Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myelogenous Leukemia

Myelodysplastic Syndromes (MDS) Clinical Trial

Official title:

A Phase 1, Open-label, Dose-Escalation Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myelogenous Leukemia (AML).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00528983
• Other study ID #: AZA PH US 2007 CL005
• Status: Completed
• Phase: Phase 1
• Start date: September 11, 2007
• Est. completion date: April 5, 2016

Study information

• Verified date: November 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether a tablet form of azacitidine that taken by mouth is safe. This Phase I study will also look at different doses and different treatment schedules in order to better understand the effects (positive and negative) of oral azacitidine on the body and on the disease MDS, AML and CMML.

Description:

Optional Extension Phase (OEP) to the AZA PH US 2007 CL 005 study which allows subjects who continue to receive oral azacitidine and have stable disease or are demonstrating clinical benefit as assessed by the Investigator, and have consented to participate, may enter the OEP of this study (at their current doses) at the start of their next cycle.

Subjects who are entering the OEP should be discontinued from Part 1 or Part 2 protocol prescribed therapy in the AZA PH US 2007 CL 005 study.

Subjects may continue to receive oral azacitidine in the OEP until they meet the criteria for study discontinuation or oral azacitidine becomes commercially available. Subjects discontinuing from the OEP will have an OEP discontinuation visit 28 days after the last dose of study drug or at study withdrawal.

Primary Objective of OEP is to evaluate long term safety of oral azacitidine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: April 5, 2016
• Est. primary completion date: July 31, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years or older.

• Diagnosis of low or Int-1 risk MDS

• Low platelet count, and/or low hemoglobin, and/or RBC transfusion-dependent and/or platelet transfusion-dependent

• ECOG Performance status 0-2

• Standard safety inclusion for serum creatinine, AST, ALT, bilirubin.

• Serum bicarbonate greater than or equal to 20 mEq/L.

• Use of acceptable birth control.

• Signed, written informed consent.

Exclusion Criteria:

• Diagnosis of acute PML.

• Previous or concurrent malignancy.

• Prior treatment with azacitidine or other demethylating agents.

• Treatment with any anticancer therapy or investigational drugs within 21 days.

• Hypersensitivity to azacitidine or mannitol.

• Presence of GI disease.

• Active, uncontrolled infection.

• Known Human Immunodeficiency Virus (HIV) or Hepatitis C, or known active viral Hepatitis B.

• Breastfeeding or Pregnant females;

• Presence of serious illness, medical condition, or other medical history which would be likely to interfere with a subject's participation in the study or with the interpretation of the results.

• Current congestive heart failure (NY Heart Association Class III-IV), unstable angina or angina requiring surgical or medical intervention within 6 months, myocardial infarct within 6 months, or uncontrolled cardiac arrhythmia.

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia (AML)
• Chronic Myelomonocytic Leukemia (CMML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Myelodysplastic Syndromes (MDS)
• Preleukemia
• Syndrome

Intervention

Drug:
• Subcutaneous (SC) Azacitidine
75 mg/day for first 7 days of 28 day cycle for 1 cycle only.
• Oral Azacitidine
Cycle 2 and beyond starting dose of 120 mg/day for first 7 days of 28 day cycle. Dose will escalate in increments of 60 mg. Following evaluation dose escalation will occur in 120 mg increments until maximum tolerated dose (MTD) is reached.
• Oral Azacitidine
Starting dose for 14 day-QD treatment schedule will be 300 mg/day. Starting dose for 14 day-BID, 21 day-QD, 21 day-BID treatment schedules will be 100 mg, 200mg, 300mg. Dose will escalate in increments of 100 mg until MTD is reached.

Locations

Country	Name	City	State
United States	New York Oncology Hematology P.C.	Albany	New York
United States	Texas Oncology Cancer Care	Austin	Texas
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Gabrail Cancer Center	Canton	Ohio
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Florida	Gainesville	Florida
United States	Institute for Translational Oncology Research IRB	Greenville	North Carolina
United States	MD Anderson Cancer Center	Houston	Texas
United States	Central Indiana Cancer Centers	Indianapolis	Indiana
United States	Kansas City VA Medical Center University of Kansas Medical Center	Kansas City	Missouri
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	HOAST	San Antonio	Texas
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Kansas University Medical Center	Westwood	Kansas
United States	Yakima Valley Memorial Hospital/ North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Country where clinical trial is conducted

United States, 

References & Publications (2)

Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ, Laille E, Giordano H, Sakoian S, Jabbour E, Kantarjian H, Skikne B. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011 Jun 20;29(18):2521-7. doi: 10.1200/JCO.2010.34.4226. Epub 2011 May 16. — View Citation

Garcia-Manero G, Gore SD, Kambhampati S, Scott B, Tefferi A, Cogle CR, Edenfield WJ, Hetzer J, Kumar K, Laille E, Shi T, MacBeth KJ, Skikne B. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016 Apr;30(4):889-96. doi: 10.1038/leu.2015.265. Epub 2015 Oct 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety evaluation as measured by monitoring AEs, dose limiting toxicities, scheduled lab assessments, vital sign measurements, ECGs, & physical exams for study duration. Adverse changes in physical signs/symptoms will be graded according to CTC AE V.3.0.		60 months
Primary	Maximum-tolerated dose		60 months
Primary	Pharmacodynamic blood and bone marrow samples will be collected and evaluated.		60 months
Secondary	Efficacy assessed by evidence of response (MDS subjects) and/or hematologic improvement (MDS subjects) examined using IWG criteria.		60 months
Secondary	Biologically active dose based on safety, PK and PD data.		60 months