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

Primary Purpose

Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bortezomib
Laboratory Biomarker Analysis
Tipifarnib
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Basophilic Leukemia

Eligibility Criteria

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

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

Sites / Locations

  • Moffitt Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

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.

Outcomes

Primary Outcome Measures

Dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib

Secondary Outcome Measures

Changes in apoptotic protein expression (Bim, Bax, AKT)
Clinical efficacy (response rate) evaluated using the revised International Working Group Criteria (IWG) for AML
Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells
Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells

Full Information

First Posted
September 29, 2006
Last Updated
April 14, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00383474
Brief Title
Tipifarnib and Bortezomib in Treating Patients With Acute Leukemia or Chronic Myelogenous Leukemia in Blast Phase
Official Title
A Phase I Dose-Escalation Study of R115777 (Tipifarnib) Plus PS-341 (Bortezomib) in Relapsed or Refractory Acute Leukemias
Study Type
Interventional

2. Study Status

Record Verification Date
April 2013
Overall Recruitment Status
Completed
Study Start Date
August 2006 (undefined)
Primary Completion Date
June 2012 (Actual)
Study Completion Date
June 2012 (Actual)

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 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Erythroleukemia, Adult Pure Erythroid Leukemia, Blastic Phase, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Disease, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Tipifarnib
Other Intervention Name(s)
R115777, Zarnestra
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
Dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib
Time Frame
21 days
Secondary Outcome Measure Information:
Title
Changes in apoptotic protein expression (Bim, Bax, AKT)
Time Frame
Baseline and day 8
Title
Clinical efficacy (response rate) evaluated using the revised International Working Group Criteria (IWG) for AML
Time Frame
Up to 3 years
Title
Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells
Time Frame
Day 8
Title
Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells
Time Frame
Day 15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Lancet
Organizational Affiliation
Moffitt Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States

12. IPD Sharing Statement

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

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