Tipifarnib, Cytarabine, and Daunorubicin in Treating Older Patients With Acute Myeloid Leukemia

Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00101153
• Other study ID #: PMH-PHL-026
• Secondary ID: CDR0000405840NCI
• Status: Completed
• Phase: Phase 1
• First received: January 7, 2005
• Last updated: July 22, 2015
• Start date: April 2007

Study information

• Verified date: July 2015
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and daunorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving tipifarnib together with cytarabine and daunorubicin may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of tipifarnib when given with cytarabine and daunorubicin in treating older patients with acute myeloid leukemia.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 56 Years and older

Eligibility

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

Study Design

Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• cytarabine

• daunorubicin hydrochloride

• tipifarnib

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	London Regional Cancer Program at London Health Sciences Centre	London	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	National Cancer Institute (NCI)

Country where clinical trial is conducted

Canada, 

References & Publications (1)

Brandwein JM, Leber BF, Howson-Jan K, Schimmer AD, Schuh AC, Gupta V, Yee KW, Wright J, Moore M, MacAlpine K, Minden MD; NCI CTEP Protocol 6670. A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously un — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of tipifarnib when administered with cytarabine and daunorubicin		minimum of 30 days per treatment cycle	Yes
Primary	Toxicity		All cycles	Yes
Primary	Pharmacokinetics		Day 6	No