloma (MM) and refractory to, or relapsed after greater than or equal to 2 prior lines of antineoplastic therapy including both bortezomib and an immunomodulatory (IMiD) agent such as lenalidomide or thalidomide.

      OR

      Histologically documented or cytologically confirmed diagnosis of Waldenstrom s macroglobulinemia (WM) or Hairy Cell Leukemia (HCL) and refractory to, or relapsed after greater than or equal to 1 line of antineoplastic therapy.

    2. Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic disease or monoclonal paraproteins).
    3. Failed to respond to, relapsed following, not eligible for, or opted not to participate in other standard of care treatment options.
    4. Age greater than or equal to 18 and less than or equal to 99.

EXCLUSION CRITERIA:

  1. Less than 4 weeks since having received any other treatments directed toward their malignancy (standard or investigational). Steroids permissible up to 2 weeks prior to enrollment.
  2. Malignant disease other than MCL, CLL/SLL, PLL, WM, HCL or MM requiring treatment with cytotoxic therapy.
  3. Active infection not adequately responding to appropriate therapy.
  4. HIV positive patients and taking anti-retroviral therapy.
  5. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy.
  6. Symptomatic congestive heart failure, unstable angina pectoris, history of life threatening cardiac arrhythmia, myocardial infarction within 6 months or new conduction abnormalities by EKG. Patients with symptoms of coronary artery disease or EKG abnormalities must be evaluated and cleared by cardiology prior to enrollment.
  7. Uncontrolled hypertension (defined as systolic pressure greater than or equal to 160 and/or diastolic pressure greater than or equal to 110).
  8. New onset seizures (within 3 months prior to the first dose of ON 01910.Na) or poorly controlled seizures.
  9. ECOG performance status 3 or 4.
  10. Life expectancy less than 3 months.
  11. Absolute neutrophil count (ANC) less than 500.
  12. Platelet count less than 25,000 micro/L, unless responsive to platelet transfusion so that count can be maintained greater than 10,000 micro/L.
  13. Total bilirubin greater than or equal to 1.5 mg/dL not related to hemolysis or Gilbert s disease, ALT or AST greater than or equal to 2 times ULN.
  14. Serum creatinine greater than 1.5 times ULN or a calculated creatinine clearance of less than 40 mL/min/1.73 m(2).
  15. Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of less than 134 meq/L).
  16. Current pregnancy, unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding.
  17. Male patients with female sexual partners who are unwilling to follow the strict contraception requirements described in this protocol.
  18. Major surgery within 3 weeks of ON 01910.Na treatment initiation
  19. Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements.
  20. Unable to understand the investigational nature of the study or give informed consent.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Outcomes

Primary Outcome Measures

Safety of escalating doses ON01910.Na at day 28.

Secondary Outcome Measures

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).

Full Information

First Posted
March 12, 2009
Last Updated
November 30, 2019
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00861510
Brief Title
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
Official Title
A Pilot Study of the Safety and Efficacy of Escalating Doses of ON 01910.Na in Patients With Relapsed Mantle Cell Lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukemia, and Related Lymphoid Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
September 4, 2014
Overall Recruitment Status
Completed
Study Start Date
March 5, 2009 (undefined)
Primary Completion Date
October 19, 2012 (Actual)
Study Completion Date
October 19, 2012 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

5. Study Description

Brief 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, Mantle-cell, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Hairy Cell, Waldenstrom Macroglobulinemia, Multiple Myeloma
Keywords
Small Lymphocytic Lymphoma (SLL), Prolymphocytic Lymphoma (PLL), Hairy Cell Leukemia (HCL), Mantle Cell Lymphoma, MCL, Chronic Lymphocytic Leukemia, CLL, Multiple Myeloma, MM

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
ON01910 Na
Primary Outcome Measure Information:
Title
Safety of escalating doses ON01910.Na at day 28.
Secondary Outcome Measure Information:
Title
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).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Histologically documented or cytologically confirmed diagnosis of Mantle Cell Lymphoma (MCL) and refractory to, or relapsed after, greater than or equal to 1 prior lines of antineoplastic therapy (including an anthracycline or mitoxantrone and rituximab, each in one or more lines). OR Histologically documented or cytologically confirmed diagnosis of Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), or Prolymphocytic Lymphoma (PLL) and refractory to, or relapsed after, greater than or equal to 1 prior lines of antineoplastic therapy (including either a nucleoside analogue or an alkylating agent or a combination thereof. Must have relapsed after, failed or opted not to receive rituximab or alemtuzumab. Not a candidate for or opted not to participate in bone marrow transplantation. OR Histologically documented or cytologically confirmed diagnosis of Multiple Myeloma (MM) and refractory to, or relapsed after greater than or equal to 2 prior lines of antineoplastic therapy including both bortezomib and an immunomodulatory (IMiD) agent such as lenalidomide or thalidomide. OR Histologically documented or cytologically confirmed diagnosis of Waldenstrom s macroglobulinemia (WM) or Hairy Cell Leukemia (HCL) and refractory to, or relapsed after greater than or equal to 1 line of antineoplastic therapy. Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic disease or monoclonal paraproteins). Failed to respond to, relapsed following, not eligible for, or opted not to participate in other standard of care treatment options. Age greater than or equal to 18 and less than or equal to 99. EXCLUSION CRITERIA: Less than 4 weeks since having received any other treatments directed toward their malignancy (standard or investigational). Steroids permissible up to 2 weeks prior to enrollment. Malignant disease other than MCL, CLL/SLL, PLL, WM, HCL or MM requiring treatment with cytotoxic therapy. Active infection not adequately responding to appropriate therapy. HIV positive patients and taking anti-retroviral therapy. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy. Symptomatic congestive heart failure, unstable angina pectoris, history of life threatening cardiac arrhythmia, myocardial infarction within 6 months or new conduction abnormalities by EKG. Patients with symptoms of coronary artery disease or EKG abnormalities must be evaluated and cleared by cardiology prior to enrollment. Uncontrolled hypertension (defined as systolic pressure greater than or equal to 160 and/or diastolic pressure greater than or equal to 110). New onset seizures (within 3 months prior to the first dose of ON 01910.Na) or poorly controlled seizures. ECOG performance status 3 or 4. Life expectancy less than 3 months. Absolute neutrophil count (ANC) less than 500. Platelet count less than 25,000 micro/L, unless responsive to platelet transfusion so that count can be maintained greater than 10,000 micro/L. Total bilirubin greater than or equal to 1.5 mg/dL not related to hemolysis or Gilbert s disease, ALT or AST greater than or equal to 2 times ULN. Serum creatinine greater than 1.5 times ULN or a calculated creatinine clearance of less than 40 mL/min/1.73 m(2). Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of less than 134 meq/L). Current pregnancy, unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients with female sexual partners who are unwilling to follow the strict contraception requirements described in this protocol. Major surgery within 3 weeks of ON 01910.Na treatment initiation Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements. Unable to understand the investigational nature of the study or give informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark J Roschewski, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
17369860
Citation
Park IW, Reddy MV, Reddy EP, Groopman JE. Evaluation of novel cell cycle inhibitors in mantle cell lymphoma. Oncogene. 2007 Aug 16;26(38):5635-42. doi: 10.1038/sj.onc.1210350. Epub 2007 Mar 19.
Results Reference
background
PubMed Identifier
16109604
Citation
Paul JT, Henson ES, Mai S, Mushinski FJ, Cheang M, Gibson SB, Johnston JB. Cyclin D expression in chronic lymphocytic leukemia. Leuk Lymphoma. 2005 Sep;46(9):1275-85. doi: 10.1080/10428190500158797.
Results Reference
background
PubMed Identifier
15766665
Citation
Gumireddy K, Reddy MV, Cosenza SC, Boominathan R, Baker SJ, Papathi N, Jiang J, Holland J, Reddy EP. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell. 2005 Mar;7(3):275-86. doi: 10.1016/j.ccr.2005.02.009. Erratum In: Cancer Cell. 2005 May;7(5):497. Boomi Nathan, R [corrected to Boominathan, R].
Results Reference
background

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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

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