Back to resultsSafety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myelogenous Leukemia
Primary Purpose
Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), Acute Myelogenous Leukemia (AML)
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Subcutaneous (SC) Azacitidine
Oral Azacitidine
Oral Azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes (MDS) focused on measuring Myelodysplastic Syndromes MDS, Acute Myelogenous Leukemia AML, Chronic Myelomonocytic Leukemia CMML
Eligibility Criteria
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.
Sites / Locations
- University of Florida
- University of Chicago Medical Center
- Central Indiana Cancer Centers
- Kansas University Medical Center
- Johns Hopkins Hospital
- Mayo Clinic
- Kansas City VA Medical Center University of Kansas Medical Center
- Comprehensive Cancer Centers of Nevada
- New York Oncology Hematology P.C.
- Institute for Translational Oncology Research IRB
- Gabrail Cancer Center
- Sarah Cannon Research Institute
- Texas Oncology Cancer Care
- MD Anderson Cancer Center
- HOAST
- Virginia Oncology Associates
- Fred Hutchinson Cancer Research Center
- Yakima Valley Memorial Hospital/ North Star Lodge
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Subcutaneous (SC) Azacitidine and Oral Azacitidine
Oral Azacitidine
Arm Description
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.
Subjects receive Oral Azacitidine (experimental) QD or BID for the first 14 or 21 days of 28 day cycle.
Outcomes
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.
Maximum-tolerated dose
Pharmacodynamic blood and bone marrow samples will be collected and evaluated.
Secondary Outcome Measures
Efficacy assessed by evidence of response (MDS subjects) and/or hematologic improvement (MDS subjects) examined using IWG criteria.
Biologically active dose based on safety, PK and PD data.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00528983
Brief Title
Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myelogenous Leukemia
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).
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
September 11, 2007 (Actual)
Primary Completion Date
July 31, 2013 (Actual)
Study Completion Date
April 5, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Celgene
4. Oversight
Data Monitoring Committee
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), Acute Myelogenous Leukemia (AML)
Keywords
Myelodysplastic Syndromes MDS, Acute Myelogenous Leukemia AML, Chronic Myelomonocytic Leukemia CMML
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
133 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Subcutaneous (SC) Azacitidine and Oral Azacitidine
Arm Type
Experimental
Arm Description
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.
Arm Title
Oral Azacitidine
Arm Type
Experimental
Arm Description
Subjects receive Oral Azacitidine (experimental) QD or BID for the first 14 or 21 days of 28 day cycle.
Intervention Type
Drug
Intervention Name(s)
Subcutaneous (SC) Azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
75 mg/day for first 7 days of 28 day cycle for 1 cycle only.
Intervention Type
Drug
Intervention Name(s)
Oral Azacitidine
Other Intervention Name(s)
CC-486
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Oral Azacitidine
Other Intervention Name(s)
CC-486
Intervention Description
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.
Primary Outcome Measure Information:
Title
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.
Time Frame
60 months
Title
Maximum-tolerated dose
Time Frame
60 months
Title
Pharmacodynamic blood and bone marrow samples will be collected and evaluated.
Time Frame
60 months
Secondary Outcome Measure Information:
Title
Efficacy assessed by evidence of response (MDS subjects) and/or hematologic improvement (MDS subjects) examined using IWG criteria.
Time Frame
60 months
Title
Biologically active dose based on safety, PK and PD data.
Time Frame
60 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barry Skikne, M.D., FACP; FCP (SA)
Organizational Affiliation
Celgene Corporation
Official's Role
Study Director
Facility Information:
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0277
Country
United States
Facility Name
University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Central Indiana Cancer Centers
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46219
Country
United States
Facility Name
Kansas University Medical Center
City
Westwood
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231-1000
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Kansas City VA Medical Center University of Kansas Medical Center
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64128
Country
United States
Facility Name
Comprehensive Cancer Centers of Nevada
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89169
Country
United States
Facility Name
New York Oncology Hematology P.C.
City
Albany
State/Province
New York
ZIP/Postal Code
12206
Country
United States
Facility Name
Institute for Translational Oncology Research IRB
City
Greenville
State/Province
North Carolina
ZIP/Postal Code
29605
Country
United States
Facility Name
Gabrail Cancer Center
City
Canton
State/Province
Ohio
ZIP/Postal Code
44718
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Texas Oncology Cancer Care
City
Austin
State/Province
Texas
ZIP/Postal Code
78731
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
HOAST
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Virginia Oncology Associates
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23502
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109-4417
Country
United States
Facility Name
Yakima Valley Memorial Hospital/ North Star Lodge
City
Yakima
State/Province
Washington
ZIP/Postal Code
98902
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
21576646
Citation
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.
Results Reference
background
PubMed Identifier
26442612
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.
Results Reference
background
PubMed Identifier
26296092
Citation
Laille E, Shi T, Garcia-Manero G, Cogle CR, Gore SD, Hetzer J, Kumar K, Skikne B, MacBeth KJ. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies. PLoS One. 2015 Aug 21;10(8):e0135520. doi: 10.1371/journal.pone.0135520. eCollection 2015.
Results Reference
derived
Learn more about this trial
Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myelogenous Leukemia
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