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Completed

NCT Number: NCT02093351

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

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.

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Key information

Conditions

Solid Tumours Neoplasms

Age range

18 year–130 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Research Site, Brussels, Belgium

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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
  • 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
  • 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)
  • Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment, and scheduled visits and examinations
  • 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

  • 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
  • Patients with known active Hepatitis B or C, or human immunodeficiency virus (HIV).
  • 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.

Treatment and study plan

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)

Tamoxifen

Drug

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

Anastrozole

Drug

1mg Anastrozole once daily Day 10 - Day 24

letrozole

Drug

2.5mg Letrozole once daily Day 10 - Day 43

Pharmacokinetic sampling

Procedure

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Primary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

Sponsors and collaborators

Lead sponsor

AstraZeneca

Industry

Registry information

Official study title

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

Important dates

Study start
2014
Primary completion
2015
Study completion
2019
First posted
Mar 21, 2014
Registry last updated
Oct 2, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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