Clinical trial NCT00096122: Idarubicin, Cytarabine, and Tipifarnib in Treating Patients With Newly Diagnosed Myelodysplastic Syndromes or Acute Myeloid Leukemia
Official title: PHASE I-II STUDY OF IDARUBICIN, CYTARABINE AND R115777 (TIPIFARNIB, ZARNESTRA; 702818; IND 58359), A FARNESYLTRANSFERASE INHIBITOR, IN PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIAS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: 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)
Childhood Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Refractory Anemia With Excess Blasts
Refractory Anemia With Excess Blasts in Transformation
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-11-09
Enrollment: 95
Sex: ALL
Minimum age (years): 15
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial is studying the side effects and best dose of tipifarnib when given with idarubicin and cytarabine and to see how well it works in treating patients with newly diagnosed myelodysplastic syndromes or acute myeloid leukemia. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Tipifarnib (Zarnestra) may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Giving idarubicin and cytarabine with tipifarnib may kill more cancer cells.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the tolerability of the combination of R115777 (Zarnestra™) and Idarubicin plus cytarabine by defining the DLT and MTD. (Phase I) II. To determine the efficacy of the combination of Idarubicin, cytarabine and ZARNESTRA in patients with high-risk MDS and AML. (Phase II)

OUTLINE: This is a dose-escalation study of tipifarnib. Patients are stratified according to age (\< 50 versus ≥ 50) and, in patients ≥ 50 years of age, cytogenetics (diploid versus unfavorable).

INDUCTION THERAPY:

PHASE I: Patients receive cytarabine IV continuously on days 1-3 (or 1-4), idarubicin intravenous (IV) over 1 hour on days 1-3, and oral tipifarnib twice daily on days 1-21. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 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 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive cytarabine, idarubicin, and tipifarnib as in phase I at the MTD.

Patients in both phases who respond to induction therapy proceed to consolidation maintenance therapy.

CONSOLIDATION MAINTENANCE THERAPY: Patients receive consolidation therapy comprising cytarabine IV continuously on days 1-3, idarubicin IV over 1 hour on days 1-2, and tipifarnib twice daily on days 1-14. Treatment repeats every 4-6 weeks for 5 courses in the absence of unacceptable toxicity.

Patients then begin maintenance therapy comprising oral tipifarnib twice daily on day 1-21. Treatment repeats every 4-6 weeks for 6 courses in the absence of unacceptable toxicity.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of 1) AML (WHO classification definition of \> 20% blasts), or 2) high risk MDS (defined as the presence of \> 10% blasts)
* Patients must be chemo-naïve, i.e. not have received any prior chemotherapy (except hydrea) for AML or MDS; they could have received transfusions, hematopoietic growth factors or vitamins; temporary measures such as pheresis or hydrea (0.5 to 5g daily for up to 3 days) are allowed
* ECOG PS of 0-1 at screening
* Creatinine =\< 2 mg/dl
* Total bilirubin =\< 2 mg/dL, unless increase is due to hemolysis
* Transaminases (SGPT) =\< 2.5 x ULN
* Ability to take oral medication
* Ability to understand and provide signed informed consent

Exclusion Criteria:

* Subjects with APL
* Presence of active systemic infection
* Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results
* Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, IUD, diaphragm, abstinence, or condoms by their partner) over the entire course of the study
* Known allergy to imidazole drugs (such as clotrimazole, ketoconazole, miconazole, econazole, fenticonazole, isoconazole, sulconazole, tioconazole, terconazole)

Primary outcomes:
measure: Number of Participants With Complete Response
timeFrame: 21 Day Cycle
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Jorge Cortes
role: PRINCIPAL_INVESTIGATOR
References: