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Pharmacokinetics and Safety Study of Azacitidine in Cancer Patients With and Without Impaired Renal Function

Information source: Celgene Corporation
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: MDS; AML; Solid Tumors; Multiple Myeloma; Non-Hodgkin's Lymphoma; Hodgkin's Disease

Intervention: azacitidine (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Celgene Corporation

Official(s) and/or principal investigator(s):
CL Beach, PharmD, Study Director, Affiliation: Celgene Corporation

Summary

The primary study objectives were:

- to assess the dose proportionality of azacitidine pharmacokinetics (PK) after single

subcutaneous (SC) doses of the drug ranging from 25 to 100 mg/m^2 (Part 1)

- to determine the effect of renal impairment on azacitidine PK after single and multiple

(5 days) SC doses of 75mg/m^2 azacitidine (Part 2)

- to assess the safety and tolerability of azacitidine given SC in cancer patients with

normal renal function (Part 1) and in patients with varying degrees of renal impairment (Part 2).

Clinical Details

Official title: A Phase 1, Open-Label, Multi-Center, Parallel Group Study to the Pharmacokinetics and Safety of Subcutaneous Azacitidine in Adult Cancer Patients With and Without Impaired Renal Function

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label

Primary outcome:

Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity

Maximum Plasma Concentration of Azacitidine (Cmax)

Time to Maximum Plasma Concentration of Azacitidine (Tmax)

Terminal Phase Half-life of Azacitidine (t½)

Apparent Total Clearance of Azacitidine (CL/F)

Apparent Volume of Distribution of Azacitidine (Vz/F)

Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine

Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine

Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine

Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine

Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine

Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine

Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine

Number of Participants With Adverse Events (AEs)

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Diagnosis of one of the following:

- Myelodysplastic syndromes (MDS) according to the French-American-British (FAB)

classification system: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML); or

- Acute myelogenous leukemia (AML) in remission,

- Malignant solid tumor,

- Multiple myeloma (MM),

- Non-Hodgkin lymphoma (NHL), or

- Hodgkin lymphoma (HD)

- Solid tumor patients with metastatic (except hepatic) or inoperable solid tumors for

which no standard treatment existed, or had progressed or recurred following prior therapy. The lack of eligibility for therapy of higher curative potential (where an alternative therapy has been shown to prolong survival in an analogous population).

- Patients with a history of treated brain metastases should be clinically stable for

greater than 4 weeks prior to signing the informed consent form and off glucocorticoid therapy for central nervous system (CNS) edema for at least 4 weeks.

- Be capable of giving informed consent

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Have a life expectancy ≥ 3 months

- Have stable renal function for at least 2 months

- Have average calculated creatinine clearance of:

- >80 mL/min/1. 73m^2 for Cohorts 1, 2, 3, and 4

- <30 mL/min/1. 73m^2 for Cohort 5 - Severe renal impairment,

- 50-80 mL/min/1. 73m^2 for Cohort 6 - Mild renal impairment,

- 30 to <50 mL/min/1. 73m^2 for Cohort 7 - Moderate renal impairment

- Have organ and marrow function at the screening and pre-dose visits as defined below:

- Hemoglobin ≥8 g/dL,

- Absolute neutrophil count ≥0. 75 x 10^3/µL,

- Platelets ≥30 x 10^3/µL,

- Total bilirubin ≤1. 5 times the upper limit of normal (ULN),

- Aspartate aminotransferase (AST) ≤2 times the ULN, and

- Alanine transaminase (ALT) ≤2 times the ULN;

- Have a 12-lead electrocardiogram (ECG) that is not clinically significant, as

determined by the Investigator, at screening

- Have serum bicarbonate:

- ≥20 milliequivalents (mEq)/L for patients with normal renal function (cohorts 1,

2, 3 and 4),

- ≥16 mEq/L for patients with impaired renal function (cohorts 5, 6 and 7)

- Women of childbearing potential may participate, providing are not pregnant and agree

to use at least 2 effective contraceptive methods throughout the study.

- Males with a female partner of childbearing potential must agree to use at least 2

effective contraceptive methods throughout the study.

- Be a nonsmoker or must not have smoked for at least 30 days before the screening

visit and agree to abstain from smoking during study participation. Exclusion Criteria:

- Women who are pregnant or nursing.

- Had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or

mitomycin C) prior to Day 1.

- Have been treated with an investigational agent within 4 weeks prior to Day 1.

- Have ongoing clinically significant adverse event(s) due to chemotherapy,

radiotherapy or investigational agents administered more than 4 weeks prior to Day 1 as determined by the Investigator.

- Have known or suspected hypersensitivity to azacitidine or mannitol.

- Have an uncontrolled intercurrent illness including, but not limited to, ongoing or

active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia.

- Have low blood pressure (supine blood pressure <90/60 mmHg).

- Have human immunodeficiency virus (HIV), or active hepatitis virus B or C.

- Have advanced malignant hepatic tumors.

- Have end stage renal disease requiring dialysis.

- Have psychiatric illness or alcohol/chemical abuse, which could have prevented

granting of informed consent.

- Have advanced malignant hepatic tumors.

Locations and Contacts

Sutter East Bay Hospitals, Berkley, California 94704, United States

Palm Springs Research Institute, Hialeah, Florida 33012, United States

MCG Cancer Center, Augusta, Georgia 30912, United States

Joliet Oncology-Hematology Associates, Ltd., Joliet, Illinois 60435, United States

University of Kentucky-Markey Cancer Center Clinical Research Organization, Lexington, Kentucky 40536, United States

Nevada Cancer Institute, Las Vegas, Nevada 89135, United States

Montefiore Medical Center, Bronx, New York 10461, United States

Mid Dakota Clinical P.C. - Cancer Treatment and Research Center, Bismarck, North Dakota 58501, United States

Gabrail Cancer Center, Canton, Ohio 44718, United States

Pharma Resource, East Providence, Rhode Island 02915, United States

Cancer Therapy and Research Center, San Antonio, Texas 78229, United States

Additional Information

Starting date: November 2008
Last updated: August 2, 2013

Page last updated: August 23, 2015

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