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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


Phase 1/Phase 2
15 Years
70 Years
Not Enrolling
Both
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

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Trial Information

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


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.


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)

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Number of Participants With Complete Response

Outcome Description:

Complete Response (CR) is required bone marrow blasts ≤5% and recovery of normal hematopoiesis with an absolute neutrophil count (ANC) of 1*10^9/L or more and platelet count of 100*10^9/L or more; and a complete response without platelets (CRp) is the same criteria as CR but with platelet counts from 20*10^9/L to less than 100*10^9/L.

Outcome Time Frame:

21 Day Cycle

Safety Issue:

No

Principal Investigator

Jorge Cortes

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02862

NCT ID:

NCT00096122

Start Date:

September 2004

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Hypereosinophilic Syndrome
  • Anemia, Aplastic

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030