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

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

The purpose of this study is to evaluate three things. The first being whether azacitidine is absorbed in the body at the same rate or proportion for different concentrations. The second is to determine the effect renal impairment has or does not have on the absorption of azacitidine. The third is to determine if azacitidine is safe and well tolerated in patients with renal function impairment.

Inclusion Criteria:

• Diagnosis of one of the following:

  • 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)

• 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 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 and to avoid fathering a child for 6 months following the date of the last dose of study medication

• 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 signing informed consent
• Have been treated with an investigational agent within 4 weeks prior to signing the informed consent form
• Have ongoing clinically significant adverse event(s) due to chemotherapy, radiotherapy or investigational agents administered more than 4 weeks prior to signing the informed consent 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