Protocol Number: 07-H-0225

Title:

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

Number:

07-H-0225

Summary:

This study will determine the highest dose of the experimental drug ON 01910.Na that can safely be given to patients with the bone marrow disorder myelodysplasia (MDS) and patients with refractory AML with trisomy 8. In this disease, the bone marrow can make some blood cells, but very few of these cells are released into the blood for use in the body. ON 01910.Na is an experimental drug that inhibits a protein called cyclinD1that is important for keeping MDS cells alive. In laboratory experiments, ON 01910.Na has acted against cyclinD1, causing MDS cells to die. The study will also evaluate how the body handles ON 01910.Na, the effect of the drug on MDS and AML and its side effects.

Patients 18 to 85 years old with MDS or AML who do not have a suitable sibling donor for a marrow transplant or who are not willing to have a transplant may be eligible for this study.

Participants receive ON 01910.Na in 2-week treatment cycles, with 3 to 5 days of drug infusion through a vein followed by 9 to 11 days of observation. To find the highest safe dose of ON 01910.Na, the first person enrolled in the study is given the smallest study dose of the drug for 3 days, followed 2 weeks later with a second dose for 3 days. If these doses are found safe, the next two people receive the same dose. If these subjects do well, the next group of patients receives the next higher dose level. The dose continues to be increased in groups of 3 to 6 subjects until the fourth and highest dose level is reached. Patients who do well on the treatment may receive an additional six cycles of ON 01910.Na (3 to 5 days of infusion once every other week for 12 weeks).

Before, during and after the treatment period, patients are periodically evaluated and monitored with the following tests and procedures:

-Physical examination and review of medical and medication history.

-Blood and urine tests.

-Pregnancy test for women of childbearing age.

-Electrocardiogram (EKG) and chest X-ray.

-Bone marrow biopsy.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility 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.

INCLUSION CRITERIA:

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

OR

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

OR

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

OR

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

OR

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.

EXCLUSION CRITERIA:

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 consent.

Special Instructions:

Currently Not Provided

Keywords:

Myelodyplastic Syndrome (MDS)

Selective Mitotic Inhibitor

Targeted Therapy

Recruitment Keyword(s):

Myelodysplastic Syndrome

MDS

Condition(s):

Myelodysplastic Syndrome (MDS)

Investigational Drug(s):

ON 01910 Na

Investigational Device(s):

None

Intervention(s):

Drug: ON 01910 Na

Supporting Site:

National Heart, Lung, and Blood Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Barrett J, Saunthararajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: distinct entities or diseases linked by a common pathophysiology? Semin Hematol. 2000 Jan;37(1):15-29.

Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S, et al. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia. 1993 Apr;7(4):499-508.

de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C, Selleslag D, Ferrant A, Wijermans P, Mandelli F, Amadori S, Jehn U, Muus P, Boogaerts M, Zittoun R, Gratwohl A, Zwierzina H, Hagemeijer A, Willemze R. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood. 2001 Oct 15;98(8):2326-31.

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