Clinical trial NCT00528983: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelodysplastic Syndromes (MDS)
Chronic Myelomonocytic Leukemia (CMML)
Acute Myelogenous Leukemia (AML)
Keywords: Myelodysplastic Syndromes MDS
Acute Myelogenous Leukemia AML
Chronic Myelomonocytic Leukemia CMML
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2007-09-14
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 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.
timeFrame: 60 months
measure: Maximum-tolerated dose
timeFrame: 60 months
measure: Pharmacodynamic blood and bone marrow samples will be collected and evaluated.
timeFrame: 60 months
Secondary outcomes:
measure: Efficacy assessed by evidence of response (MDS subjects) and/or hematologic improvement (MDS subjects) examined using IWG criteria.
timeFrame: 60 months
measure: Biologically active dose based on safety, PK and PD data.
timeFrame: 60 months
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Central Indiana Cancer Centers
state: Indiana
city: Westwood
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City VA Medical Center University of Kansas Medical Center
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Albany
country: United States
facility: New York Oncology Hematology P.C.
state: New York
city: Greenville
country: United States
facility: Institute for Translational Oncology Research IRB
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology Cancer Care
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: HOAST
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Yakima
country: United States
facility: Yakima Valley Memorial Hospital/ North Star Lodge
state: Washington
Study officials:
affiliation: Celgene Corporation
name: Barry Skikne, M.D., FACP; FCP (SA)
role: STUDY_DIRECTOR
References:
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.
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.
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.