Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Myelodysplastic Syndrome, Myelofibrosis
Conditions
Brief summary
The purpose of this study is to assess the bioequivalence of subcutaneous Vidaza® and subcutaneous Luitpold Azacitidine pharmacokinetics and to assess the comparative safety of subcutaneous Vidaza® versus subcutaneous Luitpold Azacitidine.
Detailed description
To assess the bioequivalence of Vidaza® and Luitpold Azacitidine pharmacokinetics, in terms of Maximal Concentration (Cmax), Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC 0-t), and Area Under the Curve From Time Zero Extrapolated to Infinity (AUC 0-∞), following SC administration. To assess the comparative safety of Vidaza® versus Luitpold Azacitidine during the 2 day study period.
Interventions
DRUGLuitpold Azacitidine
Subcutaneous (SC) at a dose of 75 mg/m\^2 per day on days 1 and 2 of a treatment cycle
DRUGVidaza®
Subcutaneous (SC) at a dose of 75 mg/m\^2 per day on days 1 and 2 of a treatment cycle
Sponsors
American Regent, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent obtained prior to initiation of any study-specific procedures. * Patients with one of the following - myelodysplastic syndrome of the following French-American- British (FAB) subtypes: refractory anemia (RA), RA with ringed sideroblasts (if accompanied by neutropenia, or thrombocytopenia, or requiring transfusion), RA with excess of blasts (RAEB), RAEB in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMMoL); myelofibrosis; chronic myeloid leukemia; or chronic lymphocytic leukemia who's physician feels should receive azacitidine. * Male or female patients aged at least 18 years. * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2. * Life expectancy \> or = to 3 months. * Adequate organ function, including the following: Hepatic - Total bilirubin \< or = to 1.5 x the upper limit of normal (ULN), aspartate transaminases (AST) and alanine transaminases (ALT) \< or = to 2 x ULN and Renal - Serum creatinine \< or = to 1.5 x ULN. * Female patients of child-bearing potential must have a negative pregnancy test and must be using at least one form of contraception as approved by the Investigator for 4 weeks prior to the study and 4 months after the last dose of azacitidine. * Male patients must use a form of barrier contraception approved by the investigator during the study and for 4 months after the last dose of azacitidine.
Exclusion criteria
* Hypersensitivity to azacitidine or mannitol. * Anticipated need for red blood cells (RBC) or platelet transfusion 2 days prior to or up to 2 days after treatment initiation. * Chemotherapy (excluding previous azacitidine treatment) or radiotherapy within 4 weeks of randomization (6 weeks for nitrosoureas or mitomycin C). * Significant electrophysical abnormalities in pre-trial EKG. * Present history of locally advanced or metastatic malignant disease or leukemia. * Use of recreational drugs or history of drug addiction, within the prior 6 months. * Known history of a positive hepatitis screen, including hepatitis B surface antigens or hepatitis C virus (HCV) antibodies. * Known history of HIV or syphilis. * History of clinically significant adverse events due to chemotherapy, radiotherapy or investigational agents. * Presence of an advanced malignant hepatic tumor. * Presence of an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled medical disorders. * Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patients compliance. * Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to study entry. * Pregnant or breast-feeding patients or any patient with childbearing potential not using adequate contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC 0-t) | 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing on days 1 and 2. | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; AUC 0-t is defined as AUC from time 0 to the last data point |
| Area Under the Curve From Time Zero Extrapolated to Infinity (AUC 0-∞) | 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing on days 1 and 2 | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC 0-∞ is defined as area under the concentration vs. time curve from zero to infinity. |
| Observed Maximal Concentration (Cmax) | 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing on days 1 and 2 | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
Countries
United States
Participant flow
Pre-assignment details
Thirty-eight subjects were randomized, 33 subjects were treated, and 33 subjects were analyzed for safety and pharmacokinetics (PK)
Participants by arm
| Arm | Count |
|---|---|
| Luitpold Azacitidine First, Then Vidaza® Participants first received Luitpold Azacitidine subcutaneously (SC) on Day 1. After a washout period of 24 hours, they then received Vidaza on Day 2. | 15 |
| Vidaza® First, Then Luitpold Azacitidine Participants first received Vidaza subcutaneously (SC) on Day 1. After a washout period of 24 hours, they then received Luitpold Azacitidine on Day 2. | 18 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Expiration of time for screening window | 1 | 0 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Luitpold Azacitidine First, Then Vidaza® | Vidaza® First, Then Luitpold Azacitidine |
|---|---|---|---|
| Age, Continuous | 65.7 Years STANDARD_DEVIATION 12.84 | 62.5 Years STANDARD_DEVIATION 14.66 | 68.4 Years STANDARD_DEVIATION 10.79 |
| Age, Customized | 67 Years | 65 Years | 68.5 Years |
| Body Mass Index | 26.22 kg/m^2 | 26.61 kg/m^2 | 25.73 kg/m^2 |
| Body Surface Area | 1.85 m^2 STANDARD_DEVIATION 0.201 | 1.85 m^2 | 1.89 m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 15 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 167 cm | 168 cm | 165.85 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 33 Participants | 15 Participants | 18 Participants |
| Region of Enrollment Poland | 22 participants | 10 participants | 12 participants |
| Region of Enrollment United States | 11 participants | 5 participants | 6 participants |
| Sex: Female, Male Female | 20 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 13 Participants | 8 Participants | 5 Participants |
| Weight | 74.95 kg STANDARD_DEVIATION 14.935 | 76.18 kg STANDARD_DEVIATION 19.277 | 73.92 kg STANDARD_DEVIATION 10.553 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 33 |
| other Total, other adverse events | 10 / 33 | 12 / 33 |
| serious Total, serious adverse events | 0 / 33 | 0 / 33 |
Outcome results
Primary
Area Under the Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC 0-t)
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; AUC 0-t is defined as AUC from time 0 to the last data point
Time frame: 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing on days 1 and 2.
Population: Intent to treat
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luitpold Azacitidine | Area Under the Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC 0-t) | 1065 ng*hr/mL | Geometric Coefficient of Variation 29.3 |
| Vidaza® | Area Under the Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC 0-t) | 1024 ng*hr/mL | Geometric Coefficient of Variation 43.6 |
Primary
Area Under the Curve From Time Zero Extrapolated to Infinity (AUC 0-∞)
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC 0-∞ is defined as area under the concentration vs. time curve from zero to infinity.
Time frame: 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing on days 1 and 2
Population: Intent to treat
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luitpold Azacitidine | Area Under the Curve From Time Zero Extrapolated to Infinity (AUC 0-∞) | 1097 ng*hr/mL | Geometric Coefficient of Variation 28.8 |
| Vidaza® | Area Under the Curve From Time Zero Extrapolated to Infinity (AUC 0-∞) | 1041 ng*hr/mL | Geometric Coefficient of Variation 43.1 |
Primary
Observed Maximal Concentration (Cmax)
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing on days 1 and 2
Population: Intent to treat
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luitpold Azacitidine | Observed Maximal Concentration (Cmax) | 749 ng/mL | Geometric Coefficient of Variation 35.9 |
| Vidaza® | Observed Maximal Concentration (Cmax) | 854 ng/mL | Geometric Coefficient of Variation 77.1 |