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

Sponsor

Celgene (Industry)

Overall Status

Completed

CT.gov ID

NCT01519011

Collaborator

(none)

Enrollment

Locations

Arms

39.1

Actual Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic Leukemia, Myeloid, Acute	Drug: oral azacitidine Drug: oral azacitidine	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

34 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (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 OR ACUTE MYELOID LEUKEMIA

Actual Study Start Date :

Feb 7, 2012

Actual Primary Completion Date :

Dec 31, 2012

Actual Study Completion Date :

May 12, 2015

Arms and Interventions

Arm	Intervention/Treatment
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.

Outcome Measures

Primary Outcome Measures

PK-(AUC) [Up to 10 days]
PK-Area under the plasma concentration time curve (AUC)
PK-(T½) [Up to 10 days]
PK-Terminal half-life (T½)
PK-(Cmax) [Up to 10 days]
Observed maximum concentration in plasma (Cmax)
PK-(Tmax) [Up to 10 days]
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 [Up to 10 days]
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 [Up to 2 years]
Number of participants with adverse events
Hematological response/improvement [Up to 2 years]
Proportion of subjects achieving hematological response/improvement
Transfusion independence [Up to 2 years]
Proportion of subjects achieving RBC transfusion independence
Platelet transfusion independence [Up to 2 years]
Proportion of subjects achieving platelet transfusion independence

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Moores UCSD Cancer Center MC-0987	La Jolla	California	United States	92093
2	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218-1210
3	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
4	University of Cincinnati Physician's Inc.	Cincinnati	Ohio	United States	45267-0562
5	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
6	Texas Oncology	Dallas	Texas	United States	75230
7	Virginia Oncology Associates	Norfolk	Virginia	United States	23502
8	Northwest Cancer Specialists, P.C.	Vancouver	Washington	United States	98684