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

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumours
• Intervention / Treatment: Drug: Olaparib; Drug: Tamoxifen; Procedure: Pharmacokinetic sampling; Drug: Anastrozole; Drug: Letrozole

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1090
    • Research Site
  • Edegem, Belgium, 2650
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Liège, Belgium, 4000
    • Research Site
  • Wilrijk, Belgium, 2610
    • Research Site
• Denmark
  • Herlev, Denmark, 2730
    • Research Site
• France
  • Bordeaux, France, 33076
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Research Site
  • Utrecht, Netherlands, 3584 CX
    • Research Site
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Research Site
  • Sutton, United Kingdom, SM2 5PT
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 126 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 - Tamoxifen; Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.	Drug: Olaparib; 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); Drug: Tamoxifen; 60mg Tamoxifen once daily, Day 10 - Day 13; 20mg Tamoxifen once daily, Day 14 - Day 31; Procedure: Pharmacokinetic sampling; Blood sampling over 12-24 hour period for pharmacokinetic analysis
Experimental: Cohort 2 - Anastrozole; Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.	Drug: Olaparib; 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); Procedure: Pharmacokinetic sampling; Blood sampling over 12-24 hour period for pharmacokinetic analysis; Drug: Anastrozole; 1mg Anastrozole once daily Day 10 - Day 24
Experimental: Cohort 3 - Letrozole; Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.	Drug: Olaparib; 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); Procedure: Pharmacokinetic sampling; Blood sampling over 12-24 hour period for pharmacokinetic analysis; Drug: Letrozole; 2.5mg Letrozole once daily Day 10 - Day 43

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
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	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
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	Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
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	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
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	Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
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	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
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	Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
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	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
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	Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
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	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
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	Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
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	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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Tsveta Milenkova, AstraZeneca; Principal Investigator: Ruth Plummer, Sir Bobby Robson Cancer Trials Research Centre

Publications and helpful links

General Publications

• Plummer R, Verheul HM, De Vos FYFL, Leunen K, Molife LR, Rolfo C, Grundtvig-Sorensen P, De Greve J, Rottey S, Jerusalem G, Italiano A, Spicer J, Dirix L, Goessl C, Birkett J, Spencer S, Learoyd M, Bailey C, Dean E. Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours. Adv Ther. 2018 Nov;35(11):1945-1964. doi: 10.1007/s12325-018-0804-z. Epub 2018 Oct 15.

Helpful Links

• Clinical Study Protocol REDACTED

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): April 30, 2015
• Study Completion (Actual): April 29, 2019

Study Registration Dates

• First Submitted: March 6, 2014
• First Submitted That Met QC Criteria: March 19, 2014
• First Posted (Estimate): March 21, 2014

Study Record Updates

• Last Update Posted (Actual): October 2, 2019
• Last Update Submitted That Met QC Criteria: September 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: oncology, cancer, tumour, neoplasm, anticancer drug, pharmacokinetics, olaparib, anastrozole, tamoxifen, letrozole,
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Poly(ADP-ribose) Polymerase Inhibitors; Hormone Antagonists; Bone Density Conservation Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Olaparib; Letrozole; Tamoxifen; Anastrozole
• Other Study ID Numbers: D081CC00001