Augmerosen Plus Fludarabine and Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00004862
First received: March 7, 2000
Last updated: January 31, 2013
Last verified: May 2002
  Purpose

Phase I trial to study the effectiveness of augmerosen plus fludarabine and cytarabine in treating patients who have refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Gene therapy such as augmerosen may make cancer cells more sensitive to chemotherapy drugs. Combining more than one drug with augmerosen may kill more cancer cells.


Condition Intervention Phase
Leukemia
Biological: filgrastim
Biological: oblimersen sodium
Drug: cytarabine
Drug: fludarabine phosphate
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of G3139 (NSC 683428) in Combination With Salvage Chemotherapy for Treatment of Refractory and Relapsed Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)

Resource links provided by NLM:


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

Enrollment: 24
Study Start Date: October 1999
Primary Completion Date: December 2001 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
Patients receive augmerosen IV continuously on days 1-10 and filgrastim (G-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover. Patients receive fludarabine IV over 30 minutes followed 3.5 hours later by cytarabine IV over 4 hours on days 6-10. Patients who achieve complete response (CR) receive a second course beginning 4 weeks after completion of the first course. Patients who achieve CR and have a matched sibling or unrelated bone marrow donor may undergo allogeneic bone marrow transplantation. Cohorts of 3-6 patients receive escalating doses of fludarabine and cytarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
Biological: filgrastim Biological: oblimersen sodium Drug: cytarabine Drug: fludarabine phosphate

Detailed Description:

OBJECTIVES:

I. Determine the maximum tolerated dose of fludarabine and cytarabine when combined with augmerosen (G3139) in patients with refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia and recommend a starting dose for phase II studies.

II. Determine the qualitative and quantitative toxic effects of this regimen in these patients with regard to organ specificity, time course, predictability, and reversibility.

III. Document the therapeutic response in patients treated with this regimen. IV. Measure bcl-2 and related antiapoptotic and proapoptotic proteins in circulating and/or marrow leukemia cells before, during, and after treatment with G3139.

V. Measure WT1 expression in leukemic blasts as a surrogate marker for minimal residual disease and correlate it with bcl-2 and related antiapoptotic and proapoptotic gene expression.

VI. Determine the time required for bcl-2 levels to recover after treatment with this regimen.

VII. Determine if TP53 mutations are present in leukemic blasts and how these mutations may affect expression of BAX, level of treatment induced apoptosis, and clinical endpoints.

VIII. Assess apoptosis in leukemic cells before, during, and after treatment with this regimen.

IX. Determine the pharmacokinetics of fludarabine and cytarabine in patients treated with this regimen.

X. Perform pharmacodynamic studies of fludarabine and cytarabine on the leukemic cells of patients prior to treatment.

OUTLINE: This is a dose-escalation study of fludarabine and cytarabine.

Patients receive augmerosen IV continuously on days 1-10 and filgrastim (G-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover. Patients receive fludarabine IV over 30 minutes followed 3.5 hours later by cytarabine IV over 4 hours on days 6-10. Patients who achieve complete response (CR) receive a second course beginning 4 weeks after completion of the first course. Patients who achieve CR and have a matched sibling or unrelated bone marrow donor may undergo allogeneic bone marrow transplantation. Cohorts of 3-6 patients receive escalating doses of fludarabine and cytarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically proven refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia
  • Marrow cellularity must be at least 20%
  • Must have diagnostic lumbar puncture and treatment with prophylactic intrathecal methotrexate within 1 week prior to entering study
  • No active CNS involvement
  • CNS involvement allowed if no residual leukemic cells are detected in CSF following intrathecal chemotherapy

PATIENT CHARACTERISTICS:

  • Age: 16 and over
  • Performance status: ECOG 0-2
  • Life expectancy: At least 4 weeks
  • Bilirubin no greater than 2 times upper limit of normal(ULN)

    • ALT and AST no greater than 2 times ULN
    • Alkaline phosphatase no greater than 2 times ULN*
    • Unless attributable to malignancy
  • Creatinine no greater than 1.5 mg/dL unless attributable to malignancy
  • No symptomatic congestive heart failure
  • No unstable angina pectoris No or cardiac arrhythmia
  • Resting cardiac ejection fraction no less than 45% unless attributable to malignancy
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception before and during study
  • No history of allergy to study medications
  • No uncontrolled concurrent illness
  • No active infection
  • No serious medical or psychiatric illness that would preclude informed consent or limit survival to less than 4 weeks

PRIOR CONCURRENT THERAPY:

  • At least 2 weeks since prior chemotherapy except hydroxyurea
  • No concurrent corticosteroids except for grade 4 toxicity unresponsive to all other agents
  • At least 4 weeks since prior radiotherapy
  • No other concurrent investigational or standard agents or therapies for leukemia
  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: NCT00004862

Locations
United States, Ohio
Arthur G. James Cancer Hospital - Ohio State University
Columbus, Ohio, United States, 43210-1240
Sponsors and Collaborators
Investigators
Study Chair: Guido Marcucci, MD Ohio State University Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00004862     History of Changes
Other Study ID Numbers: NCI-2012-01399, OSU-99H0257, OSU-9977, NCI-T99-0057, CDR0000067515
Study First Received: March 7, 2000
Last Updated: January 31, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
recurrent adult acute myeloid leukemia
recurrent adult acute lymphoblastic leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Fludarabine phosphate
Vidarabine
Fludarabine
Lenograstim
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on August 20, 2014