Clinical Trial: Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Phase I Study of Azacitidine Combined With Mitoxantrone and Etoposide (A-NOVE) Chemotherapy for Patients' Age ≥ 60 With Poor Prognosis Acute Myeloid Leukemia (AML)

Brief Summary: This phase I trial studies the best dose of azacitidine and to see how well it works with mitoxantrone hydrochloride and etoposide in treating older patients with acute myeloid leukemia that has a lower chance of responding to treatment or higher risk of returning (poor prognosis). Drugs used in chemotherapy, such as azacitidine, mitoxantrone hydrochloride, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the highest tolerated dose of two dosing schedules of azacitidine when combined with mitoxantrone (mitoxantrone hydrochloride) and etoposide (A-NOVE) chemotherapy in poor prognosis older patients with acute myeloid leukemia (AML).

II. To evaluate the toxicity of this regimen.

SECONDARY OBJECTIVES:

I. To determine the complete response (CR) rate and using this regimen. II. To evaluate changes in topoisomerase II activity, deoxyribonucleic acid (DNA) methylation and DNA expression arrays in leukemia cells during azacitidine treatment, and to correlate these changes with responses to A-NOVE chemotherapy.

III. To evaluate relapse-free survival (RFS) and overall survival (OS) in patients receiving post-remission consolidation with A-NOVE in patients achieving CR. (OS follow-up discontinued as of 08/07/2014)

OUTLINE: This is a dose-escalation study of azacitidine.

Patients receive induction therapy comprising azacitidine subcutaneously (SC) once daily (QD) on days 1-7, mitoxantrone hydrochloride IV over 30 minutes, and etoposide IV over 1 hour on days 4-8. Patients may receive up to 2 additional courses of the same treatment as re-induction or consolidation therapy beginning 35-60 days from the start of the previous course.

After completion of study treatment, patients are followed up every 3 months.


Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: Maximum-tolerated dose of azacitidine that can be safely combined with mitoxantrone hydrochloride and etoposide chemotherapy [ Time Frame: Up to 2 courses of treatment ]

The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.


Original Primary Outcome:

  • Maximum-tolerated dose of azacitidine that can be safely combined with mitoxantrone hydrochloride and etoposide chemotherapy
  • Complete response
  • Relapse-free survival


Current Secondary Outcome:

  • Changes in DNA methylation [ Time Frame: Baseline to day 4 ]
    Nonquantitative comparisons will be made between responders and non-responders with respect to changes in DNA methylation.
  • Changes in gene expression [ Time Frame: Baseline to day 4 ]
    Nonquantitative comparisons will be made between responders and non-responders with respect to changes in gene expression.
  • Changes in topoisomerase II levels [ Time Frame: Baseline to day 4 ]
    These will be compared between responders (i.e. those achieving either CR or morphologic leukemia-free state [MLFS]) vs. non-responders (those not achieving CR/MLFS after 1-2 induction cycles), with 95% confidence intervals and 2-tailed t-tests of significance.
  • Complete response rate [ Time Frame: Up to 4 years ]
  • Overall survival [ Time Frame: From the start of study treatment until death from any cause or last follow up, assessed up to 4 years ]
  • Relapse-free survival [ Time Frame: From documentation of CR or MLFS to time of disease recurrence or last follow up, assessed up to 4 years ]


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: December 14, 2010
Date Started: December 2010
Date Completion:
Last Updated: August 18, 2015
Last Verified: June 2015