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 (VIOLETTE Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Feb 2018 → ongoing

Decision date (initial)

2024-10-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2024-514205-60-00

EudraCT number

2017-002361-22

ClinicalTrials.gov

NCT03330847

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacogenetic, Pharmacokinetic, Safety

For BRCAm, Non BRCAm HRRm, Non HRRm subject population
- To assess the efficacy of the combination of ceralasertib+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy by assessment of PFS

Secondary objectives 8

1. For HRRm, All subject population - To assess the efficacy of the combination of ceralasertib+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy by assessment of PFS
2. For BRCAm, Non BRCAm HRRm, Non HRRm subject population - To assess the efficacy of the combination of ceralasertib+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy in terms of DoR, tumour change
3. For BRCAm, Non BRCAm HRRm, Non HRRm subject population - - To compare the efficacy of the combination of ceralasertib+olaparib with the combination of AZD1775+olaparib in terms of DoR, tumour change
4. For BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm subject population - To assess the efficacy of the combination of ceralasertib+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy in terms of ORR, OS
5. For BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm subject population - To compare the efficacy of the combination of ceralasertib+olaparib with the combination of AZD1775+olaparib in terms of PFS, ORR, OS
6. For All subject population - To explore the frequency of and describe the nature of tumour HRR (including BRCA) mutation(s) in tumour samples and to compare this with germline HRR (including BRCA) mutation status
7. For All subject population - To assess exposure to olaparib, ceralasertib and AZD1775 in all patients
8. For All subject population - To assess the safety and tolerability of the combination of ceralasertib+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy

Conditions and MedDRA coding

Triple Negative Breast Cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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).
11. Patient is willing to comply with the protocol requirements.
12. Life expectancy of ≥16 weeks.

Exclusion criteria 18

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-free Survival Per Stratum (BICR).
2. Progression-free Survival Per Stratum (Sensitivity Analysis).

Secondary endpoints 9

1. Progression-free Survival (Per BICR).
2. Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis).
3. Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis)
4. Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis]
5. Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis]
6. Overall Survival (OS)
7. Plasma Drug Concentrations of olaparib
8. Plasma Drug Concentrations of ceralasertib and adavosertib
9. Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

3 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications