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

Recurrent Adult Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00383474
• Other study ID #: NCI-2009-00147
• Secondary ID: NCI-2009-00147CD
• Status: Completed
• Phase: Phase 1
• First received: September 29, 2006
• Last updated: April 14, 2015
• Start date: August 2006
• Est. completion date: June 2012

Study information

• Verified date: April 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• 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
• Hypereosinophilic Syndrome
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Lymphoid
• Leukemia, Megakaryoblastic, Acute
• Leukemia, Monocytic, Acute
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrent Adult Acute Lymphoblastic Leukemia
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Disease
• Untreated Adult Acute Lymphoblastic Leukemia
• Untreated Adult Acute Myeloid Leukemia

Intervention

Drug:
• Bortezomib
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Tipifarnib
Given orally

Locations

Country	Name	City	State
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib		21 days	Yes
Secondary	Changes in apoptotic protein expression (Bim, Bax, AKT)		Baseline and day 8	No
Secondary	Clinical efficacy (response rate) evaluated using the revised International Working Group Criteria (IWG) for AML		Up to 3 years	No
Secondary	Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells		Day 8	No
Secondary	Farnesytransferase and proteasome inhibition in peripheral blood mononuclear cells		Day 15	No