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

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ClinicalTrials.gov Identifier: NCT03330847
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : June 8, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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 (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.

Condition or disease Intervention/treatment Phase
Metastatic Triple Negative Breast Cancer Drug: Olaparib Continuous (28-Day cycle) 300 mg BD. Drug: AZD6738 160 mg OD + olaparib continuous 300 mg BD (28-day cycle). Drug: AZD1775 175 mg BD + olaparib 200 mg BD (21-day cycle). Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
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.
Primary Purpose: Treatment
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).
Actual Study Start Date : February 21, 2018
Estimated Primary Completion Date : January 20, 2021
Estimated Study Completion Date : January 20, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

Arm Intervention/treatment
Active Comparator: Olaparib monotherapy
All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).
Drug: Olaparib Continuous (28-Day cycle) 300 mg BD.
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).

Active Comparator: Olaparib+AZD6738
All randomized patients will receive Olaparib 300 mg twice daily+AZD6738 160 mg once daily (OD).
Drug: AZD6738 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).
Patients will be administered AZD6738 OD at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle.

Active Comparator: Olaparib+AZD1775
All randomized patients will receive Olaparib 200 mg BD +AZD1775 175 mg BD.
Drug: AZD1775 175 mg BD + olaparib 200 mg BD (21-day cycle).
Patients will be administered AZD1775 BD at 175mg from Day 1 to Day 3 and Day 8 to Day 10.




Primary Outcome Measures :
  1. 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. ]
    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 :
  1. 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. ]
    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.

  2. 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. ]

    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.


  3. 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. ]
    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.

  4. Tumour change assessment to evaluate the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy compared to olaparib monotherapy. [ Time Frame: At week 16. ]
    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.

  5. 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. ]
    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.

  6. 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. ]
    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.

  7. 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. ]
    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.

  8. 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. ]
    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.

  9. Tumour change assessment to compare the efficacy of AZD6738+olaparib and AZD1775+olaparib combination therapy. [ Time Frame: At week 16. ]
    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.

  10. 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. ]
    Time to death for any cause. OS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All,Non HRRm patient population.

  11. 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). ]
    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.

  12. 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. ]
    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.

  13. 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. ]
    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).

  14. 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. ]
    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.

  15. 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). ]
    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.

  16. 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. ]
    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.

  17. 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. ]
    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.

  18. Laboratory assessments of urinalysis. [ Time Frame: At screening Part 2 (visit 1; from day -28 to 0). ]
    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.

  19. 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. ]
    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.

  20. 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. ]
    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.



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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03330847


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

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Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Andrew Tutt, MB ChB PhD Guy's Hospital, Great Maze Pond, London.

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03330847     History of Changes
Other Study ID Numbers: D5336C00001
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: June 8, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
Germline BRCA mutation
Human epidermal growth factor receptor 2
Olaparib
Homologous Recombinant Repair (HRR)-related Genes

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents