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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Recurrent Disease, 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, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Bortezomib
* Other: Laboratory Biomarker Analysis
* Drug: Tipifarnib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: Bortezomib<br>* Given IV<br>* Other names: Velcade;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Tipifarnib<br>* Given orally<br>* Other names: Zarnestra;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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