Solid Tumours
Conditions
Keywords
oncology,, cancer,, neoplasm,, anticancer drug,, pharmacokinetics,, area under curve,, olaparib,, solid tumour,, mild renal impairment,, moderate renal impairment
Brief summary
This is a 2-part study in patients with advanced solid tumours. Part A will investigate the PK of olaparib in patients with mild or moderate renal impairment compared to patients with normal renal function; Part B will allow eligible study patients continued access to olaparib after the PK phase and will provide additional safety data.
Interventions
Part A - single 300mg oral dose olaparib (administered as 2x150mg tablets) Part B - 300mg oral dose olaparib (administered as 2x150mg tablets) bd
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
- For inclusion in the study as a patient with renal impairment, the following criterion must be met: 1. Patients must have stable renal impairment (moderate or mild), depending on creatinine clearance estimated using the Cockcroft-Gault equation (moderate 31 to 50 mL/min; mild 51 to 80 mL/min), for at least 2 months prior to the start of the study. For inclusion in the study as a patient with normal renal function, the following criterion must be met: 2. Calculated serum creatinine clearance greater than or equal to 81 mL/min (using Cockcroft-Gault equation). All patients must fulfil the following criteria: 3. Provision of written informed consent prior to any study specific procedures . 4. Patients must be greater than or equal to 18 and less than or equal to 75 years of age. 5. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists. 6. BMI between 18-30 kg/m2. 7. Normal liver and bone marrow function measured within 28 days prior to administration of IP as defined below: Haemoglobin (Hb) greater than or equal to 10.0 g/dL, with no blood transfusions in the previous 28 days. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L. White blood cells (WBC) greater than 3 x 109/L. Platelet count greater than or equal to 100 x 109/L. Total bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN) (except in the case of Gilbert's disease). Aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST), alanine aminotransferase or serum glutamic pyruvic transaminase (ALT) less than or equal to 2.5 x institutional ULN unless liver metastases are present in which case it must be less than or equal to 5x ULN. 8. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. 9. Patients must have a life expectancy greater than or equal to 12 weeks. 10. Evidence of non childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of the first treatment period in Part A. Postmenopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments. Luteinising hormone and follicle-stimulating hormone levels in the postmenopausal range for women under 50 years of age. Radiation-induced oophorectomy with last menses greater than 1 year ago. Chemotherapy-induced menopause with greater than 1 year interval since last menses Surgical sterilisation (bilateral oophorectomy or hysterectomy). 11. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. 12. Patients must be on a stable concomitant medication regimen (with the exception of electrolyte supplements), defined as no changes in medication or in dose within 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab and corticosteroids, which should be stable for at least 4 weeks prior to start of olaparib dosing.
Exclusion criteria
- Patients must not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Terminal half-life of olaparib |
| Tmax of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Time to reach maximum plasma concentration of olaparib |
| Vz/F of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Apparent volume of distribution of olaparib |
| CL/F of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Apparent plasma clearance of olaparib |
| CLR of Olaparib | Part A: Day 1, 0-12 hours and 12-24 hours post-dose | Renal clearance of olaparib, calculated as the ratio of amount of drug excreted over 24 hours to AUC0-24 |
| Cmax of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Maximum plasma drug concentration of olaparib |
| AUC of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Area under plasma concentration-time curve from zero to infinity of olaparib |
| AUC0-t of Olaparib | Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose | Area under plasma concentration-time curve from zero to the last measurable time point of olaparib |
Other
| Measure | Time frame | Description |
|---|---|---|
| Free Cmax of Olaparib | Part A: Day 1, 1 hour post-dose | Cmax of unbound olaparib; calculated by multiplying total Cmax value by estimated protein binding |
| Free AUC of Olaparib | Part A: Day 1, 1 hour post-dose | AUC of unbound olaparib; calculated by multiplying total AUC by estimated protein binding |
| CL/F of Unbound Olaparib | Part A: Day 1, 1 hour post-dose | Calculated from dose divided by free AUC |
| Protein Binding of Olaparib | Part A: Day 1, 1 hour post-dose | Degree to which olaparib binds to the proteins within blood plasma |
Countries
Belgium, Denmark, France, Netherlands, United Kingdom
Participant flow
Recruitment details
First patient enrolled: 20 Nov 2013; last completed Part A: 27 Mar 2015. Patients were enrolled at 13 sites in 5 countries. Part A assessed PK of olaparib in patients with mild/moderate renal impairment vs normal renal function; Part B provided additional safety data. Data are presented for Part A and Part B.
Pre-assignment details
56 patients were enrolled into the study, of which 12 did not fulfill the eligibility criteria. Consequently, 44 patients were assigned to treatment and received at least one dose of olaparib in Part A. Forty-three of these 44 patients were assigned treatment and received at least one dose of olaparib in Part B.
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function Patients with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation). Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing). | 15 |
| Mild Renal Impairment Patients with stable renal impairment with calculated serum creatinine clearance 51 to 80 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.
Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing). | 15 |
| Moderate Renal Impairment Patients with stable renal impairment with calculated serum creatinine clearance 31 to 50 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.
Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing). | 14 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A | Adverse Event | 0 | 1 | 0 |
| Part B | Death | 0 | 1 | 1 |
| Part B | Lack of Efficacy | 15 | 12 | 13 |
| Part B | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Normal Renal Function | Mild Renal Impairment | Moderate Renal Impairment | Total |
|---|---|---|---|---|
| Age, Continuous | 57.1 Years STANDARD_DEVIATION 9.9 | 63.5 Years STANDARD_DEVIATION 6.92 | 65.4 Years STANDARD_DEVIATION 12.86 | 61.9 Years STANDARD_DEVIATION 10.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 15 Participants | 14 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 14 Participants | 14 Participants | 43 Participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 7 Participants | 25 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 7 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 15 | 11 / 15 | 6 / 14 | 15 / 15 | 14 / 14 | 14 / 14 |
| serious Total, serious adverse events | 0 / 15 | 1 / 15 | 0 / 14 | 3 / 15 | 3 / 14 | 3 / 14 |
Outcome results
Primary
AUC0-t of Olaparib
Area under plasma concentration-time curve from zero to the last measurable time point of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | AUC0-t of Olaparib | 39.97 μg*h/mL | Geometric Coefficient of Variation 48.3 |
| Mild Renal Impairment | AUC0-t of Olaparib | 62.80 μg*h/mL | Geometric Coefficient of Variation 70.3 |
| Moderate Renal Impairment | AUC0-t of Olaparib | 69.19 μg*h/mL | Geometric Coefficient of Variation 71.6 |
Primary
AUC of Olaparib
Area under plasma concentration-time curve from zero to infinity of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | AUC of Olaparib | 43.70 μg*h/mL | Geometric Coefficient of Variation 50.1 |
| Mild Renal Impairment | AUC of Olaparib | 70.56 μg*h/mL | Geometric Coefficient of Variation 75.6 |
| Moderate Renal Impairment | AUC of Olaparib | 76.44 μg*h/mL | Geometric Coefficient of Variation 78.2 |
Comparison: Null hypothesis: There are no clinically significant differences in the PK of olaparib when administered to patients with moderate or mild renal impairment compared to patients with normal renal function.90% CI: [1.06, 1.47]
Comparison: Null hypothesis: There are no clinically significant differences in the PK of olaparib when administered to patients with moderate or mild renal impairment compared to patients with normal renal function.90% CI: [1.1, 1.89]
Primary
CL/F of Olaparib
Apparent plasma clearance of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | CL/F of Olaparib | 7.598 L/hour | Standard Deviation 3.649 |
| Mild Renal Impairment | CL/F of Olaparib | 5.285 L/hour | Standard Deviation 3.876 |
| Moderate Renal Impairment | CL/F of Olaparib | 4.788 L/hour | Standard Deviation 2.904 |
Primary
CLR of Olaparib
Renal clearance of olaparib, calculated as the ratio of amount of drug excreted over 24 hours to AUC0-24
Time frame: Part A: Day 1, 0-12 hours and 12-24 hours post-dose
Population: Subset of PK analysis set with urine samples available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | CLR of Olaparib | 1.4810 L/hour | Standard Deviation 0.4848 |
| Mild Renal Impairment | CLR of Olaparib | 0.6137 L/hour | Standard Deviation 0.2859 |
| Moderate Renal Impairment | CLR of Olaparib | 0.2989 L/hour | Standard Deviation 0.1746 |
Primary
Cmax of Olaparib
Maximum plasma drug concentration of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Cmax of Olaparib | 7.227 μg/mL | Geometric Coefficient of Variation 31 |
| Mild Renal Impairment | Cmax of Olaparib | 9.081 μg/mL | Geometric Coefficient of Variation 40.6 |
| Moderate Renal Impairment | Cmax of Olaparib | 9.977 μg/mL | Geometric Coefficient of Variation 44.2 |
Comparison: Null hypothesis: There are no clinically significant differences in the PK of olaparib when administered to patients with moderate or mild renal impairment compared to patients with normal renal function.90% CI: [1.04, 1.27]
Comparison: Null hypothesis: There are no clinically significant differences in the PK of olaparib when administered to patients with moderate or mild renal impairment compared to patients with normal renal function.90% CI: [1.06, 1.48]
Primary
t1/2 of Olaparib
Terminal half-life of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | t1/2 of Olaparib | 24.26 Hours | Standard Deviation 9.749 |
| Mild Renal Impairment | t1/2 of Olaparib | 17.45 Hours | Standard Deviation 8.035 |
| Moderate Renal Impairment | t1/2 of Olaparib | 16.09 Hours | Standard Deviation 9.384 |
Primary
Tmax of Olaparib
Time to reach maximum plasma concentration of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Tmax of Olaparib | 1.99 Hours |
| Mild Renal Impairment | Tmax of Olaparib | 1.55 Hours |
| Moderate Renal Impairment | Tmax of Olaparib | 2.00 Hours |
Primary
Vz/F of Olaparib
Apparent volume of distribution of olaparib
Time frame: Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Population: PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Vz/F of Olaparib | 283.4 L | Standard Deviation 177.9 |
| Mild Renal Impairment | Vz/F of Olaparib | 131.2 L | Standard Deviation 118.9 |
| Moderate Renal Impairment | Vz/F of Olaparib | 125.7 L | Standard Deviation 167.2 |
Other Pre-specified
CL/F of Unbound Olaparib
Calculated from dose divided by free AUC
Time frame: Part A: Day 1, 1 hour post-dose
Population: Subset of PK analysis set with protein binding blood sample available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | CL/F of Unbound Olaparib | 127.7 L/hour | Standard Deviation 92.09 |
| Mild Renal Impairment | CL/F of Unbound Olaparib | 71.41 L/hour | Standard Deviation 37.4 |
| Moderate Renal Impairment | CL/F of Unbound Olaparib | 59.95 L/hour | Standard Deviation 29.73 |
Other Pre-specified
Free AUC of Olaparib
AUC of unbound olaparib; calculated by multiplying total AUC by estimated protein binding
Time frame: Part A: Day 1, 1 hour post-dose
Population: Subset of PK analysis set with protein binding blood sample available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Free AUC of Olaparib | 2.819 μg*h/mL | Geometric Coefficient of Variation 65.6 |
| Mild Renal Impairment | Free AUC of Olaparib | 4.771 μg*h/mL | Geometric Coefficient of Variation 58.5 |
| Moderate Renal Impairment | Free AUC of Olaparib | 5.590 μg*h/mL | Geometric Coefficient of Variation 52.2 |
Other Pre-specified
Free Cmax of Olaparib
Cmax of unbound olaparib; calculated by multiplying total Cmax value by estimated protein binding
Time frame: Part A: Day 1, 1 hour post-dose
Population: Subset of PK analysis set with protein binding blood sample available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Free Cmax of Olaparib | 0.4604 μg/mL | Geometric Coefficient of Variation 60 |
| Mild Renal Impairment | Free Cmax of Olaparib | 0.5904 μg/mL | Geometric Coefficient of Variation 40.4 |
| Moderate Renal Impairment | Free Cmax of Olaparib | 0.7296 μg/mL | Geometric Coefficient of Variation 37.1 |
Other Pre-specified
Protein Binding of Olaparib
Degree to which olaparib binds to the proteins within blood plasma
Time frame: Part A: Day 1, 1 hour post-dose
Population: Subset of PK analysis set with protein binding blood sample available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.~Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Protein Binding of Olaparib | 7.593 % plasma | Standard Deviation 3.447 |
| Mild Renal Impairment | Protein Binding of Olaparib | 6.530 % plasma | Standard Deviation 2.102 |
| Moderate Renal Impairment | Protein Binding of Olaparib | 8.022 % plasma | Standard Deviation 3.996 |