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

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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