Advanced Solid Malignancies, Cancer
Conditions
Keywords
Cancer, Tumour, Solid Malignancies
Brief summary
The objective of this study will be to investigate the safety and tolerability of olaparib tablet when given orally to Japanese patients with advanced solid malignancies. In addition, the pharmacokinetic profile, MTD (if possible) and efficacy of olaparib will be investigated.
Detailed description
MTD - maximum tolerated dose
Interventions
DRUGolaparib
tablet oral
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Subjects diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists. * Subjects who have overall good overall general condition. * Subjects who agree to hospitalisation from starting olaparib to multiple dose period at day 15. * Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status. * Subjects who have at least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI at baseline and follow up visits
Exclusion criteria
* Subjects who received any previous treatment with a PARP (poly adenosine diphosphate-ribose polymerase) inhibitor, including olaparib. * Subjects receiving inhibitors of CYP3A4 (cytochrome P450 3A4). * Subjects with symptomatic uncontrolled brain metastases. * Subjects with myelodysplastic syndrome/acute myeloid leukaemia. * Subjects with a known hypersensitivity to olaparib or any of the excipients of the product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the start dose to 30 days after the last dose of study drug | An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. This was recorded if it happend from the start dose to 30 days after the last of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax Following Single Dosing | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose | — |
| Cmax Following Multiple Dosing | Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose | — |
| Tmax Following Single Dosing | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose | — |
| Number of Participants With Dose Limiting Toxicities | From the start dose to 28 days after the first dose of study drug | Dose Limiting Toxicities were defined as study specific events that is determined to be possibly or probably related to olaparib (as determined by the investigator) and occurring during the first cycle of treatment (28 days after the first dose), irrespective of whether the toxicity resolved. |
| AUC Following Single Dosing | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose | — |
| AUC at Steady State Following Multiple Dosing | Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose | — |
| Tmax Following Multiple Dosing | Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose | — |
Countries
Japan
Participant flow
Recruitment details
First patient enrolled on 25 March 2013. Last patient enrolled on 31 October 2013. Data cut off on 31 July 2014.
Pre-assignment details
A total of 28 participants gave informed consent to join this study. Five participants were screen failures so that 23 participants were assigned and received study treatment
Participants by arm
| Arm | Count |
|---|---|
| 200 mg Bid, Dose Escalation Part Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part | 4 |
| 300 mg Bid, Dose Escalation Part Olaparib table 300 mg bid, 600 mg/day, dose escalation part | 7 |
| 300 mg Bid, Expansion Part Olaparib tablet 300 mg bid, 600 mg/day, expansion part | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 6 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 200 mg Bid, Dose Escalation Part | 300 mg Bid, Dose Escalation Part | 300 mg Bid, Expansion Part | Total |
|---|---|---|---|---|
| Age, Continuous | 42.0 Years STANDARD_DEVIATION 8.68 | 55.4 Years STANDARD_DEVIATION 8.98 | 57.3 Years STANDARD_DEVIATION 12.43 | 54.1 Years STANDARD_DEVIATION 11.94 |
| Primary tumour location Breast | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Primary tumour location Cervix | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Primary tumour location Colon | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Primary tumour location Colorectal | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Primary tumour location Gastric Antrum | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Primary tumour location Lung | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Primary tumour location Other | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Primary tumour location Ovary | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Primary tumour location Pancreas | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Primary tumour location Peritoneum | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Primary tumour location Uterus | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Sex Female | 4 Participants | 4 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Sex Male | 0 Participants | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 10 / 12 |
| serious Total, serious adverse events | 1 / 4 | 0 / 7 | 0 / 12 |
Outcome results
Primary
Number of Participants With Adverse Events
An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. This was recorded if it happend from the start dose to 30 days after the last of study drug.
Time frame: From the start dose to 30 days after the last dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | Number of Participants With Adverse Events | At least 1 AE of CTCAE Grade 3 or higher | 1 Participants |
| 200 mg Bid, Dose Escalation Part | Number of Participants With Adverse Events | At least 1 Adverse Events (AE) | 4 Participants |
| 200 mg Bid, Dose Escalation Part | Number of Participants With Adverse Events | At least 1 Serious Adverse Events (SAE) | 1 Participants |
| 300 mg Bid, Dose Escalation Part | Number of Participants With Adverse Events | At least 1 AE of CTCAE Grade 3 or higher | 3 Participants |
| 300 mg Bid, Dose Escalation Part | Number of Participants With Adverse Events | At least 1 Adverse Events (AE) | 7 Participants |
| 300 mg Bid, Dose Escalation Part | Number of Participants With Adverse Events | At least 1 Serious Adverse Events (SAE) | 0 Participants |
| 300 mg Bid, Expansion Part | Number of Participants With Adverse Events | At least 1 Adverse Events (AE) | 10 Participants |
| 300 mg Bid, Expansion Part | Number of Participants With Adverse Events | At least 1 Serious Adverse Events (SAE) | 0 Participants |
| 300 mg Bid, Expansion Part | Number of Participants With Adverse Events | At least 1 AE of CTCAE Grade 3 or higher | 1 Participants |
Secondary
AUC at Steady State Following Multiple Dosing
Time frame: Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose
Population: Dose escalation part only. Two participants (1 in 200 mg bid and 1 in 300 mg bid) had no PK data due to early discontinuation prior to Day 15.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | AUC at Steady State Following Multiple Dosing | 36.50 μg*h/mL | Geometric Coefficient of Variation 71.94 |
| 300 mg Bid, Dose Escalation Part | AUC at Steady State Following Multiple Dosing | 52.34 μg*h/mL | Geometric Coefficient of Variation 68.17 |
Secondary
AUC Following Single Dosing
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose
Population: Dose escalation part only. One participant in 200 mg bid had no AUC data because AUC was not calculable for this participant.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | AUC Following Single Dosing | 61.97 μg*h/mL | Geometric Coefficient of Variation 473.4 |
| 300 mg Bid, Dose Escalation Part | AUC Following Single Dosing | 46.21 μg*h/mL | Geometric Coefficient of Variation 64.64 |
Secondary
Cmax Following Multiple Dosing
Time frame: Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose
Population: Dose escalation part only. Two participants (1 in 200 mg bid and 1 in 300 mg bid) had no PK data due to early discontinuation prior to Day 15.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | Cmax Following Multiple Dosing | 7.668 μg/mL | Geometric Coefficient of Variation 46.93 |
| 300 mg Bid, Dose Escalation Part | Cmax Following Multiple Dosing | 8.434 μg/mL | Geometric Coefficient of Variation 35.05 |
Secondary
Cmax Following Single Dosing
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose
Population: Dose escalation part only
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | Cmax Following Single Dosing | 6.697 μg/mL | Geometric Coefficient of Variation 95.69 |
| 300 mg Bid, Dose Escalation Part | Cmax Following Single Dosing | 7.743 μg/mL | Geometric Coefficient of Variation 34.76 |
Secondary
Number of Participants With Dose Limiting Toxicities
Dose Limiting Toxicities were defined as study specific events that is determined to be possibly or probably related to olaparib (as determined by the investigator) and occurring during the first cycle of treatment (28 days after the first dose), irrespective of whether the toxicity resolved.
Time frame: From the start dose to 28 days after the first dose of study drug
Population: All patients in only the dose escalation part who received olaparib and completed the safety follow-up through the dose-limiting toxicity (DLT) evaluation period (28 days), or who experienced a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 200 mg Bid, Dose Escalation Part | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| 300 mg Bid, Dose Escalation Part | Number of Participants With Dose Limiting Toxicities | 0 Participants |
Secondary
Tmax Following Multiple Dosing
Time frame: Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose
Population: Dose escalation part only. Two participants (1 in 200 mg bid and 1 in 300 mg bid) had no PK data due to early discontinuation prior to Day 15.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | Tmax Following Multiple Dosing | 1.50 hour | Full Range 46.93 |
| 300 mg Bid, Dose Escalation Part | Tmax Following Multiple Dosing | 3.00 hour | Full Range 35.05 |
Secondary
Tmax Following Single Dosing
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose
Population: Dose escalation part only
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| 200 mg Bid, Dose Escalation Part | Tmax Following Single Dosing | 2.00 hour | Full Range 95.69 |
| 300 mg Bid, Dose Escalation Part | Tmax Following Single Dosing | 1.98 hour | Full Range 34.76 |