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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00112853
First received: June 2, 2005
Last updated: January 8, 2013
Last verified: January 2013
  Purpose

This phase I trial is studying the side effects and best dose of tipifarnib and etoposide in treating older patients with newly diagnosed 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


Condition Intervention Phase
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)
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Drug: tipifarnib
Drug: etoposide
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Oral Etoposide in Combination With the Farnesyltransferase Inhibitor R115777 (ZARNESTRA, Tipifarnib, NSC #702818, IND #58,359) in Elderly Adults With Newly Diagnosed Acute Myelogenous Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Number of patients who experience dose limiting toxicities (DLT), based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
  • Clinical response in terms of optimal dose combination for further study [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    A response surface will be constructed using a flexible two dimensional polynomial.

  • Clinical tolerance in terms of additive or synergistic non-hematologic toxicities grade 2 or greater [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    A response surface will be constructed using a flexible two dimensional polynomial.

  • Surrogates of response in terms of cell cycle progression and apoptosis, deoxyribonucleic acid (DNA) damage, and results of in vitro model studies (using pre-post assessments). [ Time Frame: Up to day 63 ] [ Designated as safety issue: No ]
    A response surface will be constructed using a flexible two dimensional polynomial.


Enrollment: 100
Study Start Date: March 2005
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (tipifarnib, etoposide)

Patients receive oral tipifarnib twice daily on days 1-14 OR 1-21 and oral etoposide once daily on days 1-3 and 8-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a CR may receive up to 5 additional courses of therapy beyond documentation of CR.

Cohorts of 3-6 patients receive escalating doses of tipifarnib and etoposide until the 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. Up to 14 additional patients receive treatment at the MTD.

Drug: tipifarnib
Given orally
Other Names:
  • R115777
  • Zarnestra
Drug: etoposide
Given orally
Other Names:
  • EPEG
  • VP-16
  • VP-16-213

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the feasibility, tolerability, and toxicities of administering a fixed dose of R115777 in combination with escalating doses of VP-16 in elderly adults ( = 70 years) with newly diagnosed, previously untreated acute myelogenous leukemia (AML).

II. To determine the maximal tolerated dose (MTD) of R115777 + VP-16 combination, including the duration of R115777 administration, for future Phase II trials.

III. To obtain preliminary descriptive data regarding the effects of R115777 + VP-16 on cell cycle progression and apoptosis in AML marrow cells.

IV. To study mechanisms of leukemia cell resistance to R115777 in combination with etoposide.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive oral tipifarnib twice daily on days 1-14 OR 1-21 and oral etoposide once daily on days 1-3 and 8-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) may receive up to 5 additional courses of therapy beyond documentation of CR.

Cohorts of 3-6 patients receive escalating doses of tipifarnib and etoposide 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. Up to 14 additional patients receive treatment at the MTD.

After completion of study treatment, patients are followed at 1 month and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 3-100 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   70 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults age with established, pathologically confirmed diagnoses of newly diagnosed AML, including de novo and secondary AMLs but excluding newly diagnosed acute progranulocytic leukemia (APL, M3), will be considered eligible for study
  • ECOG performance status 0-2
  • Patient must be able to give informed consent
  • Serum creatinine =< 2.0 mg/dl
  • SGOT and SGPT =< 5 x upper limit normal (ULN)
  • Bilirubin =< 2 mg/dl
  • Disease-specific criteria:

    • Newly diagnosed AML, subtypes M0,1,2,4-7 but excluding M3 (APL), including myelodysplasia (MDS)-related AML (MDS/AML) and treatment-related AML
    • Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for MDS (e.g., thalidomide, interferon, cytokines, 5-azacytidine) will be eligible for this trial

Exclusion Criteria:

  • Any previous treatment with R115777 or VP-16
  • Patients receiving concomitant chemotherapy, radiation therapy or immunotherapy
  • Hyperleukocytosis with >= 30,000 blasts/uL or rapidly rising blast count with projected doubling time of =< 2 days
  • Acute progranulocytic leukemia (APL,M3)
  • Active CNS leukemia
  • Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
  • Presence of other life-threatening illness
  • Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
  • Patients on enzyme-inducing anti-convulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine); patients may be changed to non-enzyme inducing anti-convulsants and stabilized before starting study treatment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00112853

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
Sponsors and Collaborators
Investigators
Principal Investigator: Judith Karp Johns Hopkins University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00112853     History of Changes
Other Study ID Numbers: NCI-2012-03160, J04110, N01CM62204, U01CA070095
Study First Received: June 2, 2005
Last Updated: January 8, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Monocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Myeloproliferative Disorders
Etoposide
Etoposide phosphate
Tipifarnib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014