Malignant Solid Tumor
Conditions
Keywords
Solid Tumor
Brief summary
This is a phase 1 open label, 4 treatment, 4 sequence and 4 period crossover study in subjects with solid tumours no longer responding to, or eligible for standard therapies, and for whom there are no additional standard therapies likely to benefit the subject.
Detailed description
The study is an open-label, randomised, 4-period, 4-sequence crossover pharmacokinetic study designed to generate in vivo PK data from tablet variants with different size/geometry and dose, to correlate with their corresponding in vitro dissolution profiles. The duration of each dosing period is 7 days including the washout period. Subjects will be randomised to a treatment sequence, following a balanced Latin Squares design. Twelve subjects who meet inclusion/exclusion criteria and have provided informed consent will be randomly assigned to the treatment sequences: ABCD, BDAC, CADB, or DCBA. On Day 1 of each period, subjects will receive a single dose of either Treatment A, B, C, or D, according to the randomisation schedule. Serial blood samples for determination of olaparib in plasma will be collected for up to 72 hours. Cancer subjects with advanced solid tumours are required for this study, as pre-clinical toxicology data preclude the use of olaparib in healthy volunteers. The olaparib doses chosen will deliver exposure at or below that which has been previously demonstrated to be acceptable and tolerated in cancer subjects.
Interventions
DRUGOlaparib Treatment A
Olaparib Tablet 25 mg
DRUGOlaparib Treatment B
Olaparib Tablet 100 mg
DRUGOlaparib Treatment C
Olaparib Tablet 150 mg
DRUGOlaparib Treatment D
Olaparib Tablet 250 mg
Sponsors
Iqvia Pty Ltd
Merck Sharp & Dohme LLC
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Protocol designed to evaluate one or more interventions for treating a disease, syndrome or condition
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. 2. Female or male subject, aged \> 18 years. 3. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy for which no suitable effective standard therapy is available and in the opinion of the investigator might benefit from olaparib therapy. 4. Subjects must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * Haemoglobin ≥ 100 g/L with no blood transfusion in the past 28 days. * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. * Platelet count ≥ 100 x 109/L. * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). * Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN. * Subjects must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance =\[(140-age \[years\]) x weight (kg) x 1.2\] (x F)a serum creatinine (μmol/L) a where F=0.85 for females and F=1 for males 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 6. Subjects must have a life expectancy ≥ 16 weeks. 7. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. 8 Male subjects must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male subjects should also use a highly effective form of contraception if they are of childbearing potential. 9 Subjects must have normal GI tract anatomy and function (see
Exclusion criteria
for specifics). 10 Subjects is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| %PECmax | 0 to 72 hours | Percent prediction error for Cmax |
| %PEAUC | 0 to 72 hours | Percent prediction error for AUC |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(0-t)) calculated by linear up/log down trapezoidal summation. | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
| Area under the plasma concentration time curve from zero (pre-dose) extrapolated to infinity (AUC) | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration divided by the terminal rate constant: AUC(0-t) + Clast/λz. |
| Apparent plasma clearance (CL/F). | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
| Maximum plasma concentration (Cmax) obtained directly from the observed concentration versus time data. | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
| Apparent volume of distribution (Vz/F). | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
| Terminal rate constant (λz) estimated by log-linear least squares regression of the terminal part of the concentration-time curve. | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
| Terminal half-life (t½). Visual assessment will be used to identify the terminal linear phase of the concentration-time profile. | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
| Time to maximum plasma concentration (tmax) obtained directly from the observed concentration versus time data. | Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles. | Evaluation of the PK parameters for the different Olaparib tablet variants. |
Countries
Belgium
Outcome results
None listed