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A Pilot Study of the Safety and Activity of Escalating Doses of ON 01910.Na in Patients With RAEB-1 AND RAEB-2 Myelodysplastic Syndrome (MDS) and AML With Trisomy 8

Phase 1
18 Years
85 Years
Not Enrolling
Myelodysplastic Syndrome (MDS)

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Trial Information

A Pilot Study of the Safety and Activity of Escalating Doses of ON 01910.Na in Patients With RAEB-1 AND RAEB-2 Myelodysplastic Syndrome (MDS) and AML With Trisomy 8

The myelodysplastic syndromes (MDS) and acute myelogenous leukemias (AML) are a group of
heterogeneous diseases with wide variation in clinical presentation and disease severity.
Typically patients are older adults with co-morbidities. AML and MDS are characterized by
variable degrees of cytopenias (anemia, neutropenia, thrombocytopenia) due to ineffective
hematopoiesis and dysplastic bone marrow morphology or hematological malignancy.

Treatment of MDS is unsatisfactory: chemotherapy has a limited role in the management of
leukemic progression; autologous stem cell transplantation does not prolong relapse-free
survival and stem cell transplantation is poorly tolerated in older individuals. Some MDS
patients have been shown to respond to a wide variety of immunosuppressive agents ranging
from corticosteroids to cyclosporine (CsA) and horse antithymocyte globulin (h-ATG).
However, the overall response rate is less than 30% and relapse continues to be a problem.
Few treatments appear to change the natural history of MDS however, growth factors,
decitabine, and lenalidomide can improve cytopenias, and 5-azacytidine, can reduce
transfusion requirements, and improve quality of life when compared to supportive care. In
addition most MDS patients are older and tolerate aggressive therapies poorly.

Some AML patients can be cured with chemotherapy or by allogeneic stem cell transplantation.
However standard treatment approaches are not effective for patients who become refractory
to chemotherapy, elderly patients, and those who relapse after transplantation.

The management of MDS and relapsed/refractory AML patients therefore remains unsatisfactory
and targeted therapies are needed. One such investigational drug, ON 01910.Na, is a potent
inhibitor of cyclin D1 and mitosis. ON01910.Na shows activity against a broad spectrum of
tumor cell lines. Animal model studies show little toxicity with a high therapeutic index
in these tumors. In addition, the fact that MDS bone marrow (particularly trisomy 8) and
patients with AML with the trisomy 8 abnormality (Sloand, unpublished data) over-express
cyclin D1 and in vitro studies have demonstrated activity against cytogenetically abnormal
cells and blasts despite minimal inhibition of normal hematopoiesis provides a rationale for
its use in select patients with MDS or AML.

We therefore propose a non-randomized, pilot, dose escalating Phase I study of ON 01910.Na
in MDS and patients with refractory AML with trisomy 8.

The primary objective is to determine the safety (including the maximum tolerated dose
and/or dosing regimen) of ON 01910.Na when administered in escalating doses in select
patients with MDS or AML and bone marrow RNA analysis to assess if gene expression can
predict clinical response to ON 01910.Na in subjects with MDS.

Secondary objectives include plasma pharmacokinetics and biological effects of ON 01910.Na
on cell-cycle pathways of MDS or AML cells, and bone marrow RNA analysis to assess if gene
expression can predict clinical response to ON 01910.Na in subjects with MDS.

The primary endpoint will be the toxicity profile at each dose level. Secondary endpoints
will include the evaluation of early evidence of disease response by blast and cytogenetic

Inclusion Criteria

- All patients 18-85 years old with RAEB1 or RAEB 2 MDS or refractory AML with trisomy
8 who lack a suitable matched sibling marrow will be considered for enrollment.
Patients who have a suitable matched sibling donor will be referred for consideration
of allogeneic bone marrow transplantation. Patients not willing to undergo
transplantation or have relapsed following transplantation will be considered for
protocol participation.


1. Histologically documented or cytologically confirmed diagnosis of MDS with WHO
classification of RAEB-1 or 2 or Intermediate to High IPSS risk group.


Refractory acute myelogenous leukemia (AML) with trisomy 8

2. Anemia requiring transfusion support with at least one unit of packed red blood cells
per month for greater than or equal to 2 months


Anemia (hemoglobin less than 9 or a reticulocyte count less than 60,000/microL)


thrombocytopenia (platelet count less than 50,000/microL)


neutropenia (absolute neutrophil count less than 500/microL).

3. Failed to respond to, relapsed following, or opted not to participate in bone marrow
transplantation or other standard of care treatment options.

4. ECOG Performance Status of 0, 1, or 2.

5. Off all other treatments for MDS or AML (except filgrastim (G-CSF), erythropoietin,
and transfusion support and related medications) for at least four weeks. Filgrastim
(G-CSF) can be used before, during and after the protocol treatment for patients with
documented neutropenia (less than 500/microL) as long as they meet the criteria for
anemia and/or thrombocytopenia as stated above. Post transplant patients may
continue to receive DLIs as needed.

6. Ages 18-85.


1. Active infection not adequately responding to appropriate therapy.

2. Hypoplastic MDS (cellularity less than 10 percent) or an absolute neutrophil count of
less than 200 cells/microL.

3. Active malignant disease (excluding non-melanoma skin carcinoma) other than AML.

4. Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

5. An expected survival, in the opinion of the investigator that would not permit a
sufficient observation period for evaluating ON 01910.Na.

6. HIV positive patients.

7. Total bilirubin greater than 1.5 mg/dL not related to hemolysis or Gilbert's disease.

8. Serum creatinine greater than 1.5 mg/dL, or a calculated creatinine clearance of less
than 60 mL/min/1.73 m(2).

9. Ascites requiring active medical management including paracentesis, peripheral
bilateral edema, hyponatremia (serum sodium less than 134 meq/L.

10. Currently receiving any other investigational agents or concurrent chemotherapy,
radiotherapy, or immunotherapy.

11. Current pregnancy, unwilling to take oral contraceptives or refrain from pregnancy if
of childbearing potential or currently breastfeeding. Pregnant and nursing women are
excluded from this study.

12. Psychiatric illness/social situations that would limit the patient's ability to
tolerate and/or comply with study requirements.

13. Unable to understand the investigational nature of the study or give informed

Type of Study:


Study Design:

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

Outcome Measure:

The toxicity profile at each dose level.

Principal Investigator

Neal S Young, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)


United States: Federal Government

Study ID:




Start Date:

September 2007

Completion Date:

June 2012

Related Keywords:

  • Myelodysplastic Syndrome (MDS)
  • Myelodyplastic Syndrome (MDS)
  • Selective Mitotic Inhibitor
  • Targeted Therapy
  • Myelodysplastic Syndrome
  • MDS
  • Myelodysplastic Syndromes
  • Preleukemia



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892