Clinical trial NCT01260714: Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
Adult Acute Megakaryoblastic Leukemia
Adult Acute Monoblastic Leukemia
Adult Acute Monocytic Leukemia
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With Maturation
Adult Acute Myeloid Leukemia With Minimal Differentiation
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
Adult Acute Myeloid Leukemia Without Maturation
Adult Acute Myelomonocytic Leukemia
Adult Erythroleukemia
Adult Pure Erythroid Leukemia
Alkylating Agent-Related Acute Myeloid Leukemia
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-12-15
Enrollment: 13
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 description: 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.

Eligibility criteria: Inclusion Criteria:

* Acute myeloid leukemia (AML) as defined by World Health Organization (WHO) criteria, any subtype, de novo or secondary, except acute promyelocytic leukemia (APL)
* One of the following:

  * Previously untreated, with adverse-risk cytogenetics, including any one of the following:

    * Complete or partial deletion of chromosome 7
    * Complete or partial deletion of chromosome 5
    * At least 3 numerical or structural abnormalities, other than t(15;17), t(8;21) or inv(16) or variant
    * 11q23 abnormalities
    * Inv(3) or variant such as t(3:3)
  * Previously untreated, transformed from prior myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD) other than CML
  * Persistent leukemia following one cycle of 3+7 induction therapy (cytarabine plus either daunorubicin or idarubicin), any cytogenetic risk group
* Left ventricular ejection fraction (LVEF) \> 50% based on multi gated acquisition scan (MUGA) scan or 2-dimensional (2-D) echocardiogram
* Serum creatinine =\< 1.5 x upper limit of normal (ULN)
* Serum bilirubin =\< 1.5 x ULN
* Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky \>= 60%)
* Patients with high initial white blood cell (WBC) should have the WBC reduced to below 50 x 10\^9/L with hydroxyurea, to minimize the risk of leukostasis related-complications; hydroxyurea is permitted up to 24 hours prior to starting azacitidine
* Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; men should not father a child while participating in this study
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients who have had chemotherapy, radiotherapy or investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
* Patients who have received prior radiation greater than 3000 cGy to marrow producing areas
* Patients may not be receiving any other investigational agents
* Patients with active central nervous system (CNS) leukemia; prior CNS leukemia is permitted provided the cerebrospinal fluid has cleared and there is no other evidence of active CNS leukemia
* Prior therapy for AML with decitabine, azacitidine, mitoxantrone, or etoposide
* Prior therapy with azacitidine or decitabine for pre-existing MDS
* History of allergic reactions attributed to decitabine, azacitidine, etoposide, mitoxantrone, or compounds of similar chemical or biologic composition
* Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Human immunodeficiency virus (HIV)-positive patients with cluster of differentiation (CD) counts less than 500/mm\^3 and/or a history of HIV/acquired immune deficiency syndrome (AIDS)-related complications will be excluded from the study

Primary outcomes:
measure: Maximum-tolerated dose of azacitidine that can be safely combined with mitoxantrone hydrochloride and etoposide chemotherapy
timeFrame: Up to 2 courses of treatment
Secondary outcomes:
measure: Changes in DNA methylation
timeFrame: Baseline to day 4
measure: Changes in gene expression
timeFrame: Baseline to day 4
measure: Changes in topoisomerase II levels
timeFrame: Baseline to day 4
measure: Complete response rate
timeFrame: Up to 4 years
measure: Overall survival
timeFrame: From the start of study treatment until death from any cause or last follow up, assessed up to 4 years
measure: Relapse-free survival
timeFrame: From documentation of CR or MLFS to time of disease recurrence or last follow up, assessed up to 4 years
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: University Health Network-Princess Margaret Hospital
name: Joseph Brandwein
role: PRINCIPAL_INVESTIGATOR
References: