To Assess Safety and Effect of Olaparib on the Pharmacokinetics of Anastrozole, Letrozole & Tamoxifen, and Their Effect on Olaparib, in Patients With Advanced Solid Cancer

Phase 1

Completed

• Conditions: Solid Tumours
• Interventions: Drug: Olaparib; Drug: Letrozole; Drug: Tamoxifen; Drug: Anastrozole; Procedure: Pharmacokinetic sampling

• Registration Number: NCT02093351
• Lead Sponsor: AstraZeneca

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-03-06
• Study First Submitted QC: 2014-03-19
• Study First Posted: 2014-03-21
• Study Start: 2014-09-01
• Primary Completion: 2015-04-30
• Results First Submitted: 2016-04-26
• Results First Submitted QC: 2016-04-26
• Results First Posted: 2016-06-01
• Study Completion: 2019-04-29
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-18
• Last Update Posted: 2019-10-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 79

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3 - Letrozole	Olaparib	Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
Cohort 3 - Letrozole	Letrozole	Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
Cohort 3 - Letrozole	Pharmacokinetic sampling	Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
Cohort 1 - Tamoxifen	Olaparib	Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
Cohort 1 - Tamoxifen	Tamoxifen	Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
Cohort 1 - Tamoxifen	Pharmacokinetic sampling	Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
Cohort 2 - Anastrozole	Anastrozole	Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
Cohort 2 - Anastrozole	Pharmacokinetic sampling	Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
Cohort 2 - Anastrozole	Olaparib	Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.

Primary Outcome Measures

Name	Time	Method
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 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 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 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

Trial Locations

Locations (1)

Research Site; 🇬🇧 Sutton, United Kingdom