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Tipifarnib and Etoposide in Treating Older Patients With Newly Diagnosed, Previously Untreated Acute Myeloid Leukemia

Primary Purpose

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
tipifarnib
etoposide
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome

Eligibility Criteria

70 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

Criteria:

  • Pathologically confirmed newly diagnosed acute myeloid leukemia (AML)
  • Subtypes M0, M1, M2, M4-7 disease
  • No newly diagnosed acute promyelocytic leukemia (M3)
  • Any of the following diseases:
  • De novo disease
  • Secondary AML
  • Myelodysplasia (MDS)-related AML (MDS/AML)
  • Treatment-related AML
  • Previously untreated disease
  • Patients who have received prior hydroxyurea alone or non-cytotoxic therapies for MDS (e.g., thalidomide, interferon, cytokines, 5-azacytidine, or revlimid) will be eligible for this study
  • Must be considered ineligible for traditional antileukemia chemotherapy
  • No hyperleukocytosis with ≥ 30,000 blasts/uL or rapidly rising blast count with projected doubling time of =< 2 days
  • Patients may receive hydroxyurea to lower blast count to < 30,000 blasts/uL up to 24 hours before beginning tipifarnib and etoposide
  • No active CNS leukemia
  • No prior tipifarnib or etoposide
  • No concurrent radiotherapy, immunotherapy, or other chemotherapy
  • No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, or oxcarbazepine)
  • Patients may be changed to non-enzyme-inducing anticonvulsants and stabilized before starting study treatment

Inclusion Criteria:

  • ECOG performance status 0-2
  • Serum creatinine =< 2.0 mg/dL
  • SGOT and SGPT =< 3 times upper limit of normal
  • Bilirubin =< 2 mg/dL

Exclusion Criteria:

  • Active, uncontrolled infection
  • Patients with infection under active treatment and controlled with antimicrobials are eligible
  • Presence of other life-threatening illnesses
  • Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
  • Allergies to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, or econazole)

Sites / Locations

  • Blood and Marrow Transplant Group of Georgia
  • Johns Hopkins University/Sidney Kimmel Cancer Center
  • University of Michigan
  • Mayo Clinic
  • Weill Medical College of Cornell University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I

Arm II (closed to accrual as of November 2008)

Arm Description

Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.

Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.

Outcomes

Primary Outcome Measures

Complete Response
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/mcL and a platelet count of 100,000 mcL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. A CR must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the CR.

Secondary Outcome Measures

Full Information

First Posted
January 19, 2008
Last Updated
October 1, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00602771
Brief Title
Tipifarnib and Etoposide in Treating Older Patients With Newly Diagnosed, Previously Untreated Acute Myeloid Leukemia
Official Title
A Randomized Phase II Trial of Tipifarnib (R115777, ZARNESTRA, NSC #702818) in Combination With Oral Etoposide (VP-16) in Elderly Adults With Newly Diagnosed, Previously Untreated Acute Myelogenous Leukemia (AML)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
October 2011 (Actual)
Study Completion Date
October 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This randomized phase II trial is studying the side effects and how well giving tipifarnib together with etoposide works in treating older patients with newly diagnosed, previously untreated acute myeloid leukemia. Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as etoposide, 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 etoposide may kill more cancer cells.
Detailed Description
OBJECTIVES: I. To compare the efficacy and toxicity of two schedules of tipifarnib plus etoposide as induction therapy in older patients with newly diagnosed, previously untreated acute myeloid leukemia. II. To study mechanisms of leukemia cell resistance to tipifarnib in combination with etoposide. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10. ARM II: Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10. (closed to accrual as of November 2008) Treatment in both arms repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 30 days and then every 90 days thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, 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 Del(5q), 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), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
84 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.
Arm Title
Arm II (closed to accrual as of November 2008)
Arm Type
Experimental
Arm Description
Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.
Intervention Type
Drug
Intervention Name(s)
tipifarnib
Other Intervention Name(s)
R115777, Zarnestra
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
EPEG, VP-16, VP-16-213
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
Complete Response
Description
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/mcL and a platelet count of 100,000 mcL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. A CR must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the CR.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Criteria: Pathologically confirmed newly diagnosed acute myeloid leukemia (AML) Subtypes M0, M1, M2, M4-7 disease No newly diagnosed acute promyelocytic leukemia (M3) Any of the following diseases: De novo disease Secondary AML Myelodysplasia (MDS)-related AML (MDS/AML) Treatment-related AML Previously untreated disease Patients who have received prior hydroxyurea alone or non-cytotoxic therapies for MDS (e.g., thalidomide, interferon, cytokines, 5-azacytidine, or revlimid) will be eligible for this study Must be considered ineligible for traditional antileukemia chemotherapy No hyperleukocytosis with ≥ 30,000 blasts/uL or rapidly rising blast count with projected doubling time of =< 2 days Patients may receive hydroxyurea to lower blast count to < 30,000 blasts/uL up to 24 hours before beginning tipifarnib and etoposide No active CNS leukemia No prior tipifarnib or etoposide No concurrent radiotherapy, immunotherapy, or other chemotherapy No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, or oxcarbazepine) Patients may be changed to non-enzyme-inducing anticonvulsants and stabilized before starting study treatment Inclusion Criteria: ECOG performance status 0-2 Serum creatinine =< 2.0 mg/dL SGOT and SGPT =< 3 times upper limit of normal Bilirubin =< 2 mg/dL Exclusion Criteria: Active, uncontrolled infection Patients with infection under active treatment and controlled with antimicrobials are eligible Presence of other life-threatening illnesses Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol Allergies to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, or econazole)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Judith Karp
Organizational Affiliation
Johns Hopkins University/Sidney Kimmel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Blood and Marrow Transplant Group of Georgia
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Weill Medical College of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23996484
Citation
Ding H, McDonald JS, Yun S, Schneider PA, Peterson KL, Flatten KS, Loegering DA, Oberg AL, Riska SM, Huang S, Sinicrope FA, Adjei AA, Karp JE, Meng XW, Kaufmann SH. Farnesyltransferase inhibitor tipifarnib inhibits Rheb prenylation and stabilizes Bax in acute myelogenous leukemia cells. Haematologica. 2014 Jan;99(1):60-9. doi: 10.3324/haematol.2013.087734. Epub 2013 Aug 30.
Results Reference
derived
PubMed Identifier
22001391
Citation
Karp JE, Vener TI, Raponi M, Ritchie EK, Smith BD, Gore SD, Morris LE, Feldman EJ, Greer JM, Malek S, Carraway HE, Ironside V, Galkin S, Levis MJ, McDevitt MA, Roboz GR, Gocke CD, Derecho C, Palma J, Wang Y, Kaufmann SH, Wright JJ, Garret-Mayer E. Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia. Blood. 2012 Jan 5;119(1):55-63. doi: 10.1182/blood-2011-08-370825. Epub 2011 Oct 14.
Results Reference
derived

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Tipifarnib and Etoposide in Treating Older Patients With Newly Diagnosed, Previously Untreated Acute Myeloid Leukemia

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