Tipifarnib in Treating Patients With Myelofibrosis and Myeloid Metaplasia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00047190

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

Phase II trial to study the effectiveness of tipifarnib in treating patients who have myelofibrosis with myeloid metaplasia. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth.

Condition or Disease	Intervention/Treatment	Phase
Essential Thrombocythemia Polycythemia Vera Primary Myelofibrosis	Drug: tipifarnib Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To evaluate the response rate in MMM patients treated with R115777. II. To evaluate the toxicity of R115777 in patients with MMM.

SECONDARY OBJECTIVES:

To evaluate the benefit of therapy with R115777 in alleviating disease-associated anemia in patients with MMM.
To evaluate the benefit of R115777 in reducing palpable splenomegaly in patients with MMM.
To evaluate the effect of R115777 on the hypercatabolic symptoms from MMM. IV. To evaluate the effect of R115777 on the pathologic increase in circulating myeloid progenitors in MMM patients through baseline measurement and measurement after the first cycle.
To correlate response/relapse with in vitro myeloid colony sensitivity to R115777 at the time of either response or relapse.
To evaluate the effect of R115777 on bone marrow histologic features of MMM including osteosclerosis, reticulin fibrosis, and angiogenesis (through serial bone marrow microvessel density grading).

OUTLINE: This is a multicenter study.

Patients receive oral tipifarnib twice daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months until disease progression and then every 6 months for up to 2 years.

PROJECTED ACCRUAL: A total of 18-35 patients will be accrued for this study within 15 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

35 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Trial of R115777 in Myelofibrosis With Myeloid Metaplasia (MMM)

Study Start Date :

Aug 1, 2002

Actual Primary Completion Date :

Apr 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive oral tipifarnib twice daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: tipifarnib Given PO Other Names: R115777 Zarnestra Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Arm I

Patients receive oral tipifarnib twice daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Drug: tipifarnib

Given PO

Other Names:

R115777

Zarnestra

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Confirmed response defined as the objective status of complete response (CR) or partial response (PR) on 2 consecutive evaluations at least 4 weeks apart [Up to 2 years]
Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Overall survival [Time from registration to death due to any cause, assessed up to 2 years]
Estimated using the method of Kaplan-Meier.
Time to progression [Time from registration to the time of progression, assessed up to 2 years]
Estimated using the method of Kaplan-Meier.
Duration of response [Date of complete response to the date progression is documented (if one has occurred) or to the date of last follow-up (for those patients who have not progressed), assessed up to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histopathologic confirmation (on bone marrow trephine and aspirate) of myelofibrosis with myeloid metaplasia by a pathologist/hematologist at the registering institution; included in the diagnosis of MMM are AMM (agnogenic myeloid metaplasia), PPMM (post-polycythemic myeloid metaplasia), and PTMM (post-thrombocythemic myeloid metaplasia); the bone marrow should show the presence of reticulin fibrosis, and the peripheral blood smear should show the presence of leukoerythroblastosis and dacrocytosis
Bone marrow showing no evidence of other conditions associated with myelofibrosis, such as metastatic carcinoma, lymphoma, myelodysplasia, hairy cell leukemia, mast cell disease, acute leukemia (including M7 type), or acute myelofibrosis
Bone marrow chromosome analysis or peripheral blood or bone marrow Fluorescent In Situ Hybridization (FISH) showing absence of chromosomal translocation t(9:22); prior demonstration is sufficient for enrollment purposes
At least one of the following:
Anemia evidenced by hemoglobin < 10 g/dL
Palpable hepato-splenomegaly
ANC ≥ 750/mm^3
PLT ≥ 100,000/mm^3
Total bilirubin (direct if total elevated) ≤ UNL
Alkaline phosphatase =< 3 x UNL (unless felt to be secondary to disease)
AST ≤ 2.5 x UNL
Creatinine =< 1.5 x UNL
Ability to understand and the willingness to sign a written informed consent document
Willingness to follow the schedule for returning to the registering P2C institution (monthly) while receiving protocol treatment
ECOG performance status 0, 1, or 2

Exclusion Criteria:

Any of the following as this regimen may be harmful to a developing fetus or nursing child:
Pregnant women
Breastfeeding women
Men or women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.)
NOTE: The effects of the agent(s) on the developing human fetus at the recommended therapeutic dose are unknown
Use of cytotoxic chemotherapy or other myelosuppressive agents within =< 2 weeks prior to study entry
Uncontrolled intercurrent illness or any co-morbid condition that would limit compliance with study requirements or with which the use of R115777 is felt to be potentially harmful; such conditions include, but are not limited to:
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia, or
Psychiatric illness/social situations
Other concurrent therapy directed at the disease (including Thalidomide) or use of erythropoietin while enrolled in this study; such agents must be discontinued at the time of or prior to study entry
Known quinolone sensitivity