Brief Title
Tipifarnib and Etoposide in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
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)
Brief Summary
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
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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
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
Condition
Adult Acute Megakaryoblastic Leukemia (M7)
Intervention
tipifarnib
Study Arms / Comparison Groups
Treatment (tipifarnib, etoposide)
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
100
Start Date
March 2005
Primary Completion Date
May 2009
Eligibility 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
Gender
All
Ages
70 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Judith Karp, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00112853
Organization ID
NCI-2012-03160
Secondary IDs
J04110
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Judith Karp, Principal Investigator, Johns Hopkins University
Verification Date
January 2013