To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.

Study Overview
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Brief Summary
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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.

Detailed Description
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This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ceralasertib) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib) in second or third line setting in patients with TNBC prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the HRR pathway. Eligible patients will be randomised by a ratio 1:1:1 to treatment Arm 1: olaparib continuous in a 28-day cycle, Arm 2: Ceralasertib Days 1-7 with olaparib continuous in a 28-day cycle or Arm 3: adavosertib Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Following closure of this arm the randomisation ratio will be 1:1 to olaparib monotherapy or Ceralasertib+olaparib. Patients who were receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). The study subject population will be divided into Stratum A (patients with mutations in BRCA1 or BRCA2 (Breast cancer susceptible gene mutation (BRCAm)), Stratum B (patients with mutations in any of the other genes involved in the HRR pathway and no mutation in BRCA1 and no mutation in BRCA2), and Stratum C (patients with no detected tumour mutations in any of the HRR genes). Within each stratum A, B and C, there will be further stratification by whether the patient received prior platinum-based therapy. In the olaparib monotherapy treatment arm as well as in the Ceralasertib+olaparib treatment arm, patients will be administered olaparib bd at 300 mg continuously. Two (2) 150 mg olaparib tablets will be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL). In the adavosertib+olaparib treatment arm, patients will be given olaparib 200 mg bd (2 x 100 mg tablets twice a day) and adavosertib 150 mg bd from Day 1 to Day 3 (inclusive) and Day 8 to Day 10 (inclusive) of every 21-day cycle. Ceralasertib will be supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered Ceralasertib od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg of Ceralasertib tablets will be taken at the same time on each day of dosing with approximately 250 mL of water. Adavosertib will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg of drug substance. Adavosertib will be taken with approximately 250 mL of water approximately 2 hours before or 2 hours after food. Olaparib, Ceralasertib and adavosertib will be provided by AstraZeneca. Primary outcome measures (progression free survival [PFS]) will be analysed for the 3 patient populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5 patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and Non HRRm patient populations. Tumour and germline mutation status will be analysed only in the all patient population. PK outcome measures will be analysed only in the all patient population. Blinded Independent Central Review (BICR) of radiological imaging data will be carried out using RECIST version 1.1 and Investigator assessments will also be analysed for sensitivity purposes.

Official Title
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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).

Conditions
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Metastatic Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Olaparib Continuous (28-Day cycle) 300 mg BD.
* Drug: Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).
* Drug: Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).


Participation Criteria
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Eligibility Criteria
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Pertinent Inclusion criteria: 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). 13. Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16 weeks. Pertinent Exclusion criteria: 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. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Patients with a known hypersensitivity to olaparib, adavosertib, Ceralasertib, or any of the excipients of the products. Pregnant or breast feeding women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Olaparib monotherapy<br>All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD). | Drug: Olaparib Continuous (28-Day cycle) 300 mg BD.<br>* 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).<br>|
| Active Comparator: Olaparib+Ceralasertib<br>All randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD). | Drug: Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).<br>* Patients will be administered Ceralasertib OD at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle.<br>|
| Active Comparator: Olaparib+adavosertib<br>All 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). | Drug: Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).<br>* Patients will be administered adavosertib BD at 150mg from Day 1 to Day 3 and Day 8 to Day 10.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Per 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 BICR using 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 presented as follows: HRRm and all enrolled patients. | 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) | The objective response was defined as patients with at least one BICR assessed visit response of CR or PR. For sensitivity analysis, objective response was defined as the patients with at least one visit response of CR or PR based on Investigator data. These are unadjusted percentages of responders (100 * number of responders / number of patients in full analysis set). The objective response was assessed per RECIST 1.1 guidelines for: measurable lesions (measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) using CT or MRI, non-measurable lesions (all other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15mm short axis at baseline), based on target lesions [TL] (maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), non-target lesions [NTL] (lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline) and any new lesions. | 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) | The ORR was defined using BICR data to define a visit response of CR or PR, with denominator defined as number of patients in FAS. For sensitivity analysis, ORR is defined as the percentage of patients with at least one investigator-assessed visit response of CR or PR, with denominator defined as number of patients in FAS. These are summarized using adjusted response rates, which are computed with a logistic regression including factors study treatment and prior platinum-based therapy (no, yes), i.e. these response rates are adjusted for prior platinum-based therapy, which is one of the randomisation stratification factors. The adjusted response rates have been presented as a percentage of patients. | 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] | The DoR was defined as the time from the date of first documented response according to BICR data until date of documented progression according to BICR data or death in the absence of disease progression. For sensitivity analysis, DoR was defined as the time from the date of first documented response according to Investigator assessment until date of documented progression according to Investigator assessment or death in the absence of disease progression. Here, the median DoR and the 25th and 75th percentile of DoR are presented. The DoR from onset of response was calculated using Kaplan-Meier technique. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients. | 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] | Tumour size was the sum of the longest diameters of the target lesions (TLs). The percentage change in TL tumour size at Week 16 was obtained for each patient as follows (considering a visit window around the scheduled day of the Week 16 assessment): (TL at Week 16 minus TL at baseline) divided by (TL at baseline) multiplied by 100. Here, the percentage change data have been reported as per BICR and as per sensitivity analysis per investigator assessments. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients. | Baseline, at Week 16 | 
| Overall Survival (OS) | Overall survival was defined as the time from the date of randomisation until death due to any cause. Any patient not known to have died at the time of data cut-off was censored based on the last recorded date on which the patient was known to be alive. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients. | From the date of randomisation until time of data cut-off date or death due to any cause (assessed up to 32 months) | 
| Plasma Drug Concentrations of Olaparib | Plasma drug concentrations of olaparib are evaluated to assess exposure to olaparib in all patients. | Pre-dose at Cycle 1 Day 7 [olaparib monotherapy or ceralasertib+olaparib] or Cycle 1 Day 10 [adavosertib+olaparib] (each cycle is 21 days for olaparib+adavosertib, and 28 days for olaparib monotherapy and olaparib+ceralasertib) | 
| Plasma Drug Concentrations of Ceralasertib and Adavosertib | Plasma drug concentrations of ceralasertib and adavosertib are evaluated to assess exposure to ceralasertib and adavosertib in all patients. | Pre-dose at Cycle 1 Day 7 [ceralasertib+olaparib] or Cycle 1 Day 10 [adavosertib+olaparib] (each cycle is 21 days for olaparib+adavosertib, and 28 days for olaparib+ceralasertib) | 
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Treatment-emergent adverse events reported after treatment with olaparib monotherapy, the combination of ceralasertib and olaparib or the combination of adavosertib and olaparib. The data includes adverse events (AEs) with an onset or worsening date on or after the date of first dose and up to and including 30 days following the date of last dose of study medication. | From screening until Follow-up 30 Days after last dose of study treatment (assessed up to 32 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Germline BRCA mutation, Human epidermal growth factor receptor 2, Olaparib, Homologous Recombinant Repair (HRR)-related Genes