The purpose of this study is to determine the safety profile, the maximum tolerated dose (MTD) and the associated dose-limiting toxicities (DLTs) of S 81694 in combination with paclitaxel in metastatic breast cancer (mBC) patients, and to investigate the antitumour activity of the combination in metastatic triple negative breast cancer (mTNBC) patients.

Inclusion Criteria:

For Phase I :

• Histologically or cytologically confirmed metastatic breast cancer, refractory to any standard therapy or for which the standard therapy is considered unsuitable;
• Patient must have at least one evaluable or measurable metastatic lesion (lesions as defined by revised Response Evaluation Criteria in Solid Tumors).

For Phase II :

• Histologically or cytologically confirmed advanced inoperable triple negative breast cancer with no prior anticancer therapy regimen in metastatic setting;
• Patient with a minimum washout period of 12 months following previous taxane based adjuvant therapy;
• Patient must have at least one measurable metastatic lesion. Ascites, pleural effusion, and bone metastases are not considered measurable;
• Acceptance of pre-treatment metastatic biopsies for all patients and on-treatment metastatic biopsies in selected centres.

For the whole study:

• Male or female subjects aged ≥ 18 years old, or legal age of the majority in the country;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
• Estimated life expectancy of at least 3 months;
• Adequate haematological function based on the last assessment performed within 7 days prior to the first IMP (investigational medicinal product) administration;
• Adequate renal function based on the last assessment performed within 7 days prior to the first IMP administration;
• Adequate hepatic function based on the last assessment performed within 7 days prior to the first IMP administration;
• Female participant of childbearing potential must have a negative pregnancy test (serum) within 7 days prior to the first day of test drug administration. Effective contraception both for female patients of childbearing potential and male patients with parteners of childbearing potential.

Exclusion Criteria:

• Other active malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer or intra-mucosal gastro-intestinal cancers that were treated curatively);
• Presence of grade ≥ 2 toxic effects (excluding alopecia) due to prior cancer therapy;
• Known hypersensitivity to the IMP (S 81694 and paclitaxel) or their excipients;
• Evidence of peripheral neuropathy of grade 2 or higher;
• Participant previously received paclitaxel and discontinued due to toxicity related to paclitaxel;
• Participant known as refractory to taxanes;
• Any prior cancer therapy within 4 weeks or 5 half-life (whichever is the shorter) before the first IMP administration;
• Participant with current, serious, uncontrolled infections;
• Participant with brain metastasis or leptomeningeal metastasis (except patients with brain metastasis that have been stable post-radiation therapy and who are off steroids for > 2 months);
• History of cardiac disease;
• Uncontrolled arterial hypertension;
• Presence of risk factors for torsades de pointes (e.g. heart failure, hypokalaemia, family history of long QT syndrome);
• Any clinically significant medical condition (e.g. organ dysfunction) or laboratory abnormality likely to jeopardize the patient's safety or to interfere with the conduct of the study, in the investigator's opinion.

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

After Marketing Authorisation in EEA or US if the study is used for the approval.

Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.