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Phase I Investigation of the Feasibility of Combining 5-azacytidine With Highdose Cytarabine (HiDAC) and Mitoxantrone Chemotherapy in a Sequential Manner for Remission Induction in High-risk Acute Myelogenous Leukemia (AML)


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), 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 in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), 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), Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

Phase I Investigation of the Feasibility of Combining 5-azacytidine With Highdose Cytarabine (HiDAC) and Mitoxantrone Chemotherapy in a Sequential Manner for Remission Induction in High-risk Acute Myelogenous Leukemia (AML)


PRIMARY OBJECTIVES:

I. To establish the recommended phase II dose of 5-azacytidine (azacitidine) when combined
with high-dose cytarabine (HiDAC) and mitoxantrone (mitoxantrone hydrochloride) chemotherapy
in high-risk acute myeloid leukemia (AML) patients.

SECONDARY OBJECTIVES:

I. To determine the complete remission (CR) rate following the use of induction chemotherapy
regimen of 5-azacytidine followed by high-dose cytarabine (HiDAC) and mitoxantrone
chemotherapy in high-risk AML patients.

II. To determine the toxicity of the combination regimen. III. To determine the disease-free
survival (DFS) and overall survival (OS) of the patient population.

IV. To determine the gene expression levels of topoisomerase II and deoxycytidine kinase in
leukemia blasts pre-treatment and following therapy with 5-azacytidine.

V. To collect specimens for banking for use in future research studies with a view to
elucidating the predictors of response to epigenetic therapies.

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

INDUCTION: Patients receive azacitidine intravenously (IV) over 10-40 minutes or
subcutaneously (SC) once daily (QD) on days 1-5, cytarabine IV over 4 hours on days 6 and
10, and mitoxantrone hydrochloride IV over 60 minutes on days 6 and 10.

CONSOLIDATION: Patients receive azacitidine IV over 10-40 minutes or SC QD on days 1-5.
Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity. Patients ineligible for allogeneic stem cell transplantation continue
on to maintenance.

MAINTENANCE: Patients receive azacitidine IV over 10-40 minutes or SC QD on days 1-5.
Courses repeat every 28 days for up to 1 year in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.


Inclusion Criteria:



- Patients must have one of the following disease characteristics:

- Therapy-related myeloid neoplasm (t-MN) age >= 18 years

- Patients must have received cytotoxic chemotherapy, radiation, or a drug
known to affect the properties of deoxyribonucleic acid (DNA) or cell
growth, prior to current diagnosis of therapy-related myeloid neoplasm
(t-MN); this broad definition is meant to include any prior therapy with
chemicals that affect DNA replication, DNA integrity, or DNA structure, or
chemicals that alter cell growth; this includes traditional cytotoxic
chemotherapy, newer immunologic agents that have been shown to have
cytotoxic activities in addition to immunosuppressive functions, and other
chemicals; note that patients with primary AML could be diagnosed with a t-
MN if morphology/cytogenetic analysis clearly indicated that the second
process is not a relapse of the original disease

- AML arising from an antecedent hematological disorder age >= 18 years

- De novo AML in patients age >= 60 years

- Relapsed and/or refractory AML >= 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment

- Male and female patients must use an effective contraceptive method during the study
and for at least 6 months after study treatment

- Patients must be at least 2 weeks from major surgery, radiation therapy,
participation in other investigational trials and must have recovered from clinically
significant toxicities of these prior treatments

- Ability to understand and willingness to sign the informed consent form

Exclusion Criteria:

- Concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified
in this protocol

- Diagnosis of acute promyelocytic leukemia (APL)

- Use of investigational agents/any anticancer therapy within 2 weeks before study
entry with the exception of hydroxyurea (note: for patients with hyperleukocytosis
[white blood cell (WBC) > 20,000/uL], hydroxyurea [and leukapheresis, if clinically
indicated] will be initiated and these patients will receive 5-azacytidine when the
WBC count has decreased to =< 20,000/uL; hydroxyurea can be overlapped with
5-azacytidine in selected cases, after consultation with the study chair; hydroxyurea
must be discontinued before the initiation of the HiDAC/mitoxantrone chemotherapy)

- Prior treatment with 5-azacytidine followed immediately by HiDAC and mitoxantrone as
proposed in this study (note: prior therapy with 5-azacytidine or decitabine or HiDAC
or mitoxantrone would be allowed-in patients with relapsed/refractory disease- unless
the prior therapy was identical to the schema/schedule proposed in this study)

- Active second cancer other than specified; active cancer refers to cancer that
requires systemic chemotherapy or biological therapy within 6 months of the study
entry; patients who have received only hormonal therapy in the neoadjuvant or
adjuvant setting in the past 6 months may participate in this study

- Have any other severe concurrent disease, or have a history of serious organ
dysfunction (e.g. uncontrolled or severe cardiovascular disease, diabetes, pulmonary
disease, infection, psychiatric illness) that may in the judgment of the treating
physician/ principal investigator place the patient at undue risk to undergo
treatment

- Pregnant or lactating patients

- Any significant concurrent illness that would, in the judgment of the treating
physician/principal investigator, compromise patient safety or compliance, or study
participation

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended phase II dose of azacitidine when combined with high-dose cytarabine and mitoxantrone hydrochloride, based on incidence of dose limiting toxicity (DLT) graded according to the National Cancer Institute Common Toxicity Criteria, version 4

Outcome Description:

DLT defined as any grade 4 or greater non-hematologic toxicity (except transient [less than 48 hours] nausea/vomiting, transient [less than 48 hours] liver function test derangements) or a grade 3 non-hematological toxicity lasting more than 7 days. Persistent bone marrow aplasia (in the absence of bone marrow involvement with disease) lasting more than 56 days would also be regarded as a DLT.

Outcome Time Frame:

56 days

Safety Issue:

Yes

Principal Investigator

Olatoyosi Odenike

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

12-0111

NCT ID:

NCT01839240

Start Date:

June 2012

Completion Date:

December 2015

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • 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 in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • 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)
  • Recurrent Adult Acute Myeloid Leukemia
  • 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

University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470