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Tipifarnib in Treating Patients With Myelodysplastic Syndromes

Primary Purpose

Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
tipifarnib
laboratory biomarker analysis
pharmacological study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Myelomonocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (tipifarnib)

Arm Description

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.

Outcomes

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
The final analysis will report all toxicities by grade, dose, cycle, and by cumulative dose.
Response rate
Will be reported overall and by dose level.

Secondary Outcome Measures

FTase inhibition
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
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
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).

Full Information

First Posted
June 2, 2000
Last Updated
December 13, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00005845
Brief Title
Tipifarnib in Treating Patients With Myelodysplastic Syndromes
Official Title
Phase I Study of the Farnesyl Transferase Inhibitor R115777 (NSC #702818) in Patients With Myelodysplastic Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
December 2013
Overall Recruitment Status
Completed
Study Start Date
June 2002 (undefined)
Primary Completion Date
September 2009 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. 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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
65 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (tipifarnib)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
tipifarnib
Other Intervention Name(s)
R115777, Zarnestra
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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
Description
The final analysis will report all toxicities by grade, dose, cycle, and by cumulative dose.
Time Frame
Up to 8.5 years
Title
Response rate
Description
Will be reported overall and by dose level.
Time Frame
Up to 8.5 years
Secondary Outcome Measure Information:
Title
FTase inhibition
Description
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).
Time Frame
Up to 8.5 years
Title
Accumulation of unfarnesylated lamin B1
Description
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).
Time Frame
Up to 8.5 years
Title
Accumulation of RAS proteins
Description
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).
Time Frame
Up to 8.5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Razelle Kurzrock
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

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Tipifarnib in Treating Patients With Myelodysplastic Syndromes

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