A Phase I Study Of Therapy With The Farnesyl Transferase Inhibitor R115777 (Zarnestra) Combined With Conventional Induction And Consolidation Chemotherapy For Previously Untreated Patients Over Age 55 With Acute Myeloid Leukemia (AML)
56 Years
N/A
Both
Leukemia
Trial Information
A Phase I Study Of Therapy With The Farnesyl Transferase Inhibitor R115777 (Zarnestra) Combined With Conventional Induction And Consolidation Chemotherapy For Previously Untreated Patients Over Age 55 With Acute Myeloid Leukemia (AML)
OBJECTIVES:
- Determine the maximum tolerated dose of tipifarnib when administered with cytarabine
and daunorubicin in older patients with previously untreated acute myeloid leukemia.
- Determine the toxicity of this regimen in these patients.
- Determine the pharmacokinetics of this regimen in these patients.
OUTLINE: This is a multicenter, dose-escalation study of tipifarnib.
Induction therapy (1 course): Patients receive cytarabine IV continuously on days 1-7,
daunorubicin IV on days 6-8, and oral tipifarnib twice daily on days 6-15 in the absence of
unacceptable toxicity. Patients achieving complete remission proceed to consolidation
therapy.
Consolidation therapy (1 course): After hematologic recovery, patients begin consolidation
therapy 35-60 days after the start of induction therapy. Patients receive cytarabine,
daunorubicin, and tipifarnib as in induction therapy.
Cohorts of 3-6 patients receive escalating doses of 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. A total of 10 patients are treated at the
recommended phase II dose.
Patients are followed every 3 months.
PROJECTED ACCRUAL: A total of 3-28 patients will be accrued for this study within 1.5-22
months.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Diagnosis of acute myeloid leukemia (AML)
- All subtypes, except acute promyelocytic leukemia, are allowed
- At least 20% bone marrow or peripheral blood blasts OR biopsy-confirmed
extramedullary disease
- No cerebrospinal fluid involvement
PATIENT CHARACTERISTICS:
Age
- 56 and over
Performance status
- ECOG 0-2 OR
- Karnofsky 60-100%
Life expectancy
- Not specified
Hematopoietic
- See Disease Characteristics
- WBC < 100,000/mm^3 (treatment with hydroxyurea allowed)
Hepatic
- Bilirubin ≤ 1.25 times upper limit of normal (ULN)
- AST and ALT ≤ 2.0 times ULN
Renal
- Creatinine < 1.7 mg/dL OR
- Creatinine clearance ≥ 60 mL/min
Cardiovascular
- LVEF ≥ 50%
- No symptomatic congestive heart failure
- No unstable angina pectoris
- No cardiac arrhythmia
Immunologic
- HIV negative
- No history of allergic reaction attributed to compounds of similar chemical or
biologic composition to tipifarnib or imidazole drugs (e.g., ketoconazole,
clotrimazole, or miconazole)
- No ongoing or active infection
Other
- Not pregnant
- Fertile patients must use effective contraception
- Able to swallow oral medications
- No other uncontrolled illness
- No psychiatric illness or social situation that would preclude study compliance
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Not specified
Chemotherapy
- No prior chemotherapy for AML except hydroxyurea for cytoreduction
- More than 4 weeks since prior chemotherapy except hydroxyurea (6 weeks for
nitrosoureas or mitomycin) and recovered
- At least 24 hours since prior hydroxyurea
Endocrine therapy
- No concurrent dexamethasone
Radiotherapy
- More than 4 weeks since prior radiotherapy and recovered
- No prior radiotherapy > 3,000 cGy to marrow-producing areas
Surgery
- Not specified
Other
- No other concurrent investigational agents
- No other concurrent antileukemic agents
- No concurrent treatment with any of the following:
- Ketoconazole
- Itraconazole
- Voriconazole
- Clarithromycin
- Erythromycin
- Phenytoin
- Carbamazepine
- Barbiturates
- Cyclosporine
- Pimozide
- Warfarin
- Grapefruit juice
- Simvastatin
- Lovastatin
- Atorvastatin
- No concurrent magnesium- or aluminum-containing antacids within 2 hours before or
after tipifarnib administration
Type of Study:
Interventional
Study Design:
Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose of tipifarnib when administered with cytarabine and daunorubicin
Safety Issue:
Yes
Principal Investigator
Joseph Brandwein, MD
Investigator Role:
Study Chair
Investigator Affiliation:
Princess Margaret Hospital, Canada
Authority:
United States: Food and Drug Administration
Study ID:
CDR0000405840
NCT ID:
NCT00101153
Start Date:
April 2007
Completion Date:
Related Keywords:
- Leukemia
- adult acute basophilic leukemia
- adult acute eosinophilic leukemia
- adult acute megakaryoblastic leukemia (M7)
- adult acute minimally differentiated myeloid leukemia (M0)
- adult acute monoblastic leukemia (M5a)
- adult acute monocytic leukemia (M5b)
- adult acute myeloblastic leukemia with maturation (M2)
- adult acute myeloblastic leukemia without maturation (M1)
- adult acute myeloid leukemia with 11q23 (MLL) abnormalities
- adult acute myeloid leukemia with inv(16)(p13;q22)
- adult acute myeloid leukemia with t(16;16)(p13;q22)
- adult acute myeloid leukemia with t(8;21)(q22;q22)
- adult acute myelomonocytic leukemia (M4)
- adult erythroleukemia (M6a)
- adult pure erythroid leukemia (M6b)
- untreated adult acute myeloid leukemia
- Leukemia
- Leukemia, Myeloid, Acute
- Leukemia, Myeloid
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