Tipifarnib in Treating Patients With Myelodysplastic Syndromes

PRIMARY OBJECTIVES:

I. To determine the toxicity profile and antitumor activity of the farnesyltransferase (FTase) inhibitor R115777 (tipifarnib) in patients with myelodysplastic syndrome (MDS) treated on a one week on/one week off schedule.

II. To determine the effect on R115777 on a one week on/one week off schedule on FTase activity, prenylation of RAS and other substrates and on downstream effects.

OUTLINE: This is a dose-escalation study.

Patients receive tipifarnib orally (PO) twice daily (BID) on weeks 1, 3, 5, and 7. Treatment repeats every 8 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Inclusion criteria

• Patients must have histologically MDS (including French-American-British [FAB] types refractory anemia [RA], refractory anemia with ringed sideroblasts [RARS], refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBT], or chronic myelomonocytic leukemia [CMMoL]); for the purpose of the study, all patients will be classified by World Health Organization (WHO) criteria

• By these criteria, FAB RA are split into:
• Pure dyserythropoietic refractory anemia (PRA)

• Refractory cytopenia with multilineage dysplasia (RCMD)
• FAB RARS is split into:

• Pure sideroblastic anemia (PSA)
• Refractory sideroblastic cytopenia with multilineage dysplasia (RSCMD)
• FAB RAEB is split into:

• RAEB I (< 10% BM blasts)
• RAEB II (10-20% BM blasts)
• Patients with CMMoL, and RAEBT by FAB classification will be included in the protocol
• Prognosis will be assessed by International Prognostic Scoring System (IPSS) criteria
• =< 2 prior therapies
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Life expectancy of greater than 12 weeks
• Bilirubin =< 1.5mg %
• Creatinine =< 1.5mg %
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Patients who have had chemotherapy or radiotherapy within 4 weeks (3 months for UCN01) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to R115777 (such as imidazoles)
• Patients eligible for bone marrow transplant (=< 60 years old), with a compatible sibling, no contraindications for transplant
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with R115777.
• Growth factors other than filgrastim (G-CSF) are excluded; patients should be off excluded growth factors for 2 weeks