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

NCT02093351 | Completed Phase 1 Results

• 1 other identifier: D081CC00001
• Study Type: interventional
• Target: 79
• Locations: 5 countries
• Sites: 14

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

Keywords

oncology, cancer, tumour, neoplasm, anticancer drug, pharmacokinetics, olaparib, anastrozole, tamoxifen, letrozole,

Outcome Measures

Primary Outcomes (12)

• 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

Study Arms (3)

Cohort 1 - Tamoxifen

EXPERIMENTAL

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

Drug: Olaparib; Drug: Tamoxifen; Procedure: Pharmacokinetic sampling

Cohort 2 - Anastrozole

EXPERIMENTAL

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

Drug: Olaparib; Drug: Anastrozole; Procedure: Pharmacokinetic sampling

Cohort 3 - Letrozole

EXPERIMENTAL

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

Drug: Olaparib; Drug: Letrozole; Procedure: Pharmacokinetic sampling

Interventions

Olaparib 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)

Cohort 1 - Tamoxifen; Cohort 2 - Anastrozole; Cohort 3 - Letrozole

Tamoxifen DRUG

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

Cohort 1 - Tamoxifen

Anastrozole DRUG

1mg Anastrozole once daily Day 10 - Day 24

Cohort 2 - Anastrozole

Letrozole DRUG

2.5mg Letrozole once daily Day 10 - Day 43

Cohort 3 - Letrozole

Pharmacokinetic sampling PROCEDURE

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Cohort 1 - Tamoxifen; Cohort 2 - Anastrozole; Cohort 3 - Letrozole

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Patients must have a life expectancy ≥16 weeks

You may not qualify if:

• 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
• Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery
• 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.
• 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
• Patients who have gastric, gastro-oesophageal, or oesophageal cancer
• Pregnant or breastfeeding women

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (14)

Research Site

Brussels, 1090, Belgium

Location

Research Site

Edegem, 2650, Belgium

Location

Research Site

Ghent, 9000, Belgium

Location

Research Site

Leuven, 3000, Belgium

Location

Research Site

Liège, 4000, Belgium

Location

Research Site

Wilrijk, 2610, Belgium

Location

Research Site

Herlev, 2730, Denmark

Location

Research Site

Bordeaux, 33076, France

Location

Research Site

Amsterdam, 1081 HV, Netherlands

Location

Research Site

Utrecht, 3584 CX, Netherlands

Location

Research Site

London, SE1 9RT, United Kingdom

Location

Research Site

Manchester, M20 4BX, United Kingdom

Location

Research Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Research Site

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30324586 DERIVED

Related Links

• Clinical Study Protocol REDACTED

MeSH Terms

Conditions

Neoplasms

Interventions

olaparib; Tamoxifen; Anastrozole; Letrozole

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

At the end of Part B, the continued access phase (CAP) allowed patients to continue to receive olaparib if deriving clinical benefit. No clinical data was databased during the CAP, thus AE data is presented to the end of Part B only.

Results Point of Contact

• Title: Dr Carsten Goessl, Indication Lead
• Organization: AstraZeneca Pharmaceuticals

clinicaltrialtransparency@astrazeneca.com

Study Officials

• Tsveta Milenkova

  AstraZeneca

  STUDY DIRECTOR

• Ruth Plummer

  Sir Bobby Robson Cancer Trials Research Centre

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2014
• First Posted: March 21, 2014
• Study Start: September 1, 2014
• Primary Completion: April 30, 2015
• Study Completion: April 29, 2019
• Last Updated: October 2, 2019
• Results First Posted: June 1, 2016

Record last verified: 2019-09

Locations

BE (6); FR (1); DK (1); NL (2); GB (4)