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A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Promyelocytic Leukemia (M3), Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Blastic Phase Chronic Myelogenous Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Philadelphia Chromosome Negative Chronic Myelogenous Leukemia, Previously Treated Myelodysplastic Syndromes, Primary Myelofibrosis, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies


PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of PXD101 (belinostat) when given in combination
with azacitidine (when azacitidine is utilized at a dose range where its effects on cellular
differentiation are known to be predominant) in patients with advanced hematologic cancers
or other diseases.

SECONDARY OBJECTIVES:

I. Identify any additive or synergistic effects of this regimen on pharmacodynamic
parameters, including apoptosis and re-expression of specific target genes.

II. Assess any evidence of clinical activity (complete remission, partial remission,
hematologic improvement, stable disease) of this regimen in these patients.

OUTLINE: This is a dose-escalation study of belinostat followed by a randomized study.

Patients receive azacitidine subcutaneously (SC) and belinostat intravenously (IV) over 30
minutes on days 1-5. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat 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. After the MTD is
determined, additional patients with myelodysplastic syndromes (MDS) or acute myeloid
leukemia (with trilineage dysplasia or arising from MDS) are randomized to 1 of 2 treatment
arms.

Arm I: Patients receive azacitidine SC on days 1-5.

Arm II: Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30
minutes on days 1-5.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. After receiving one course, patients randomized to arm I may
crossover to receive treatment on arm II.

For patients enrolled in the randomized portion of the study, bone marrow aspirates are
obtained at baseline, and after course 1 for correlative studies. Samples are examined by
gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and apoptosis by
RT-PCR and flow cytometry. Pharmacodynamic assays are also performed.

After completion of study treatment, patients are followed periodically for up to 2 years.


Inclusion Criteria:



- Histologically confirmed diagnosis of 1 of the following:

- Relapsed or refractory acute myeloid leukemia (AML)

- Relapsed or refractory acute promyelocytic leukemia (must have failed both
tretinoin and arsenic trioxide)

- Relapsed or refractory acute lymphoblastic leukemia

- Secondary AML, including AML arising from antecedent hematologic diseases, such
as myelodysplastic syndromes (MDS) or myeloproliferative disorders, OR
therapy-related AML

- Chronic myelogenous leukemia in accelerated or blast phase

- Advanced phases of Philadelphia chromosome-negative (Ph-) chronic
myeloproliferative disorders, as defined by ≥ 1 of the following:

- Presence of anemia (hemoglobin < 10 g/dL and/or red blood cell transfusion
dependent)

- Presence of palpable splenomegaly

- MDS, including chronic myelomonocytic leukemia

- Must have intermediate or high-risk International Prognostic Scoring System
(IPSS) scores (≥ 0.5)

- Low-risk IPSS scores allowed provided ≥ 1 of the following criteria are
met:

- Hemoglobin < 10 g/dL and/or red blood cell transfusion dependent

- Platelet count < 50,000/mm³

- Absolute neutrophil count < 1,000/mm³

- Refractory disease OR no standard therapy exists

- Evidence of AML associated with dysplasia on bone marrow histology for elderly
patients (i.e., > 60 years old) who are previously untreated and not candidates for
or unwilling to undergoing induction therapy

- No known active CNS involvement with disease

- CALGB performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)

- ALT ≤ 3 times upper limit of normal (unless due to disease)

- Creatinine ≤ 2 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to PXD101 or Azacitidine

- No history of allergic reactions to mannitol

- No history of dose-limiting toxicity during prior treatment with Azacitidine

- No concurrent uncontrolled illness including, but not limited to, the following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude compliance with
study requirements

- No marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a
QTc interval > 500 msec)

- No long QT syndrome

- No uncontrolled cardiovascular disease, including the following:

- Severe uncontrolled hypertension

- Uncontrolled congestive heart failure related to primary cardiac disease

- Uncontrolled cardiac arrhythmia

- Uncontrolled ischemic or severe valvular heart disease

- Myocardial infarction within the past 6 months

- See Disease Characteristics

- Recovered from prior therapy

- At least 2 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)

- At least 2 weeks since prior radiotherapy

- At least 4 weeks since prior investigational agents

- At least 24 hours since prior hydroxyurea

- At least 2 weeks since prior valproic acid

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No concurrent medication that may cause torsade de pointes

- No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or
biological agents

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of belinostat in combination with azacitidine

Outcome Description:

Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0.

Outcome Time Frame:

Course 1 (28 days)

Safety Issue:

Yes

Principal Investigator

Olatoyosi Odenike

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00146

NCT ID:

NCT00351975

Start Date:

June 2006

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Promyelocytic Leukemia (M3)
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Blastic Phase Chronic Myelogenous Leukemia
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Philadelphia Chromosome Negative Chronic Myelogenous Leukemia
  • Previously Treated Myelodysplastic Syndromes
  • Primary Myelofibrosis
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Primary Myelofibrosis
  • Blast Crisis
  • Neoplasms
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Promyelocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Myeloproliferative Disorders
  • Philadelphia Chromosome
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470