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

NCT ID: NCT02093351

Last Updated: 2019-10-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 79 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-01
• Study Completion Date: 2019-04-29

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.

Conditions

Solid Tumours

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Cohort 1 - Tamoxifen

Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.

Group Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

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)

Tamoxifen

Intervention Type: DRUG

60mg Tamoxifen once daily, Day 10 - Day 13; 20mg Tamoxifen once daily, Day 14 - Day 31

Pharmacokinetic sampling

Intervention Type: PROCEDURE

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Cohort 2 - Anastrozole

Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.

Group Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

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)

Anastrozole

Intervention Type: DRUG

1mg Anastrozole once daily Day 10 - Day 24

Pharmacokinetic sampling

Intervention Type: PROCEDURE

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Cohort 3 - Letrozole

Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.

Group Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

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)

Letrozole

Intervention Type: DRUG

2.5mg Letrozole once daily Day 10 - Day 43

Pharmacokinetic sampling

Intervention Type: PROCEDURE

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Interventions

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)

Intervention Type: DRUG

Tamoxifen

60mg Tamoxifen once daily, Day 10 - Day 13; 20mg Tamoxifen once daily, Day 14 - Day 31

Intervention Type: DRUG

Anastrozole

1mg Anastrozole once daily Day 10 - Day 24

Intervention Type: DRUG

Letrozole

2.5mg Letrozole once daily Day 10 - Day 43

Intervention Type: DRUG

Pharmacokinetic sampling

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Intervention Type: PROCEDURE

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tsveta Milenkova

Role: STUDY_DIRECTOR

AstraZeneca

Ruth Plummer

Role: PRINCIPAL_INVESTIGATOR

Sir Bobby Robson Cancer Trials Research Centre

Locations

Research Site

Brussels, , Belgium

Research Site

Edegem, , Belgium

Research Site

Ghent, , Belgium

Research Site

Leuven, , Belgium

Research Site

Liège, , Belgium

Research Site

Wilrijk, , Belgium

Research Site

Herlev, , Denmark

Research Site

Bordeaux, , France

Research Site

Amsterdam, , Netherlands

Research Site

Utrecht, , Netherlands

Research Site

London, , United Kingdom

Research Site

Manchester, , United Kingdom

Research Site

Newcastle upon Tyne, , United Kingdom

Research Site

Sutton, , United Kingdom

Countries

Belgium; Denmark; France; Netherlands; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 30324586 (View on PubMed)

Related Links

http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=2882&filename=D081CC00001%20Clinical%20Study%20Protocol_REDACTED%20SECURED.PDF

Clinical Study Protocol REDACTED

Other Identifiers

D081CC00001

Identifier Type: -

Identifier Source: org_study_id