Tipifarnib in Treating Patients With Myelodysplastic Syndromes

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00005845

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

This phase I trial studies the side effects and best dose of tipifarnib in treating patients with myelodysplastic syndromes. Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndromes Previously Treated Myelodysplastic Syndromes Refractory Anemia Refractory Anemia With Excess Blasts Refractory Anemia With Excess Blasts in Transformation Refractory Anemia With Ringed Sideroblasts Refractory Cytopenia With Multilineage Dysplasia	Drug: tipifarnib Other: laboratory biomarker analysis Other: pharmacological study	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

65 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of the Farnesyl Transferase Inhibitor R115777 (NSC #702818) in Patients With Myelodysplastic Syndrome

Study Start Date :

Jun 1, 2002

Actual Primary Completion Date :

Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (tipifarnib) Patients receive tipifarnib PO 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.	Drug: tipifarnib Given PO Other Names: R115777 Zarnestra Other: laboratory biomarker analysis Correlative studies Other: pharmacological study Correlative studies Other Names: pharmacological studies

Arm

Intervention/Treatment

Experimental: Treatment (tipifarnib)

Patients receive tipifarnib PO 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.

Drug: tipifarnib

Given PO

Other Names:

R115777

Zarnestra

Other: laboratory biomarker analysis

Correlative studies

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Outcome Measures

Primary Outcome Measures

MTD defined as the next lower dose level at which 2 patients experience dose limiting toxicity (DLT) defined as grade 3 or 4 toxicity according to the Cancer Therapy Evaluation Program Common Toxicity Criteria [Up to 8.5 years]
The final analysis will report all toxicities by grade, dose, cycle, and by cumulative dose.
Response rate [Up to 8.5 years]
Will be reported overall and by dose level.

Secondary Outcome Measures

FTase inhibition [Up to 8.5 years]
Based on the shape of the relationship (e.g. linear vs saturation vs peak), a dose response analysis will be performed to describe/summarize the relationship (correlation analysis or curve-fitting).
Accumulation of unfarnesylated lamin B1 [Up to 8.5 years]
Based on the shape of the relationship (e.g. linear vs saturation vs peak), a dose response analysis will be performed to describe/summarize the relationship (correlation analysis or curve-fitting).
Accumulation of RAS proteins [Up to 8.5 years]
Based on the shape of the relationship (e.g. linear vs saturation vs peak), a dose response analysis will be performed to describe/summarize the relationship (correlation analysis or curve-fitting).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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