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

NCT ID: NCT01519011

Last Updated: 2019-11-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-07
• Study Completion Date: 2015-05-12

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.

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).

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.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).

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.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).

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.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).

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.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).

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.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

oral azacitidine 300-mg once daily for 3 total doses with two 150-mg tablets (fasted and fed) or three 100-mg tablets (fasted).

Extension

300-mg (three 100-mg tablets) once daily for 21 days of a 28-day cycle.

Group Type: EXPERIMENTAL

oral azacitidine

Intervention Type: DRUG

300-mg (three 100-mg tablets) once daily for 21 days of a 28-day cycle.

Interventions

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).

Intervention Type: DRUG

oral azacitidine

300-mg (three 100-mg tablets) once daily for 21 days of a 28-day cycle.

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Barry Skikne, M.D.

Role: STUDY_DIRECTOR

Celgene

Locations

Moores UCSD Cancer Center MC-0987

La Jolla, California, United States

Rocky Mountain Cancer Center

Denver, Colorado, United States

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States

University of Cincinnati Physician's Inc.

Cincinnati, Ohio, United States

Sarah Cannon Cancer Center

Nashville, Tennessee, United States

Texas Oncology

Dallas, Texas, United States

Virginia Oncology Associates

Norfolk, Virginia, United States

Northwest Cancer Specialists, P.C.

Vancouver, Washington, United States

Countries

United States

References

Laille E, Savona MR, Scott BL, Boyd TE, Dong Q, Skikne B. Pharmacokinetics of different formulations of oral azacitidine (CC-486) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies. J Clin Pharmacol. 2014 Jun;54(6):630-9. doi: 10.1002/jcph.251. Epub 2014 Jan 18.

Reference Type: BACKGROUND

PMID: 24374798 (View on PubMed)

Savona MR, Kolibaba K, Conkling P, Kingsley EC, Becerra C, Morris JC, Rifkin RM, Laille E, Kellerman A, Ukrainskyj SM, Dong Q, Skikne BS. Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am J Hematol. 2018 Oct;93(10):1199-1206. doi: 10.1002/ajh.25216. Epub 2018 Sep 3.

Reference Type: BACKGROUND

PMID: 30016552 (View on PubMed)

Other Identifiers

T-AZA-006

Identifier Type: OTHER

Identifier Source: secondary_id

AZA-MDS-004

Identifier Type: -

Identifier Source: org_study_id