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

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)

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.

Study Overview

• Status: Completed
• Conditions: 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
• Intervention / Treatment: Drug: tipifarnib; Drug: etoposide

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Blood and Marrow Transplant Group of Georgia
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Weill Medical College of Cornell University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: tipifarnib; Given orally; Other Names: R115777; Zarnestra; Drug: etoposide; Given orally; Other Names: EPEG; VP-16; VP-16-213
Experimental: Arm II (closed to accrual as of November 2008); 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.	Drug: tipifarnib; Given orally; Other Names: R115777; Zarnestra; Drug: etoposide; Given orally; Other Names: EPEG; VP-16; VP-16-213

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: January 19, 2008
• First Submitted That Met QC Criteria: January 24, 2008
• First Posted (Estimate): January 28, 2008

Study Record Updates

• Last Update Posted (Estimate): October 9, 2014
• Last Update Submitted That Met QC Criteria: October 1, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Monocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Etoposide; Etoposide phosphate; Tipifarnib
• Other Study ID Numbers: NCI-2009-00278 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA006973 (U.S. NIH Grant/Contract); CDR0000584212; J07109 (Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center); 8077 (CTEP); N01CM62204 (U.S. NIH Grant/Contract); U01CA070095 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No