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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)


Phase 1
70 Years
N/A
Not Enrolling
Both
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

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Trial Information

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)


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.


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

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 patients who experience dose limiting toxicities (DLT), based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0

Outcome Time Frame:

Up to 28 days

Safety Issue:

Yes

Principal Investigator

Judith Karp

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03160

NCT ID:

NCT00112853

Start Date:

March 2005

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205