Clinical Trial: NCT03330847 - My Cancer Genome

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 (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.

Related Conditions:

Breast Carcinoma

Recruiting Status:

Active, not recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT03330847

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

Drug	Synonyms	Arms
Olaparib Continuous (28-Day cycle) 300 mg BD.		Olaparib monotherapy
Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).		Olaparib+Ceralasertib
Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).		Olaparib+adavosertib

Purpose

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 (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.

Trial Arms

Name	Type	Description	Interventions
Olaparib monotherapy	Active Comparator	All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).	Olaparib Continuous (28-Day cycle) 300 mg BD.
Olaparib+Ceralasertib	Active Comparator	All randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD).	Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).
Olaparib+adavosertib	Active Comparator	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).	Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).

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.

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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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 Ceralasertib+olaparib and adavosertib+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:	Minimum steady-state plasma drug concentration during a dosage interval (Cmin ss).
Time Frame:	At Day 1 and Day 10 of cycle 1 (each cycle is 21 days) for olaparib and adavosertib. At Day 1 and Day 7 of Cycle 1 (each cycle is 28 days) for olaparib and Ceralasertib.
Safety Issue:
Description:	To assess Cmin ss in olaparib, Ceralasertib and adavosertib treatments. At Cycle 1 Day 1: 2 hours, 4.5 hours and 9 hours; Cycle 1 Day 7: pre-dose, 0.5 hour, 2 hours, 4.5 hours and 9 hours for olaparib arm. At Cycle 1 Day 1: 3. Cycle 1 Day 1: 2 hours (±1 hour), 4.5 hours (±1.5 hour) and 9 hours, (±3 hours), Cycle 1 Day 7: pre-dose, 0.5hour (±0.5 -1 hour, 2 hours and (±1 hour), 4.5 hours. (±1.5 hours) and 9 hours (±3 hour) for olaparib and Ceralasertib. At Cycle 1 Day 1: 2 hours, 4.5 hours and 9 hours; Cycle 1 Day 10: pre-dose, 0.5 hour, 2 hours, 4.5 hours and 9 hours for olaparib arm and adavosertib.

Measure:	Number 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 adavosertib+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 Ceralasertib+olaparib; on Day 1, 10, 15 for adavosertib+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 subsequent cycles/ treatment visits (each cycle is 21 days for olaparib and adavosertib and and 28 days for olaparib and Ceralasertib), 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 Ceralasertib+olaparib treatment arms will be 28 days. The cycle length for adavosertib+olaparib treatment arm is 21 days.

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 Ceralasertib+olaparib and the combination of adavosertib +olaparib compared with olaparib monotherapy. After screening, urinalysis will only be required if clinically indicated.

Measure:	Frequency of tumour HRR mutations
Time Frame:	At Screening (up to Day-28)
Safety Issue:
Description:	To explore the frequency of HRR (including BRCA) mutation(s) in tumour samples in All patient population.

Measure:	Nature of tumour HRR mutations
Time Frame:	At Screening (up to Day-28)
Safety Issue:
Description:	To describe the nature of HRR (including BRCA) mutation(s) in tumour samples in the All patient population.

Measure:	To compare the frequency and nature of tumour HRR mutations to germline mutational status
Time Frame:	At Screening (up to Day-28)
Safety Issue:
Description:	To compare the frequency and nature of tumour HRR to germline mutational status in All patient population.

Measure:	Number of participants with abnormal laboratory assessments of clinical chemistry- Ceralasertib+olaparib
Time Frame:	At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 criterion of safety and tolerability of Ceralasertib+olaparib.

Measure:	Number of participants with abnormal laboratory assessments of clinical chemistry- adavosertib +olaparib
Time Frame:	At baseline, Cycle 1 (Day 1, 8, 10, 15 [each cycle is 21 days]), Cycle 2 (Day 1, 8, 15), Day 1 on next visits, 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 criterion of safety and tolerability of adavosertib +olaparib.

Measure:	Number of participants with abnormal laboratory assessments of clinical chemistry- olaparib monotherapy
Time Frame:	At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 criterion of safety and tolerability of olaparib monotherapy.

Measure:	Laboratory assessments of Haematology - Ceralasertib+olaparib
Time Frame:	At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 criterion of safety and tolerability of Ceralasertib+olaparib.

Measure:	Laboratory assessments of Haematology- adavosertib +olaparib
Time Frame:	At baseline, Cycle 1 (Day 1, 8, 10, 15 [each cycle is 21 days]), Cycle 2 (Day 1, 8, 15), Day 1 on next visits, 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 criterion of safety and tolerability of adavosertib +olaparib.

Measure:	Laboratory assessments of Haematology - olaparib monotherapy
Time Frame:	At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 criterion of safety and tolerability of olaparib monotherapy.

Measure:	Assessments of blood pressure- Ceralasertib+olaparib
Time Frame:	At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 (systolic and diastolic) will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Measure:	Assessments of blood pressure- adavosertib +olaparib
Time Frame:	At baseline, Cycle 1 and 2 (Day 1, 8, 15 [each cycle is 21 days]), Day 1 on subsequent treatment visits, 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 (systolic and diastolic) will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Measure:	Assessments of blood pressure- olaparib monotherapy
Time Frame:	At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 (systolic and diastolic) will be measured as a criterion 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- Ceralasertib+olaparib
Time Frame:	At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 criterion 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- adavosertib +olaparib
Time Frame:	At baseline, Cycle 1 and 2 (Day 1, 8, 15 [each cycle is 21 days]), Day 1 on subsequent treatment visits, 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 criterion 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- olaparib monotherapy
Time Frame:	At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, 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 criterion 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:	Active, not recruiting
Lead Sponsor:	AstraZeneca

Trial Keywords

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

Last Updated

June 11, 2021

Clinical Trials /

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