Solid Tumours
Conditions
Keywords
oncology, cancer, tumour, neoplasm, anticancer drug, pharmacokinetics, olaparib, anastrozole, tamoxifen, letrozole,
Brief summary
This is an open-label 2-part Phase I study in patients with advanced solid tumours. Part A of the study (mandatory) will assess the effect of olaparib on the pharmacokinetics (PK) of anastrozole, letrozole and tamoxifen and vice versa; Part B will allow patients (if eligible) continued access to olaparib after the PK phase and will provide additional safety data.
Interventions
DRUGOlaparib
2 x 150mg tablets, twice daily Day 1-5, and Day 27 onwards (Cohort 1), Day 20 onwards (Cohort 2) or Day 39 onwards (Cohort 3)
DRUGTamoxifen
60mg Tamoxifen once daily, Day 10 - Day 13; 20mg Tamoxifen once daily, Day 14 - Day 31
DRUGAnastrozole
1mg Anastrozole once daily Day 10 - Day 24
DRUGLetrozole
2.5mg Letrozole once daily Day 10 - Day 43
PROCEDUREPharmacokinetic sampling
Blood sampling over 12-24 hour period for pharmacokinetic analysis
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent prior to any study specific procedures 2. Male or female aged ≥18 years 3. Histological or cytological confirmation of any malignant solid tumour in an advanced or metastatic setting who meet one of the criteria below: * Patients should be resistant or refractory to standard treatment if such treatment exists OR * Patients for which no suitable effective standard therapy exists OR * Patients with advanced breast cancer for whom anastrozole, letrozole or tamoxifen are indicated may also enter the study (postmenopausal breast cancer patients will be eligible for any of the cohorts; however, premenopausal breast cancer patients will be eligible for the tamoxifen cohort only). 4. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * Haemoglobin (Hb) ≥10.0 g/dL with no blood transfusions 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) (except in the case of Gilbert's disease) * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 x institutional ULN unless liver metastases are present, in which case they must be ≤5x ULN * Serum creatinine ≤1.5 x institutional ULN 5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 6. Patients must have a life expectancy ≥16 weeks 7. 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 Part A. Postmenopausal is defined as: * Age ≥ 60 years * Age \<60 years and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment * Luteinising hormone (LH), follicle stimulating hormone (FSH) and plasma oestradiol levels in the postmenopausal range for women under 60 years * Radiation-induced oophorectomy with last menses \>1 year ago * Or surgical sterilisation (bilateral oophorectomy or hysterectomy) 8. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment, and scheduled visits and examinations 9. Patients must be on stable concomitant medication regimen (with the exception of electrolyte supplements), defined as no change in medication or dose within 2 weeks prior to start of study treatment.
Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents, and/or staff at the study site) 2. Previous enrolment in the present study 3. Exposure to an investigational product (IP) (including PARP inhibitor) within 30 days or 5 half lives (whichever is the longer) prior to enrolment 4. Prior chemotherapy within 3 weeks of study entry 5. Prior radiotherapy within 2 weeks of study entry 6. If prior endocrine treatment is given, adequate washout period is required: at least 2 weeks for anastrozole, at least 4 weeks for letrozole and at least 10 weeks for tamoxifen 7. Resting ECG with QTc \>470 msec detected on 2 or more time points within a 24 hour period, or family history of long QT syndrome. If ECG demonstrates QTc \>470 msec, patient will be eligible only if repeat ECG demonstrates QTc \<470 msec. 8. Patients who are receiving inhibitors or inducers of CYP3A4 unless washed out prior to start of study treatment. 9. Persistent toxicities (Common Toxicity Criteria for Adverse Events \[CTCAE\] grade ≥2) caused by previous cancer therapy, excluding alopecia and/or CTCAE grade 2 peripheral neuropathy 10. Patients with myelodysplastic syndrome/acute myeloid leukaemia 11. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery 12. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled seizures or active uncontrolled infection. 13. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with absorption of the study medication 14. Patients who have gastric, gastro-oesophageal, or oesophageal cancer 15. Pregnant or breastfeeding women 16. Patients with known active Hepatitis B or C, or human immunodeficiency virus (HIV). 17. Patients with a known hypersensitivity to olaparib (all cohorts), tamoxifen (Cohort 1) anastrozole (Cohort 2), letrozole (Cohort 3), or any of the excipients of these products.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31 | Tamoxifen, N-desmethyl tamoxifen (N-DMT) and endoxifen Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios |
| Effect of Tamoxifen on Exposure to Olaparib - Cmax ss | Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 31 | Olaparib Cmax ss in the presence and absence of co-administered tamoxifen, and associated Cmax ss treatment ratios |
| Effect of Olaparib on Exposure to Anastrozole - Cmax ss | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24 | Anastrozole maximum plasma concentration at steady state (Cmax ss) in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios |
| Effect of Anastrozole on Exposure to Olaparib - Cmax ss | Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 24 | Olaparib Cmax ss in the presence and absence of co-administered anastrozole, and associated Cmax ss treatment ratios |
| Effect of Olaparib on Exposure to Letrozole - Cmax ss | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43 | Letrozole Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios |
| Effect of Letrozole on Exposure to Olaparib - Cmax ss | Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 43 | Olaparib Cmax ss in the presence and absence of co-administered letrozole, and associated Cmax ss treatment ratios |
| Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31 | Tamoxifen, N-DMT and endoxifen AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios |
| Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ | Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 31 | Olaparib AUC0-τ, in the presence and absence of co-administered tamoxifen, and associated AUC0-τ treatment ratios |
| Effect of Olaparib on Exposure to Anastrozole - AUC0-τ | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24 | Anastrozole Area under plasma concentration-time curve over the dosing interval at steady state (AUC0-τ), in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios |
| Effect of Anastrozole on Exposure to Olaparib - AUC0-τ | Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 24 | Olaparib AUC0-τ, in the presence and absence of co-administered anastrozole, and associated AUC0-τ treatment ratios |
| Effect of Olaparib on Exposure to Letrozole - AUC0-τ | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43 | Letrozole AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios |
| Effect of Letrozole on Exposure to Olaparib - AUC0-τ | Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 43 | Olaparib AUC0-τ, in the presence and absence of co-administered letrozole, and associated AUC0-τ treatment ratios |
Countries
Belgium, Denmark, France, Netherlands, United Kingdom
Participant flow
Recruitment details
First patient enrolled: 01 Sep 2014; last completed Part A: 28 Apr 2015. Last patient completed Part B: 27 Apr 2016. Part A assessed olaparib's effect on the pharmacokinetic (PK) parameters of anastrozole, letrozole and tamoxifen and vice versa; in Part B eligible patients received olaparib providing further safety data. Target accrual was met.
Pre-assignment details
79 patients were assigned to study treatment and received at least 1 dose of olaparib in Part A; 18 patients did not fulfil eligibility criteria. Part A of the study consisted of 3 treatment periods preceded by a screening period. There was a 4-day washout between the first two treatment periods.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Tamoxifen In Part A, patients in Cohort 1 received olaparib 300 mg twice daily (bd) for 5 days in Treatment Period 1; tamoxifen 60 mg once daily (od) (loading dose) for 4 days then 20 mg od for 13 days (maintenance dose) in Treatment Period 2; and tamoxifen 20 mg od concomitantly with olaparib 300 mg bd for 5 days in Treatment Period 3. | 30 |
| Cohort 2 - Anastrozole In Part A, patients in Cohort 2 received olaparib 300 mg bd for 5 days in Treatment Period 1; anastrozole 1 mg od for 10 days in Treatment Period 2; and anastrozole 1 mg od concomitantly with olaparib 300 mg bd for 5 days in Treatment Period 3. | 23 |
| Cohort 3 - Letrozole In Part A, patients in Cohort 3 received olaparib 300 mg bd for 5 days in Treatment Period 1; letrozole 2.5 mg od for 29 days in Treatment Period 2; and letrozole 2.5 mg od concomitantly with olaparib 300 mg bd for 5 days in Treatment Period 3. | 26 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A | Adverse Event | 0 | 1 | 1 | 0 |
| Part A | Condition under investigation worsened | 2 | 0 | 2 | 0 |
| Part A | Death | 0 | 1 | 0 | 0 |
| Part B | Adverse Event | 0 | 0 | 0 | 2 |
| Part B | Adverse event + disease progression | 0 | 0 | 0 | 1 |
| Part B | Complete response | 0 | 0 | 0 | 1 |
| Part B | Condition under investigation worsened | 0 | 0 | 0 | 39 |
| Part B | Death | 0 | 0 | 0 | 1 |
| Part B | Disease progression | 0 | 0 | 0 | 4 |
| Part B | Lack of therapeutic response | 0 | 0 | 0 | 12 |
| Part B | Patient decision | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Cohort 1 - Tamoxifen | Cohort 2 - Anastrozole | Cohort 3 - Letrozole | Total |
|---|---|---|---|---|
| Age, Continuous | 52.6 years STANDARD_DEVIATION 11.32 | 59.4 years STANDARD_DEVIATION 11.68 | 64.0 years STANDARD_DEVIATION 7.79 | 58.3 years STANDARD_DEVIATION 11.37 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 23 Participants | 26 Participants | 79 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 2 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 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 27 Participants | 22 Participants | 24 Participants | 73 Participants |
| Sex: Female, Male Female | 26 Participants | 18 Participants | 20 Participants | 64 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 6 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 1 / 23 | 1 / 26 | 1 / 69 |
| other Total, other adverse events | 27 / 30 | 20 / 23 | 20 / 26 | 66 / 69 |
| serious Total, serious adverse events | 2 / 30 | 0 / 23 | 0 / 26 | 22 / 69 |
Outcome results
Primary
Effect of Anastrozole on Exposure to Olaparib - AUC0-τ
Olaparib AUC0-τ, in the presence and absence of co-administered anastrozole, and associated AUC0-τ treatment ratios
Time frame: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 24
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Anastrozole on Exposure to Olaparib - AUC0-τ | 55.49 mcg*h/mL | Geometric Coefficient of Variation 53.8 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Anastrozole on Exposure to Olaparib - AUC0-τ | 44.33 mcg*h/mL | Geometric Coefficient of Variation 63.6 |
Comparison: Analysis of olaparib PK parameters.90% CI: [0.76, 1.05]
Primary
Effect of Anastrozole on Exposure to Olaparib - Cmax ss
Olaparib Cmax ss in the presence and absence of co-administered anastrozole, and associated Cmax ss treatment ratios
Time frame: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 24
Population: PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Anastrozole on Exposure to Olaparib - Cmax ss | 9.490 mcg/mL | Geometric Coefficient of Variation 34.3 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Anastrozole on Exposure to Olaparib - Cmax ss | 8.256 mcg/mL | Geometric Coefficient of Variation 39.9 |
Comparison: Analysis of olaparib PK parameters.90% CI: [0.84, 1.04]
Primary
Effect of Letrozole on Exposure to Olaparib - AUC0-τ
Olaparib AUC0-τ, in the presence and absence of co-administered letrozole, and associated AUC0-τ treatment ratios
Time frame: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 43
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Letrozole on Exposure to Olaparib - AUC0-τ | 61.77 mcg*h/mL | Geometric Coefficient of Variation 43.2 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Letrozole on Exposure to Olaparib - AUC0-τ | 67.82 mcg*h/mL | Geometric Coefficient of Variation 44.1 |
Comparison: Analysis of olaparib PK parameters.90% CI: [1.07, 1.25]
Primary
Effect of Letrozole on Exposure to Olaparib - Cmax ss
Olaparib Cmax ss in the presence and absence of co-administered letrozole, and associated Cmax ss treatment ratios
Time frame: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 43
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Letrozole on Exposure to Olaparib - Cmax ss | 10.05 mcg/mL | Geometric Coefficient of Variation 30.2 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Letrozole on Exposure to Olaparib - Cmax ss | 10.48 mcg/mL | Geometric Coefficient of Variation 33.6 |
Comparison: Analysis of olaparib PK parameters90% CI: [0.99, 1.21]
Primary
Effect of Olaparib on Exposure to Anastrozole - AUC0-τ
Anastrozole Area under plasma concentration-time curve over the dosing interval at steady state (AUC0-τ), in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios
Time frame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Anastrozole - AUC0-τ | 696.8 mcg*h/mL | Geometric Coefficient of Variation 36.6 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Anastrozole - AUC0-τ | 582.5 mcg*h/mL | Geometric Coefficient of Variation 31.6 |
Comparison: Analysis of anastrozole PK parameters.90% CI: [0.8, 0.93]
Primary
Effect of Olaparib on Exposure to Anastrozole - Cmax ss
Anastrozole maximum plasma concentration at steady state (Cmax ss) in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios
Time frame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
Population: PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Anastrozole - Cmax ss | 40.98 micrograms per millilitre (mcg/mL) | Geometric Coefficient of Variation 36.2 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Anastrozole - Cmax ss | 35.83 micrograms per millilitre (mcg/mL) | Geometric Coefficient of Variation 31.9 |
Comparison: Analysis of anastrozole PK parameters.90% CI: [0.84, 0.97]
Primary
Effect of Olaparib on Exposure to Letrozole - AUC0-τ
Letrozole AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios
Time frame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Letrozole - AUC0-τ | 2292 mcg*h/mL | Geometric Coefficient of Variation 36.7 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Letrozole - AUC0-τ | 2167 mcg*h/mL | Geometric Coefficient of Variation 38 |
Comparison: Analysis of letrozole PK parameters.90% CI: [0.91, 0.99]
Primary
Effect of Olaparib on Exposure to Letrozole - Cmax ss
Letrozole Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios
Time frame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
Population: PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Letrozole - Cmax ss | 118.9 mcg/mL | Geometric Coefficient of Variation 32.6 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Letrozole - Cmax ss | 111.8 mcg/mL | Geometric Coefficient of Variation 30.4 |
Comparison: Analysis of letrozole PK parameters.90% CI: [0.91, 0.98]
Primary
Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ
Tamoxifen, N-DMT and endoxifen AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios
Time frame: Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | PK analysis of N-DMT | 3189 microgram x hour/millilitre (mcg*h/mL) | Geometric Coefficient of Variation 28.8 |
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | PK analysis of endoxifen | 119.3 microgram x hour/millilitre (mcg*h/mL) | Geometric Coefficient of Variation 66.1 |
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | PK analysis of tamoxifen | 2233 microgram x hour/millilitre (mcg*h/mL) | Geometric Coefficient of Variation 31.9 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | PK analysis of N-DMT | 2955 microgram x hour/millilitre (mcg*h/mL) | Geometric Coefficient of Variation 37.3 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | PK analysis of endoxifen | 115.8 microgram x hour/millilitre (mcg*h/mL) | Geometric Coefficient of Variation 64.8 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ | PK analysis of tamoxifen | 2751 microgram x hour/millilitre (mcg*h/mL) | Geometric Coefficient of Variation 28.9 |
Comparison: Analysis of tamoxifen PK parameters.90% CI: [1.11, 1.21]
Primary
Effect of Olaparib on Exposure to Tamoxifen - Cmax ss
Tamoxifen, N-desmethyl tamoxifen (N-DMT) and endoxifen Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios
Time frame: Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | PK analysis of tamoxifen | 130.3 mcg/mL | Geometric Coefficient of Variation 27.3 |
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | PK analysis of N-DMT | 162.9 mcg/mL | Geometric Coefficient of Variation 28 |
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | PK analysis of endoxifen | 5.923 mcg/mL | Geometric Coefficient of Variation 65.7 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | PK analysis of tamoxifen | 154.2 mcg/mL | Geometric Coefficient of Variation 34.9 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | PK analysis of N-DMT | 149.1 mcg/mL | Geometric Coefficient of Variation 44.8 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Olaparib on Exposure to Tamoxifen - Cmax ss | PK analysis of endoxifen | 5.727 mcg/mL | Geometric Coefficient of Variation 61.2 |
Comparison: Analysis of tamoxifen PK parameters.90% CI: [1.06, 1.22]
Primary
Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ
Olaparib AUC0-τ, in the presence and absence of co-administered tamoxifen, and associated AUC0-τ treatment ratios
Time frame: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 31
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ | 62.12 mcg*h/mL | Geometric Coefficient of Variation 51.6 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ | 42.27 mcg*h/mL | Geometric Coefficient of Variation 60.6 |
Comparison: Analysis of olaparib PK parameters.90% CI: [0.63, 0.84]
Primary
Effect of Tamoxifen on Exposure to Olaparib - Cmax ss
Olaparib Cmax ss in the presence and absence of co-administered tamoxifen, and associated Cmax ss treatment ratios
Time frame: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 31
Population: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Tamoxifen Alone (Treatment Period 2) | Effect of Tamoxifen on Exposure to Olaparib - Cmax ss | 9.456 mcg/mL | Geometric Coefficient of Variation 41.5 |
| Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3) | Effect of Tamoxifen on Exposure to Olaparib - Cmax ss | 7.216 mcg/mL | Geometric Coefficient of Variation 43.6 |
Comparison: Analysis of olaparib PK parameters.90% CI: [0.71, 0.9]