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

NCT03330847

Description:

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 (AZD6738) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (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+AZD6738 and olaparib+AZD1775. 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. Approximately 450 patients will be randomised (using randomisation ratio 1:1:1) to 3 treatment arms.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.
  • Official Title: 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).

Clinical Trial IDs

  • ORG STUDY ID: D5336C00001
  • NCT ID: NCT03330847

Conditions

  • Metastatic Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
Olaparib Continuous (28-Day cycle) 300 mg BD.Olaparib monotherapy
AZD6738 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).Olaparib+AZD6738
AZD1775 175 mg BD + olaparib 200 mg BD (21-day cycle).Olaparib+AZD1775

Purpose

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 (AZD6738) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (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+AZD6738 and olaparib+AZD1775. 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. Approximately 450 patients will be randomised (using randomisation ratio 1:1:1) to 3 treatment arms.

Detailed Description

      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 (AZD6738) and olaparib monotherapy versus olaparib in combination with an
      inhibitor of WEE1 (AZD1775) 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 olaparib
      monotherapy, AZD6738&olaparib or AZD1775&olaparib combinations. The actual treatment given to
      individual patients will be determined by a randomisation scheme that has been loaded into
      the Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) database.
      Treatment arms included: Arm 1: olaparib continuous in a 28-day cycle. Arm 2: AZD6738 Days
      1-7 with olaparib continuous in a 28-day cycle. Arm 3: AZD1775 Days 1-3 and 8-10 with
      olaparib continuous in a 21-day cycle. The study subject population will be divided into
      Stratum A (patients with tumour mutations in, BRCA1 or BRCA2 (Breast cancer susceptible gene
      mutation (BRCAm)), Stratum B (patients with tumour 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 (yes/no). In the olaparib monotherapy treatment arm as well as in the
      AZD6738+olaparib treatment arm, patients will be administered olaparib bd at 300 mg
      continually. 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
      AZD1775+olaparib treatment arm, patients will be given olaparib 200 mg bd (2 x 100 mg tablets
      twice a day). AZD6738 will be supplied as 20 mg, 80 mg, or 100 mg film coated tablets.
      Patients will be administered AZD6738 od at 160 mg from Day 1 to Day 7 (inclusive) of every
      28-day cycle. A total of 160 mg of AZD6738 tablets will be taken at the same time on each day
      of dosing with approximately 250 mL of water. AZD1775 will be supplied as capsules containing
      25 mg, 50 mg, 75 mg, 100 mg, or 200 mg of drug substance. AZD1775 will be taken with
      approximately 250 mL of water approximately 2 hours before or 2 hours after food. Olaparib,
      AZD6738 and AZD1775 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, which will be analysed only for the All patient population. PK
      outcome measures, which will be analysed only for 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.
    

Trial Arms

NameTypeDescriptionInterventions
Olaparib monotherapyActive ComparatorAll randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).
  • Olaparib Continuous (28-Day cycle) 300 mg BD.
Olaparib+AZD6738Active ComparatorAll randomized patients will receive Olaparib 300 mg twice daily+AZD6738 160 mg once daily (OD).
  • AZD6738 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).
Olaparib+AZD1775Active ComparatorAll randomized patients will receive Olaparib 200 mg BD +AZD1775 175 mg BD.
  • AZD1775 175 mg BD + olaparib 200 mg BD (21-day cycle).

Eligibility Criteria

        Inclusion criteria

        1.Provision of informed consent prior to any study specific procedures 2.Patients must be
        male or female ≥18 years of age. 3.Progressive cancer at the time of study entry with a
        life expectancy of ≥16 weeks 4.Histologically or cytologically confirmed TNBC with evidence
        of metastatic disease 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
        randomisation as defined by protocol 9.ECOG PS 0-1 within 28 days of randomisation.
        10.Patients must be willing to comply with the protocol requirements 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.

          3. Previous randomisation in the present study.

          4. Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor
             (unless treatment was for less than 3 weeks duration and at least 12 months have
             elapsed between the last dose and randomisation. Patients that did not tolerate prior
             treatment are excluded).

          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 MDS/AML or with features suggestive of MDS/AML.

          7. Patients with second primary cancer, EXCEPTIONS: adequately treated non melanoma skin
             cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ
             (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively
             treated with no evidence of disease for ≥ 5 years prior to study entry.

          8. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470
             msec/female patients and >450 msec for male patients or congenital long QT syndrome.

          9. Any of the protocol specified cardiac diseases currently or within the last 6 months
             defined by New York Heart Association (NYHA) ≥ Class 2:

         10. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or use of known
             strong or moderate CYP3A inducers.

         11. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding
             alopecia and CTCAE grade 2 peripheral neuropathy.

         12. Major surgery within 2 weeks of starting study treatment: patients must have recovered
             from any effects of any major surgery.

         13. Immunocompromised patients, eg,human immunodeficiency virus (HIV) patients.

         14. Patients with known active hepatitis (B or C).

         15. Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non malignant systemic disease or active, uncontrolled infection.

         16. Patients with symptomatic uncontrolled brain metastases.

         17. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

         18. Patients with a known hypersensitivity to olaparib, AZD1775, AZD6738, or any of the
             excipients of the products.

         19. Pregnant or breast feeding women.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS) assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy in BRCAm, Non BRCAm HRRm, Non HRRm patient population.
Time Frame:From data of randomization until date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.
Safety Issue:
Description:PFS was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomized therapy or another anti-cancer therapy prior to progression. Patients who did not progress or die at the time of analysis would be censored at the time of the latest date of assessment from their last evaluable RECIST using BICR. Sensitivity analysis of PFS using investigator assessment according to RECIST 1.1.

Secondary Outcome Measures

Measure:PFS assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy in HRRM and in All patient population.
Time Frame:From data of randomization until date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.
Safety Issue:
Description:PFS was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who did not progress or die at the time of analysis would be censored at the time of the latest date of assessment from their last evaluable RECIST according to BICR. Sensitivity analysis of PFS using investigator assessment according to RECIST 1.1.
Measure:Objective response rate (ORR) assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy.
Time Frame:From date of randomisation until progression, or last evaluable assessment in the absence of progression, assessed up to 24 months.
Safety Issue:
Description:The ORR was defined using the BICR data to define a visit response of CR or PR, with the denominator defined as subset of all randomised patients with measurable disease at baseline per BICR. ORR will be assessed by using BICR according to RECIST 1.1. For sensitivity analysis, ORR was defined as the percentage of patients with at least one Investigator-assessed visit response of CR or PR and will be based on a subset of all randomised patients with measurable disease at baseline per the site Investigator. ORR will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population.
Measure:Duration of response (DoR) assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy.
Time Frame:The time from the date of first documented response until date of documented progression according to BICR data or death in the absence of disease progression, assessed up to 24 months.
Safety Issue:
Description: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 (ie, date of PFS event or censoring - date of first response + 1). DoR will be assessed by using BICR according to RECIST 1.1. 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 (ie, date of PFS event or censoring - date of first response + 1). DoR will be assessed in BRCAm, Non BRCAm HRRm and Non HRRm patient population.
Measure:Tumour change assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy.
Time Frame:At week 16.
Safety Issue:
Description:Absolute change and percentage change from baseline in tumor lesions tumour size, at 16 weeks. Tumour change will be assessed in BRCAm, Non BRCAm HRRm and Non HRRm patient population.
Measure:Overall survival (OS) assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy.
Time Frame:From the date of randomisation until death due to any cause, assessed up to 42 months.
Safety Issue:
Description:OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis would be censored based on the last recorded date on which the patient was known to be alive. OS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population.
Measure:PFS assessment to compare the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy.
Time Frame:From data of randomization until date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.
Safety Issue:
Description:PFS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population. Sensitivity analysis of PFS using Investigator assessments according to RECIST 1.1.
Measure:ORR assessment to compare the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy.
Time Frame:From date of randomisation until progression, or last evaluable assessment in the absence of progression, assessed up to 24 months.
Safety Issue:
Description:ORR will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population. ORR will be assessed by using BICR according to RECIST 1.1. Sensitivity analysis of objective response using Investigator assessments according to RECIST 1.1.
Measure:DoR assessment to compare the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy.
Time Frame:The time from the date of first documented response until date of documented progression according to BICR data or death in the absence of disease progression, assessed up to 24 months.
Safety Issue:
Description:DoR will be assessed in BRCAm, Non BRCAm HRRm, Non HRRm patient population. DoR will be assessed by using BICR according to RECIST 1.1.Sensitivity analysis of DoR using Investigator assessments according to RECIST 1.1.
Measure:Tumour change assessment to compare the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy.
Time Frame:At week 16.
Safety Issue:
Description:Absolute change and percentage change from baseline in TLs tumour size at 16 weeks will be based on RECIST. Tumour change will be assessed in BRCAm, Non BRCAm HRRm, Non HRRm patient population. Sensitivity analysis of tumour change using Investigator assessments according to RECIST 1.1.
Measure:Overall survival (OS) assessment to compare the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy.
Time Frame:From the date of randomisation until death due to any cause, assessed up to 42 months.
Safety Issue:
Description:Time to death for any cause. OS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All,Non HRRm patient population.
Measure:Mutation status of HRR genes.
Time Frame:At Day 1, Day 8 and Day 15 of cycle 1, Day 1 of cycle 2, and at treatment discontinuation (an average of 1 year).
Safety Issue:
Description:Assessed in all patient population. To explore the frequency of and describe the nature of tumour HRR (including breast cancer (BRCA)) mutation(s) in tumour samples and to compare this with germline HRR (including BRCA) mutation Status in All patient population.
Measure:Minimum steady-state plasma drug concentration during a dosage interval (Cmin ss).
Time Frame:At cycle 1 (Day 1 and Day 10) for olaparib and AZD1775. At Cycle 1 (Day 1 and Day 7) for olaparib and AZD6738.
Safety Issue:
Description:Minimum steady-state plasma drug concentration during a dosage interval (Cmin ss). At Cycle 1 Day 1: 1-3 hours, 3-6 hours and 6-12 hours; Cycle 1 Day 10: pre-dose, 0.5-1 hour, 1-3 hours, 3-6 hours and 6-12 hours for olaparib and AZD1775. Cycle 1 Day 1: 1-3 hours, 3-6 hours and 6-12 hours, Cycle 1 Day 7: pre-dose, 0.5-1 hour, 1-3 hours, 3-6 hours and 6-12 hours for olaparib and AZD6738. To assess exposure to olaparib, AZD6738 and AZD1775 in all patients.
Measure:No of participants with adverse events (AEs)
Time Frame:Adverse events collected from informed consent until 30-day follow-up period after last dose of study medication.
Safety Issue:
Description:AEs (severity graded by Common Terminology Criteria for Adverse Event [CTCAE] v4). Safety and tolerability of the combination of AZD6738+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy by assessment of adverse events (AEs).
Measure:Assessment of twelve lead safety electrocardiography (ECG).
Time Frame:At baseline, cycle 1 [On Day 1, 7, 15 for olaparib monotherapy and AZD6738+olaparib; on Day 1, 10, 15 for AZD1775+Olaparib], at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication.
Safety Issue:
Description:ECG assessment to be done in triplicate on Day 1 of every cycle, within 1-2 hours of dosing. The patients will rest for at least 10 minutes before the start of each recording and they must be in the same supine body position (maximum 30 degrees flexion in the hip and feet not in contact with the footboard) at the recording time point.
Measure:Assessment of Eastern Cooperative Oncology Group performance status (ECOG).
Time Frame:At baseline, Day 1 of cycle 1 and at treatment discontinuation (an average of 1 year).
Safety Issue:
Description:A performance status using scales and criteria to assess how a patient's disease is Progressing. The cycle length for olaparib monotherapy and AZD6738+olaparib treatment arms will be 28 days. The cycle length for AZD1775+olaparib treatment arm is 21 days.
Measure:Laboratory assessments of clinical chemistry.
Time Frame:At baseline, cycle 1 [On Day 1, 7, 15 for olaparib monotherapy and AZD6738+olaparib; on Day 1, 10, 15 for AZD1775+Olaparib], at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication.
Safety Issue:
Description:To assess the clinical chemistry (creatinine, bilirubin total, alkaline phosphatase, aspartate transaminase, alanine transaminase, albumin, potassium, sodium, calcium, blood urea nitrogen, C-reactive protein, and total protein) as a criteria of safety and tolerability of the combination of AZD6738+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy.
Measure:Laboratory assessments of Haematology.
Time Frame:At baseline, cycle 1 [On Day 1, 7, 15 for olaparib monotherapy and AZD6738+olaparib; on Day 1, 10, 15 for AZD1775+Olaparib], at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication.
Safety Issue:
Description:To assess the hematology (haemoglobin, leukocyte count, absolute neutrophil count, absolute lymphocyte count, platelet count, and mean cell volume (MCV)) as a criteria of safety and tolerability of the combination of AZD6738+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy.
Measure:Laboratory assessments of urinalysis.
Time Frame:At screening Part 2 (visit 1; from day -28 to 0).
Safety Issue:
Description:To assess the urinalysis (Hemoglobin/erythrocytes/blood, protein/albumin, and glucose) as a criteria of safety and tolerability of the combination of AZD6738+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy. After screening, urinalysis will only be required if clinically indicated.
Measure:Assessments of blood pressure.
Time Frame:At baseline, cycle 1 [On Day 1, 7, 15 for olaparib monotherapy and AZD6738+olaparib; on Day 1, 10, 15 for AZD1775+Olaparib], at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication.
Safety Issue:
Description:Blood pressure will be measured as a criteria of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.
Measure:Assessments of pulse.
Time Frame:At baseline, cycle 1 [On Day 1, 7, 15 for olaparib monotherapy and AZD6738+olaparib; on Day 1, 10, 15 for AZD1775+Olaparib], at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication.
Safety Issue:
Description:Pulse rate will be measured as a criteria of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Germline BRCA mutation
  • Human epidermal growth factor receptor 2
  • Olaparib
  • Homologous Recombinant Repair (HRR)-related Genes

Last Updated

April 25, 2018