Study to Evaluate Pharmacokinetics, Food Effect, Safety and Efficacy of Oral Azacitidine

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT01519011
First received: January 24, 2012
Last updated: March 10, 2014
Last verified: March 2014
  Purpose

The primary purpose of this study is to evaluate the pharmacokinetics of oral azacitidine when administered once daily as two 150-mg tablets, including the effect of food, and to evaluate the bioavailability of oral azacitidine 300-mg when administered as two 150-mg tablets relative to three 100-mg tablets.


Condition Intervention Phase
Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Acute
Drug: oral azacitidine
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Multicenter, Open-label Study to Evaluate the Pharmacokinetics and Effect of Food of a New Tablet Formulation of Oral Azacitidine, and to Evaluate the Safety and Efficacy of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • PK-(AUC) [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
    PK-Area under the plasma concentration time curve (AUC)

  • PK-(T½) [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
    PK-Terminal half-life (T½)

  • PK-(Cmax) [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
    Observed maximum concentration in plasma (Cmax)

  • PK-(Tmax) [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
    PK-Time to maximum plasma concentration (Tmax)

  • To evaluate the effect of gastric acid pH modulation, through a proton pump inhibitor, on the PK of oral azacitidine [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
    To evaluate the effect of gastric acid pH modulation, through a proton pump inhibitor, on the PK of oral azacitidine.


Secondary Outcome Measures:
  • Adverse Events [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    Number of participants with adverse events

  • Hematological response/improvement [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Proportion of subjects achieving hematological response/improvement

  • Transfusion independence [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Proportion of subjects achieving RBC transfusion independence

  • Platelet transfusion independence [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Proportion of subjects achieving platelet transfusion independence


Enrollment: 34
Study Start Date: January 2012
Estimated Study Completion Date: June 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1: A, B, C

Dose A: Single oral administration with three 100-mg tablets under fasted condition Dose B: Single oral administration with two 150-mg tablets under fasted condition.

Dose C: Single oral administration with two 150-mg tablets under fed condition.

Drug: oral azacitidine
oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).
Experimental: 2: B, C, A

Dose A: Single oral administration with three 100-mg tablets under fasted condition Dose B: Single oral administration with two 150-mg tablets under fasted condition.

Dose C: Single oral administration with two 150-mg tablets under fed condition.

Drug: oral azacitidine
oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).
Experimental: 3: C, A, B

Dose A: Single oral administration with three 100-mg tablets under fasted condition Dose B: Single oral administration with two 150-mg tablets under fasted condition.

Dose C: Single oral administration with two 150-mg tablets under fed condition.

Drug: oral azacitidine
oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).
Experimental: 4: B, A, C

Dose A: Single oral administration with three 100-mg tablets under fasted condition Dose B: Single oral administration with two 150-mg tablets under fasted condition.

Dose C: Single oral administration with two 150-mg tablets under fed condition.

Drug: oral azacitidine
oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).
Experimental: 5: A, C, B

Dose A: Single oral administration with three 100-mg tablets under fasted condition Dose B: Single oral administration with two 150-mg tablets under fasted condition.

Dose C: Single oral administration with two 150-mg tablets under fed condition.

Drug: oral azacitidine
oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).
Experimental: 6: C, B, A

Dose A: Single oral administration with three 100-mg tablets under fasted condition Dose B: Single oral administration with two 150-mg tablets under fasted condition.

Dose C: Single oral administration with two 150-mg tablets under fed condition.

Drug: oral azacitidine
oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).
Experimental: Extension
300-mg (three 100-mg tablets) once daily for 21 days of a 28-day cycle.
Drug: oral azacitidine
300-mg (three 100-mg tablets) once daily for 21 days of a 28-day cycle.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 years or older at the time of signing the informed consent document
  • Diagnosis of Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • At least 3 month life expectancy
  • Adequate organ function, defined as:

    • Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN);
    • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the ULN;
    • Serum creatinine ≤ 1.5 times the ULN;
    • Serum bicarbonate ≥ 20 mEq/L
  • Females of childbearing potential (FCBP) must:

    • Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months following the last dose of oral azacitidine; and
    • Have a negative serum or urine pregnancy test (investigator's discretion; sensitivity of at least 25 mIU/mL) at screening; and
    • Have a negative serum or urine pregnancy test (investigator's discretion; sensitivity of at least 25 mIU/mL) within 72 hours prior to Day 1 of the pharmacokinetic (PK) phase (note that the screening pregnancy test can be used as the test prior to Day 1 of the PK phase if it is performed within the 72 hour timeframe).
  • Males with partners who are FCBP must agree that they and their partners will use at least two effective contraceptive methods throughout the study and will avoid fathering a child for 3 months following the date of last oral azacitidine dosing
  • Understand and voluntarily sign an informed consent document prior to the start of any study related assessments/procedures
  • Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

  • Suspected or proven acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
  • Previous treatment with azacitidine or other demethylating agents within 21 days prior to starting study therapy or ongoing adverse events from previous treatment, regardless of the time period
  • Anticancer therapy (standard or investigational) within 21 days prior to starting study therapy or ongoing adverse events from previous treatment, regardless of the time period
  • Use of any proton pump inhibitor or any other agent that may affect gastric acid level within 28 days prior to study therapy (only applicable to Part II of the PK phase)
  • Concurrent use of erythropoiesis-stimulating agents (ESAs) and other red blood cell hematopoietic growth factors, except that the subject is on a stable dose for at least 4 weeks (28 days) prior to starting study therapy
  • Concurrent use of iron-chelating agents, except that the subject is on a stable dose for at least 8 weeks (56 days) prior to starting study therapy
  • Concurrent corticosteroid use, except for medical conditions other than Myelodysplastic Syndrome and provided the subject is on a stable or decreasing dose for ≥ 1 week prior to start study therapy
  • Pregnant or lactating females
  • Any known or suspected hypersensitivity to azacitidine or mannitol or any other ingredient used in the manufacture of oral azacitidine (see the azacitidine IB)
  • Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment)
  • Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C
  • Presence of gastrointestinal disease, malignant hepatic tumors, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs
  • Current congestive heart failure (New York Heart Association Class III-IV Appendix G), unstable angina or angina requiring surgical or medical intervention within 6 months prior to starting study therapy, myocardial infarct within 6 months prior to starting study therapy, or uncontrolled cardiac arrhythmia (defined as arrhythmia that is symptomatic or requires treatment or asymptomatic sustained ventricular tachycardia). Subjects with controlled atrial fibrillation that is asymptomatic are eligible
  • Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  • Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
  • Any condition that confounds the ability to interpret data from the study
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01519011

Locations
United States, California
Moores UCSD Cancer Center
La Jolla, California, United States, 92093
United States, Colorado
Rocky Mountain Cancer Centers
Denver, Colorado, United States, 80218
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Nevada
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States, 89169
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Ohio
University of Cincinnati Cancer Institute UC Health Barrett Cancer Center
Cincinnati, Ohio, United States, 45267
Ohio State University (The James) CCC-NCI
Columbus, Ohio, United States, 43210
United States, Tennessee
Sarah Cannon Cancer Center
Nashville, Tennessee, United States, 37203
United States, Texas
Texas Oncology, PA (North)
Dallas, Texas, United States, 75246
United States, Virginia
Virginia Oncology Associates
Norfolk, Virginia, United States, 23502
United States, Washington
Northwest Cancer Specialists - Vancouver Cancer Center
Vancouver, Washington, United States, 98684
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: Barry Skikne, M.D. Celgene Corporation
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT01519011     History of Changes
Other Study ID Numbers: AZA-MDS-004, T-AZA-006
Study First Received: January 24, 2012
Last Updated: March 10, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Celgene Corporation:
Myelodysplastic Syndromes
MDS
Chronic Myelomonocytic Leukemia
CMML
Acute Myeloid Leukemia
AML
Vidaza
oral azacitidine
aza
oral aza
pharmacokinetics
hematology
myeloid disease
PK

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014