To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.
A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination With Olaparib Versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-Related Genes (Including BRCA1/2) (VIOLETTE).
2 other identifiers
interventional
273
15 countries
141
Brief Summary
This study is to assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (Ceralasertib \[AZD6738\]) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib \[AZD1775\]) in second or third line setting in patients with Triple-negative breast cancer (TNBC) prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the homologous recombination repair (HRR) pathway. Treatment arms are olaparib monotherapy, olaparib+ Ceralasertib and olaparib+adavosertib. The study subject population will be divided into Stratum A, Stratum B, and Stratum C. Due to the different schedules of administration of each of the treatment options as well as their different toxicity profiles, the study is not blinded. Study has two stage consent process- stage 1 consent (molecular screening for HRR defects) and stage 2 consent (main study). Patients with TNBC and with known qualifying BRCAm, non BRCAm HRRm and non HRRm status will be offered the option of consenting to the main part of the study within the 28-day screening period. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). Following the closure of this arm the total number of patients randomised will be lower (approximately 350 patients). Approximately 300 patients will be randomised (using randomisation ratio 1:1) to 2 ongoing treatment arms plus an additional 47 patients to a 3rd arm (olaparib+adavosertib) prior to the arm being discontinued.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Mar 2018
Longer than P75 for phase_2
141 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 16, 2017
CompletedFirst Posted
Study publicly available on registry
November 6, 2017
CompletedStudy Start
First participant enrolled
March 7, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 13, 2020
CompletedResults Posted
Study results publicly available
March 22, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
September 4, 2026
ExpectedMarch 10, 2026
February 1, 2026
2.7 years
October 16, 2017
November 10, 2021
February 18, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Progression-free Survival Per Stratum (BICR)
Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by Blinded independent central review (BICR) using Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1). Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was stratified as follows: Breast cancer susceptible gene mutation (BRCAm) patients; non BRCAm homologous recombination repair gene mutation (HRRm) patients; non HRRm patients.
Until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)
Progression-free Survival Per Stratum (Sensitivity Analysis)
Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by the site Investigator. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.
Until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)
Secondary Outcomes (9)
Progression-free Survival (Per BICR)
From randomization until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)
Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis)
From date of randomization until date of first documented progression or last evaluable assessment, or start of subsequent anti-cancer therapy (Whichever occurred first [assessed up to 32 months])
Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis)
From date of randomization until date of first documented progression or last evaluable assessment, or start of subsequent anti-cancer therapy (Whichever occurred first [assessed up to 32 months])
Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis]
From date of first documented response until date of first documented progression or last evaluable assessment (assessed up to 32 months)
Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis]
Baseline, at Week 16
- +4 more secondary outcomes
Study Arms (3)
Olaparib monotherapy
ACTIVE COMPARATORAll randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).
Olaparib+Ceralasertib
ACTIVE COMPARATORAll randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD).
Olaparib+adavosertib
ACTIVE COMPARATORAll randomized patients will receive Olaparib 200 mg BD +adavosertib 150 mg BD. Following the discontinuation of adavosertib+olaparib treatment arm on 18 April 2019, patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).
Interventions
Two (2) 150 mg olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL).
Patients will be administered Ceralasertib OD at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle.
Patients will be administered adavosertib BD at 150mg from Day 1 to Day 3 and Day 8 to Day 10.
Eligibility Criteria
You may qualify if:
- Informed consent prior to any study specific procedures.
- Male or female ≥18 years of age.
- Progressive cancer at the time of study entry.
- Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations 2013.
- Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting.
- Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.
- At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging \[MRI\] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
- Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol).
- ECOG PS 0-1 within 28 days of randomisation.
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners).
- \. Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16 weeks.
You may not qualify if:
- Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment.
- More than 2 prior lines of cytotoxic chemotherapy for metastatic disease (prior treatments with hormonal, non-hormonal, biologics or the combination of an aromatase inhibitor and everolimus are not counted as a prior line of therapy).
- Previous randomisation in the present study.
- Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor (unless less than 3 weeks duration and at least 12 months has elapsed between the last dose and randomization).
- Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomisation. The minimum washout period for immunotherapy shall be 42 days.
- Patients with second primary cancer (exceptions defined in the protocol).
- Mean resting corrected QTc interval using the Fridericia formula (QTcF) \>470 msec/female patients and \>450 msec for male patients (as calculated per institutional standards) obtained from 3 ECGs performed 2-5 minutes apart at study entry, or congenital long QT syndrome.
- Any of the following cardiac diseases currently or within the last 6 months: unstable angina pectoris, congestive heart failure ≥ Class 2 as defined by the New York Heart Association, acute myocardial infarction, conduction abnormality not controlled with pacemaker or medication (patients with a conduction abnormality controlled with pacemaker or medication at the time of screening are eligible), significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
- Concomitant use of known strong or moderate cytochrome P (CYP) 3A inhibitors, strong or moderate CYP3A inducers, or sensitive CYP3A4 substrates or CYp3A4 substrates with a narrow therapeutic index (No longer applicable from CSPv7.0).
- Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
- Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
- Immunocompromised patients, eg, human immunodeficiency virus (HIV).
- Patients with known active hepatitis (ie, hepatitis B or C).
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection.
- Patients with symptomatic uncontrolled brain metastases.
- +3 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- AstraZenecalead
Study Sites (141)
Research Site
Birmingham, Alabama, 35205, United States
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Anchorage, Alaska, 99508, United States
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Gilbert, Arizona, 85234, United States
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Aurora, Colorado, 80045, United States
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New Haven, Connecticut, 06511, United States
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Chicago, Illinois, 60637, United States
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Munster, Indiana, 46321, United States
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Hazard, Kentucky, 41701, United States
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Louisville, Kentucky, 40207, United States
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Towson, Maryland, 21204, United States
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Brick, New Jersey, 08724, United States
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East Setauket, New York, 11733, United States
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Lake Success, New York, 11042, United States
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Mineola, New York, 11501, United States
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Mount Kisco, New York, 10549, United States
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Stony Brook, New York, 11794, United States
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Cincinnati, Ohio, 45219, United States
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Knoxville, Tennessee, 37909, United States
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Seattle, Washington, 98104, United States
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Milwaukee, Wisconsin, 53212, United States
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Brasschaat, 2930, Belgium
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Brussels, 1000, Belgium
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Brussels, 1200, Belgium
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Charleroi, 6000, Belgium
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Leuven, 3000, Belgium
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Liège, 4000, Belgium
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Namur, 5000, Belgium
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Ottignies, 1340, Belgium
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Wilrijk, 2610, Belgium
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Calgary, Alberta, T2N 4N2, Canada
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Kelowna, British Columbia, V1Y 5L3, Canada
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Ottawa, Ontario, K1H 8L6, Canada
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Toronto, Ontario, M4N 3M5, Canada
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Brno, 625 00, Czechia
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Olomouc, 775 20, Czechia
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Prague, 180 81, Czechia
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Angers, 49055, France
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Besançon, 25030, France
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Bordeaux, 33076, France
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Caen, 14076, France
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Lille, 59000, France
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Lyon, 69373, France
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Marseille, 13273, France
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Montpellier, 34298, France
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Nantes, 44202, France
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Rennes, 35000, France
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Saint-Herblain, 44805, France
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Tours, 37044, France
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Villejuif, 94805, France
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Dresden, 1307, Germany
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Frankfurt am Main, 60431, Germany
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Hamburg, 20357, Germany
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Hanover, 30559, Germany
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Leipzig, 04103, Germany
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München, 81675, Germany
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Witten, 58452, Germany
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Cork, T12 DV56, Ireland
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Dublin, Ireland
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Ancona, 60126, Italy
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Bologna, 40138, Italy
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Brescia, 25124, Italy
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Cona, 44124, Italy
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Genova, 16128, Italy
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Lecco, 23900, Italy
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Macerata, 62100, Italy
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Meldola, 47014, Italy
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Messina, 98125, Italy
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Milan, 20133, Italy
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Milan, 20141, Italy
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Naples, 80131, Italy
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Novara, 28100, Italy
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Parma, 43126, Italy
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Pavia, 27100, Italy
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Pisa, 56126, Italy
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Roma, 00128, Italy
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Rozzano, 20089, Italy
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Siena, 53100, Italy
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Torino, 10123, Italy
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Breda, 4819 EV, Netherlands
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Rotterdam, 3015 GD, Netherlands
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The Hague, 2545 CH, Netherlands
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Dąbrowa Górnicza, 41-300, Poland
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Gdansk, 80-952, Poland
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Gdynia, 81-519, Poland
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Grzepnica, 72-003, Poland
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Krakow, 31-531, Poland
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Lodz, 91-211, Poland
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Olsztyn, 10-228, Poland
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Poznan, 60-192, Poland
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Warsaw, 02-781, Poland
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Wroclaw, 53-413, Poland
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Lisbon, 1400-038, Portugal
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Lisbon, 1769-001, Portugal
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Loures, 2674-514, Portugal
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Porto, 4099-001, Portugal
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Vila Nova de Gaia, 4434-502, Portugal
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Cheongju-si, 28644, South Korea
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Daegu, 41404, South Korea
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Goyang-si, 410-769, South Korea
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Incheon, 405-760, South Korea
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Seongnam-si, 13620, South Korea
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Seoul, 02841, South Korea
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Seoul, 03080, South Korea
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Seoul, 03722, South Korea
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Seoul, 05505, South Korea
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Seoul, 06351, South Korea
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Barcelona, 08035, Spain
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Barcelona, 08036, Spain
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Cáceres, 10003, Spain
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Madrid, 28007, Spain
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Madrid, 28034, Spain
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Madrid, 28040, Spain
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Madrid, 28046, Spain
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Palma de Mallorca, 07120, Spain
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San Sebastián, 20014, Spain
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Sant Cugat del Vallès, 08190, Spain
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Seville, 41009, Spain
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Seville, 41013, Spain
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Valencia, 46010, Spain
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Vigo, 36312, Spain
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Zaragoza, 50009, Spain
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Changhua, 500, Taiwan
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Kaohsiung Hsien, 83342, Taiwan
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Taichung, 40447, Taiwan
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Taipei, 10048, Taiwan
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Taipei, 10449, Taiwan
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Taipei, 11217, Taiwan
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Taipei, 11490, Taiwan
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Taoyuan District, 333, Taiwan
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Aberdeen, AB25 2ZN, United Kingdom
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Bristol, BS1 2NT, United Kingdom
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Cardiff, CF14 2TL, United Kingdom
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Durham, DH1 5TW, United Kingdom
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Edinburgh, EH4 2XR, United Kingdom
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Leicester, LE1 5WW, United Kingdom
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London, SE1 9RT, United Kingdom
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London, W1G 6AD, United Kingdom
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London, W1T 7HA, United Kingdom
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Manchester, M20 4BX, United Kingdom
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Nottingham, NG5 1PB, United Kingdom
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Southampton, SO16 6YD, United Kingdom
Related Publications (1)
Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.
PMID: 34904813DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Limitations and Caveats
The interpretation of efficacy results of the adavosertib + olaparib arm and comparison with the olaparib monotherapy arm and ceralasertib + olaparib arm is limited due to the lower number of patients with available data in the adavosertib + olaparib arm, the nature of the analysis (intent-to-treat), and the fact that some of the patients switched from adavosertib + olaparib treatment to olaparib monotherapy.
Results Point of Contact
- Title
- Global Clinical Lead
- Organization
- AstraZeneca Clinical Study Information Center
Study Officials
- PRINCIPAL INVESTIGATOR
Andrew Tutt, MB ChB PhD
Guy's Hospital, Great Maze Pond, London.
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Masking Details
- Given the study treatment design (monotherapy and 2 different combination therapies will be employed) neither patients nor Investigators will be blinded to study treatment.
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 16, 2017
First Posted
November 6, 2017
Study Start
March 7, 2018
Primary Completion
November 13, 2020
Study Completion (Estimated)
September 4, 2026
Last Updated
March 10, 2026
Results First Posted
March 22, 2022
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP
- Time Frame
- AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
- Access Criteria
- When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.