Tipifarnib in Treating Patients With Myelodysplastic Syndromes

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: tipifarnib

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.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: tipifarnib; Given PO; Other Names: R115777; Zarnestra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 8.5 years
Response rate	Will be reported overall and by dose level.	Up to 8.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 8.5 years
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).	Up to 8.5 years
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).	Up to 8.5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Razelle Kurzrock, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start: June 1, 2002
• Primary Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: June 2, 2000
• First Submitted That Met QC Criteria: August 28, 2003
• First Posted (Estimate): August 29, 2003

Study Record Updates

• Last Update Posted (Estimate): December 16, 2013
• Last Update Submitted That Met QC Criteria: December 13, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia; Leukemia, Myeloid; Syndrome; Myelodysplastic Syndromes; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Anemia; Anemia, Refractory, with Excess of Blasts; Anemia, Refractory; Antineoplastic Agents; Tipifarnib
• Other Study ID Numbers: NCI-2009-01158 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA062461 (U.S. NIH Grant/Contract); 5625 (Other Identifier: CTEP); CDR0000067862; DM01-582 (Other Identifier: M D Anderson Cancer Center)