OLAPARIB for Triple negative breast cancer

Stratification factors

• HRR mutation status (homologous recombination repair) including BRCA mutation status (strata: BRCAm, Non BRCAm HRRm, Non HRRm)

Inclusion criteria

• {"criterion_text":"- Informed consent prior to any study specific procedures.\n- Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners).\n- Patient is willing to comply with the protocol requirements.\n- Life expectancy of ≥16 weeks.\n- Male or female ≥18 years of age.\n- Progressive cancer at the time of study entry.\n- Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations 2013.\n- 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.\n- Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.\n- 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.\n- Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol).\n- ECOG PS 0-1 within 28 days of randomisation."}

Exclusion criteria

• {"criterion_text":"- 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.\n- Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.\n- Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.\n- Immunocompromised patients, eg, human immunodeficiency virus (HIV).\n- Patients with known active hepatitis (ie, hepatitis B or C).\n- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection.\n- Patients with symptomatic uncontrolled brain metastases.\n- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.\n- Patients with a known hypersensitivity to olaparib, adavosertib, Ceralasertib, or any of the excipients of the products.\n- Pregnant or breast feeding women.\n- 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).\n- Previous randomisation in the present study.\n- 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).\n- 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.\n- Patients with second primary cancer (exceptions defined in the protocol).\n- 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.\n- 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).\n- 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)."}

Primary endpoints

• {"endpoint_text":"- Progression-free Survival Per Stratum (BICR).","definition_or_measurement_approach":"Progression-free survival assessed per biomarker stratum by blinded independent central review (BICR)."}
• {"endpoint_text":"- Progression-free Survival Per Stratum (Sensitivity Analysis).","definition_or_measurement_approach":"Progression-free survival per stratum assessed using sensitivity analyses (methodology specified in protocol)."}

Secondary endpoints

• {"endpoint_text":"- Progression-free Survival (Per BICR).","definition_or_measurement_approach":"Progression-free survival assessed by blinded independent central review (BICR)."}
• {"endpoint_text":"- Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis).","definition_or_measurement_approach":"Count of patients achieving objective response as assessed by BICR and sensitivity analyses."}
• {"endpoint_text":"- Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis)","definition_or_measurement_approach":"Proportion of patients with objective response assessed by BICR and sensitivity analyses."}
• {"endpoint_text":"- Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis]","definition_or_measurement_approach":"Duration of tumor response measured per BICR and sensitivity analyses."}
• {"endpoint_text":"- Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis]","definition_or_measurement_approach":"Percent change from baseline in target lesion size assessed by BICR and sensitivity analyses (RECIST 1.1)."}
• {"endpoint_text":"- Overall Survival (OS)","definition_or_measurement_approach":"Time from randomisation to death from any cause (OS)."}
• {"endpoint_text":"- Plasma Drug Concentrations of olaparib","definition_or_measurement_approach":"Measurement of olaparib plasma concentrations (pharmacokinetic sampling)."}
• {"endpoint_text":"- Plasma Drug Concentrations of ceralasertib and adavosertib","definition_or_measurement_approach":"Measurement of plasma concentrations of ceralasertib and adavosertib (pharmacokinetic sampling)."}
• {"endpoint_text":"- Number of Patients With Treatment Emergent Adverse Events (TEAEs)","definition_or_measurement_approach":"Count of patients experiencing treatment-emergent adverse events (safety monitoring, CTCAE)."}

Spain

Latest Decision Or Authorization Date

21-08-2024

Number Of Sites

1

Number Of Participants

1

Poland

Latest Decision Or Authorization Date

02-10-2024

Number Of Sites

1

Number Of Participants

1

Portugal

Latest Decision Or Authorization Date

07-10-2024

Number Of Sites

1

Number Of Participants

1

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

sponsorDuties codes: 1,10,11,12,2,3,6,7

Third parties

• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"codes: 1,10,11,12,2,3,6,7","organisation_type":"Pharmaceutical company"}