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

Sponsor

Celgene (Industry)

Overall Status

Completed

CT.gov ID

NCT00528983

Collaborator

(none)

133

Enrollment

Locations

Arms

102.8

Actual Duration (Months)

7.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes (MDS) Chronic Myelomonocytic Leukemia (CMML) Acute Myelogenous Leukemia (AML)	Drug: Subcutaneous (SC) Azacitidine Drug: Oral Azacitidine Drug: Oral Azacitidine	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

133 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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).

Actual Study Start Date :

Sep 11, 2007

Actual Primary Completion Date :

Jul 31, 2013

Actual Study Completion Date :

Apr 5, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subcutaneous (SC) Azacitidine and Oral Azacitidine Cycle 1 subjects receive SC Azacitidine for first 7 days of 28 day cycle. For Cycle 2 and beyond subjects receive Oral Azacitidine (experimental) for first 7 days of 28 day cycle.	Drug: Subcutaneous (SC) Azacitidine 75 mg/day for first 7 days of 28 day cycle for 1 cycle only. Other Names: Vidaza Drug: 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. Other Names: CC-486
Experimental: Oral Azacitidine Subjects receive Oral Azacitidine (experimental) QD or BID for the first 14 or 21 days of 28 day cycle.	Drug: 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. Other Names: CC-486

Arm

Intervention/Treatment

Experimental: Subcutaneous (SC) Azacitidine and Oral Azacitidine

Cycle 1 subjects receive SC Azacitidine for first 7 days of 28 day cycle. For Cycle 2 and beyond subjects receive Oral Azacitidine (experimental) for first 7 days of 28 day cycle.

Drug: Subcutaneous (SC) Azacitidine

75 mg/day for first 7 days of 28 day cycle for 1 cycle only.

Other Names:

Vidaza

Drug: 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.

Other Names:

CC-486

Experimental: Oral Azacitidine

Subjects receive Oral Azacitidine (experimental) QD or BID for the first 14 or 21 days of 28 day cycle.

Drug: 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.

Other Names:

CC-486

Outcome Measures

Primary Outcome Measures

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]
Maximum-tolerated dose [60 months]
Pharmacodynamic blood and bone marrow samples will be collected and evaluated. [60 months]

Secondary Outcome Measures

Efficacy assessed by evidence of response (MDS subjects) and/or hematologic improvement (MDS subjects) examined using IWG criteria. [60 months]
Biologically active dose based on safety, PK and PD data. [60 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32610-0277
2	University of Chicago Medical Center	Chicago	Illinois	United States	60637
3	Central Indiana Cancer Centers	Indianapolis	Indiana	United States	46219
4	Kansas University Medical Center	Westwood	Kansas	United States	66205
5	Johns Hopkins Hospital	Baltimore	Maryland	United States	21231-1000
6	Mayo Clinic	Rochester	Minnesota	United States	55905
7	Kansas City VA Medical Center University of Kansas Medical Center	Kansas City	Missouri	United States	64128
8	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
9	New York Oncology Hematology P.C.	Albany	New York	United States	12206
10	Institute for Translational Oncology Research IRB	Greenville	North Carolina	United States	29605
11	Gabrail Cancer Center	Canton	Ohio	United States	44718
12	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
13	Texas Oncology Cancer Care	Austin	Texas	United States	78731
14	MD Anderson Cancer Center	Houston	Texas	United States	77030
15	HOAST	San Antonio	Texas	United States	78229
16	Virginia Oncology Associates	Norfolk	Virginia	United States	23502
17	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-4417
18	Yakima Valley Memorial Hospital/ North Star Lodge	Yakima	Washington	United States	98902