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

NCT01519011 | Completed Phase 1

• 2 other identifiers: AZA-MDS-004T-AZA-006
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 8

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

Keywords

Myelodysplastic Syndromes; MDS; Chronic Myelomonocytic Leukemia; CMML; Acute Myeloid Leukemia; AML; Vidaza; oral azacitidine; aza; oral aza; pharmacokinetics; hematology; myeloid disease; PK

Outcome Measures

Primary Outcomes (5)

• PK-(AUC)

  PK-Area under the plasma concentration time curve (AUC)

  Up to 10 days

• PK-(T½)

  PK-Terminal half-life (T½)

  Up to 10 days

• PK-(Cmax)

  Observed maximum concentration in plasma (Cmax)

  Up to 10 days

• PK-(Tmax)

  PK-Time to maximum plasma concentration (Tmax)

  Up to 10 days

• To evaluate the effect of gastric acid pH modulation, through a proton pump inhibitor, on the PK of oral azacitidine

  To evaluate the effect of gastric acid pH modulation, through a proton pump inhibitor, on the PK of oral azacitidine.

  Up to 10 days

Secondary Outcomes (4)

• Adverse Events

  Up to 2 years

• Hematological response/improvement

  Up to 2 years

• Transfusion independence

  Up to 2 years

• Platelet transfusion independence

  Up to 2 years

Study Arms (7)

1: A, B, C

EXPERIMENTAL

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

2: B, C, A

EXPERIMENTAL

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

3: C, A, B

EXPERIMENTAL

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

4: B, A, C

EXPERIMENTAL

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

5: A, C, B

EXPERIMENTAL

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

6: C, B, A

EXPERIMENTAL

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

Extension

EXPERIMENTAL

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

Drug: oral azacitidine

Interventions

oral azacitidine 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).

1: A, B, C; 2: B, C, A; 3: C, A, B; 4: B, A, C; 5: A, C, B; 6: C, B, A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Celgene: lead

Study Sites (8)

Moores UCSD Cancer Center MC-0987

La Jolla, California, 92093, United States

Location

Rocky Mountain Cancer Center

Denver, Colorado, 80218-1210, United States

Location

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89169, United States

Location

University of Cincinnati Physician's Inc.

Cincinnati, Ohio, 45267-0562, United States

Location

Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

Texas Oncology

Dallas, Texas, 75230, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

Northwest Cancer Specialists, P.C.

Vancouver, Washington, 98684, United States

Location

Related Publications (2)

• 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.

  PMID: 24374798 BACKGROUND

• 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.

  PMID: 30016552 BACKGROUND

MeSH Terms

Conditions

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

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Barry Skikne, M.D.

  Celgene

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2012
• First Posted: January 26, 2012
• Study Start: February 7, 2012
• Primary Completion: December 31, 2012
• Study Completion: May 12, 2015
• Last Updated: November 12, 2019

Record last verified: 2019-11

Locations

US (8)