Tipifarnib and Bortezomib in Treating Patients With Acute Leukemia or Chronic Myelogenous Leukemia in Blast Phase

April 14, 2015 updated by: National Cancer Institute (NCI)

A Phase I Dose-Escalation Study of R115777 (Tipifarnib) Plus PS-341 (Bortezomib) in Relapsed or Refractory Acute Leukemias

This phase I trial is studying the side effects and best dose of tipifarnib and bortezomib in treating patients with acute leukemia or chronic myelogenous leukemia in blast phase. Tipifarnib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving tipifarnib together with bortezomib may kill more cancer cells.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVE:

I. Determine the dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib in patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia in blast phase.

SECONDARY OBJECTIVES:

I. Determine the effect of this regimen on farnesyltransferase and proteasome inhibition in peripheral blood mononuclear cells in these patients.

II. Determine the clinical efficacy of this regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with partial response or stable disease may continue therapy beyond 6 courses at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of bortezomib and tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Blood is collected periodically for protein expression studies. Bone marrow aspirates obtained at baseline are examined by immunohistochemistry for Ki-67 activity.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Meets 1 of the following disease-specific criteria:

    • Relapsed disease after =< 2 prior chemotherapy regimens (consolidation therapy excluded)
    • Primary-induction failure
    • Previously untreated and deemed unfit for or refusing cytotoxic chemotherapy
  • No hyperleukocytosis (leukemic blasts >= 30,000/mm^3)
  • No acute promyelocytic leukemia (M3)
  • No active CNS leukemia
  • SGOT and SGPT =< 2 times upper limit of normal (ULN)
  • Bilirubin normal
  • Creatinine =< 1.5 times ULN
  • No uncontrolled hypertension, congestive heart failure, angina pectoris, or ventricular dysrhythmias
  • Not pregnant or nursing
  • Negative pregnancy test
  • No uncontrolled disseminated intravascular coagulation

  • Fertile patients must use effective contraception

    • Hormonal contraception must have been initiated ≥ 1 month prior to study entry
  • No active graft-vs-host disease
  • No active uncontrolled infection
  • No intrinsic impaired organ function
  • No known allergy to imidazole drugs
  • No neuropathy >= grade 1
  • No known hypersensitivity to bortezomib, tipifarnib, boron, or mannitol
  • No physical or psychiatric conditions that would preclude study participation, including poorly controlled psychosis
  • At least 48 hours since prior hydroxyurea
  • No prior tipifarnib, bortezomib, or investigational proteasomal inhibitors
  • No concurrent radiotherapy, chemotherapy, or immunotherapy
  • No concurrent enzyme-inducing antiepileptic medications (e.g., phenytoin, phenobarbital, or carbamazepine)
  • ECOG performance status 0-2
  • LVEF >= 40%

  • Pathologically confirmed diagnosis of 1 of the following:

    • Acute myeloid leukemia
    • Acute lymphoblastic leukemia
    • Chronic myelogenous leukemia in blast phase

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm I
Patients will receive an infusion of bortezomib twice a week for 2 weeks. They will also receive tipifarnib by mouth twice a day for 2 weeks.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Bortezomib
Given IV
Other Names:
  • Velcade
  • MLN341
  • PS-341
  • LDP 341
  • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
  • PS341
Drug: Tipifarnib
Given orally
Other Names:
  • R115777
  • Zarnestra

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib
Time Frame: 21 days
21 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Changes in apoptotic protein expression (Bim, Bax, AKT)
Time Frame: Baseline and day 8
Baseline and day 8
Clinical efficacy (response rate) evaluated using the revised International Working Group Criteria (IWG) for AML
Time Frame: Up to 3 years
Up to 3 years
Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells
Time Frame: Day 8
Day 8
Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells
Time Frame: Day 15
Day 15

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Jeffrey Lancet, Moffitt Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2006

Primary Completion (Actual)

June 1, 2012

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

September 29, 2006

First Submitted That Met QC Criteria

September 29, 2006

First Posted (Estimate)

October 3, 2006

Study Record Updates

Last Update Posted (Estimate)

April 15, 2015

Last Update Submitted That Met QC Criteria

April 14, 2015

Last Verified

April 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00147 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • P30CA076292 (U.S. NIH Grant/Contract)
  • N01CM62208 (U.S. NIH Grant/Contract)
  • CDR0000502258
  • MCC-14796 (Other Identifier: Moffitt Cancer Center)
  • 7306 (Other Identifier: CTEP)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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