An Open-Label, Non-randomised, Parallel Group, Multicentre, Phase I Study to Assess the Safety and Effect of Olaparib at Steady State on the Pharmacokinetics of the Anti-hormonal Agents Anastrozole, Letrozole and Tamoxifen at Steady State, and the Effect of the Anti-hormonal Agents on Olaparib, Following Administration in Patients With Advanced Solid Cancer
Overview
- Phase
- Phase 1
- Intervention
- Olaparib
- Conditions
- Solid Tumours
- Sponsor
- AstraZeneca
- Enrollment
- 79
- Locations
- 1
- Primary Endpoint
- Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ
- Status
- Completed
- Last Updated
- 6 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of written informed consent prior to any study specific procedures
- •Male or female aged ≥18 years
- •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).
- •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
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents, and/or staff at the study site)
- •Previous enrolment in the present study
- •Exposure to an investigational product (IP) (including PARP inhibitor) within 30 days or 5 half lives (whichever is the longer) prior to enrolment
- •Prior chemotherapy within 3 weeks of study entry
- •Prior radiotherapy within 2 weeks of study entry
- •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
- •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.
- •Patients who are receiving inhibitors or inducers of CYP3A4 unless washed out prior to start of study treatment.
- •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
- •Patients with myelodysplastic syndrome/acute myeloid leukaemia
Arms & Interventions
Cohort 2 - Anastrozole
Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
Intervention: Olaparib
Cohort 1 - Tamoxifen
Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
Intervention: Olaparib
Cohort 1 - Tamoxifen
Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
Intervention: Tamoxifen
Cohort 1 - Tamoxifen
Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
Intervention: Pharmacokinetic sampling
Cohort 2 - Anastrozole
Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
Intervention: Anastrozole
Cohort 2 - Anastrozole
Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
Intervention: Pharmacokinetic sampling
Cohort 3 - Letrozole
Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
Intervention: Olaparib
Cohort 3 - Letrozole
Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
Intervention: Letrozole
Cohort 3 - Letrozole
Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
Intervention: Pharmacokinetic sampling
Outcomes
Primary Outcomes
Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ
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
Olaparib AUC0-τ, in the presence and absence of co-administered tamoxifen, and associated AUC0-τ treatment ratios
Effect of Olaparib on Exposure to Tamoxifen - Cmax ss
Time Frame: 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
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
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
Time Frame: 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
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
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
Time Frame: 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
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
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
Time Frame: 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 Olaparib on Exposure to Anastrozole - AUC0-τ
Time Frame: 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
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
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
Time Frame: 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
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
Olaparib AUC0-τ, in the presence and absence of co-administered letrozole, and associated AUC0-τ treatment ratios