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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


Phase 1
18 Years
N/A
Not Enrolling
Both
Lymphoma, Mantle-Cell, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Hairy Cell, Waldenstrom Macroglobulinemia, Multiple Myeloma

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Trial Information

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


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).

Inclusion Criteria


- 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety of escalating doses ON01910.Na at day 28.

Principal Investigator

Mark J Roschewski, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

090094

NCT ID:

NCT00861510

Start Date:

March 2009

Completion Date:

October 2012

Related Keywords:

  • Lymphoma, Mantle-cell
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Waldenström Macroglobulinemia
  • Multiple Myeloma
  • Small Lymphocytic Lymphoma (SLL)
  • Prolymphocytic Lymphoma (PLL)
  • Hairy Cell Leukemia (HCL)
  • Mantle Cell Lymphoma
  • MCL
  • Chronic Lymphocytic Leukemia
  • CLL
  • Multiple Myeloma
  • MM
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Waldenstrom Macroglobulinemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Lymphoma, Mantle-Cell

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892