Clinical trial 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
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumours
Keywords: oncology, cancer, tumour, neoplasm, anticancer drug, pharmacokinetics, olaparib, anastrozole, tamoxifen, letrozole,
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-03-21
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


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.

Primary outcomes:
measure: Effect of Olaparib on Exposure to Tamoxifen - Cmax ss
timeFrame: Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
measure: Effect of Tamoxifen on Exposure to Olaparib - Cmax ss
timeFrame: 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
measure: Effect of Olaparib on Exposure to Anastrozole - Cmax ss
timeFrame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
measure: Effect of Anastrozole on Exposure to Olaparib - Cmax ss
timeFrame: 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
measure: Effect of Olaparib on Exposure to Letrozole - Cmax ss
timeFrame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
measure: Effect of Letrozole on Exposure to Olaparib - Cmax ss
timeFrame: 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
measure: Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ
timeFrame: Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
measure: Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ
timeFrame: 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
measure: Effect of Olaparib on Exposure to Anastrozole - AUC0-τ
timeFrame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
measure: Effect of Anastrozole on Exposure to Olaparib - AUC0-τ
timeFrame: 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
measure: Effect of Olaparib on Exposure to Letrozole - AUC0-τ
timeFrame: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
measure: Effect of Letrozole on Exposure to Olaparib - AUC0-τ
timeFrame: 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
Secondary outcomes:
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Wilrijk
country: Belgium
facility: Research Site
city: Herlev
country: Denmark
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Tsveta Milenkova
role: STUDY_DIRECTOR
affiliation: Sir Bobby Robson Cancer Trials Research Centre
name: Ruth Plummer
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.