SHS_492411 ELLE NASZ 17210

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).

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

Inclusion criteria

• Progressive cancer at the time of study entry with a life expectancy of ≥16 weeks
• Histologically or cytologically confirmed TNBC with evidence of metastatic disease as per ASCO-CAP HER2 guideline recommendations 2013
• 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.
• Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.
• At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) and is suitable for repeated assessment as per RECIST 1.1.
• Patients must have normal organ and bone marrow function measured within 28 days prior to randomisation as defined by protocol

Exclusion criteria

• 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.
• More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.
• 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).
• 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.
• Patients with MDS/AML or with features suggestive of MDS/AML.
• Patients with second primary cancer,
• 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.
• Any of the protocol specified cardiac diseases currently or within the last 6 months defined by New York Heart Association (NYHA) ≥ Class 2:
• Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or use of known strong or moderate CYP3A inducers.
• Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
• Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
• Immunocompromised patients, eg,human immunodeficiency virus (HIV) patients.
• Patients with known active hepatitis (B or C).
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection.
• Patients with symptomatic uncontrolled brain metastases.
Phase II
Erin Ellis, M.D.
Shaula Levy
  • Swedish Medical Center