A Phase I Dose-Escalation Study of R115777 (Tipifarnib) Plus PS-341 (Bortezomib) in Relapsed or Refractory Acute Leukemias
Overview
- Phase
- Phase 1
- Intervention
- Bortezomib
- Conditions
- Adult Acute Basophilic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 35
- Locations
- 1
- Primary Endpoint
- Dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib
- Status
- Completed
- Last Updated
- 11 years ago
Overview
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.
Investigators
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
Exclusion Criteria
- Not provided
Arms & Interventions
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.
Intervention: Bortezomib
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.
Intervention: Laboratory Biomarker Analysis
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.
Intervention: Tipifarnib
Outcomes
Primary Outcomes
Dose-limiting toxicity and maximum tolerated dose of tipifarnib and bortezomib
Time Frame: 21 days
Secondary Outcomes
- 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 15)
- Changes in apoptotic protein expression (Bim, Bax, AKT)(Baseline and day 8)