To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.
Condition: Metastatic Triple Negative Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Olaparib Continuous (28-Day cycle) 300 mg BD.; Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).; Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).
Intervention description: 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.
Intervention MeSH terms: Olaparib; Adavosertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: Given the study treatment design (monotherapy and 2 different combination therapies will be employed) neither patients nor Investigators will be blinded to study treatment.
Enrollment: 273.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Germline BRCA mutation; Human epidermal growth factor receptor 2; Olaparib; Homologous Recombinant Repair (HRR)-related Genes

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.
    

Eligibility criteria:

        Pertinent Inclusion criteria:

          1. Informed consent prior to any study specific procedures.

          2. Male or female ≥18 years of age.

          3. Progressive cancer at the time of study entry.

          4. Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of
             metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations
             2013.

          5. 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.

          6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour
             tissue by the Lynparza HRR assay.

          7. 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.

          8. Patients must have normal organ and bone marrow function measured within 28 days prior
             to randomization (defined in the protocol).

          9. ECOG PS 0-1 within 28 days of randomisation.

         10. 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:

          1. 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.

          2. 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).

          3. Previous randomisation in the present study.

          4. 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).

          5. 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.

          6. Patients with second primary cancer (exceptions defined in the protocol).

          7. 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.

          8. 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).

          9. 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).

         10. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding
             alopecia and CTCAE grade 2 peripheral neuropathy.

         11. Major surgery within 2 weeks of starting study treatment: patients must have recovered
             from any effects of any major surgery.

         12. Immunocompromised patients, eg, human immunodeficiency virus (HIV).

         13. Patients with known active hepatitis (ie, hepatitis B or C).

         14. Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non malignant systemic disease or active, uncontrolled infection.

         15. Patients with symptomatic uncontrolled brain metastases.

         16. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

         17. Patients with a known hypersensitivity to olaparib, adavosertib, Ceralasertib, or any
             of the excipients of the products.

         18. Pregnant or breast feeding women.