Clinical trial NCT02685059 (phase 2, status: completed)
Conditions: breast cancer
ICD codes: C79.81, D24.1, D24.2, D24.9, D49.3, C44.501, D48.60
Drugs: medi4736 (anti pd-l1), placebo, nab-paclitaxel, epirubicin, cyclophosphamide
SMILES: CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O, [H][C@]12[C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)C4=CC=CC=C4)C4=CC=CC=C4)C(C)=C([C@@H](OC(C)=O)C(=O)[C@]1(C)[C@@H](O)C[C@H]1OC[C@@]21OC(C)=O)C3(C)C, CN(C1=CC2=NN(C)C(C)=C2C=C1)C1=CC=NC(NC2=CC=C(C)C(=C2)S(N)(=O)=O)=N1, ClCCN(CCCl)P1(=O)NCCCO1
Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent for all study according to local regulatory requirements
             prior to beginning specific protocol procedures.

          -  Complete baseline documentation must be sent to GBG Forschungs GmbH.

          -  Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by
             core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not
             allowed. In case of bilateral cancer, the investigator has to decide prospectively
             which side will be evaluated for the primary endpoint.

          -  Tumor lesion in the breast or the nodes must be measurable in two dimensions,
             preferably by sonography. In case of inflammatory disease, the extent of inflammation
             can be used as measurable lesion.

          -  Patients must be in the following stages of disease: cT1b - cT4a-d irrespective of
             nodal involvement.

        In patients with multifocal or multicentric breast cancer, the largest lesion should be
        measured.

          -  Triple negative disease with centrally confirmed ER negative/PR negative/HER-2
             negative, and centrally confirmed Ki-67 value. ER negative is defined as <1% stained
             cells, PR negative is defined as <10% stained and HER2-negative is defined as either
             IHC 0/1+ or IHC 2+ and in-situ hybridisation (ISH) of either ratio <2.0 or less than 6
             copies of HER2 per tumor cell. Stromal TILs will be evaluated in three groups: low
             immune infiltrate (0-10% stromal TILs) intermediate immune infiltrate (11-59% stromal
             TILs), LPBC 60-100% stromal TILs. PD-L1 status and other predefined markers will be
             prospectively assessed during the study. Formalin-fixed, paraffin-embedded (FFPE)
             breast tissue from core biopsy has therefore to be sent to the GBG central pathology
             laboratory prior to randomization.

          -  Age >=18 years.

          -  ECOG Performance status 0-1.

          -  Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or
             shortening fraction) within 3 months prior to randomization. Results must be above the
             normal limit of the institution.

          -  Negative pregnancy test (urine or serum) within 14 days prior to randomization for all
             women of childbearing potential. Female subjects must either be of non-reproductive
             potential (ie, post-menopausal by history: >=60 years old and no menses for >=1 year
             without an alternative medical cause; OR history of hysterectomy, OR history of
             bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a
             negative serum pregnancy test upon study entry.

          -  Complete staging work-up within 3 months prior to randomization. All patients must
             have had breast imaging by breast ultrasound plus either bilateral mammography or
             breast MRI (one of those <= 21 days). All patients must have had chest X-ray (PA and
             lateral), abdominal ultrasound or CT scan or MRI, and bone scan (according to
             guidelines). In case of positive bone scan, bone X-ray is mandatory. Other tests may
             be performed as clinically indicated.

          -  Patients must be available and compliant for central diagnostics, treatment and
             follow-up.

          -  Laboratory requirements: Hematology, Hepatic function, Renal Function, Thyroid
             function

        Exclusion Criteria:

          -  Prior chemotherapy for any malignancy.

          -  Prior radiation therapy for breast cancer.

          -  Pregnant or lactating patients. Patients of childbearing potential must implement
             adequate non-hormonal contraceptive measures (barrier methods, intrauterine
             contraceptive devices, sterilization) during study treatment.

          -  Inadequate general condition (not fit for dose-dense, dose-intensified
             anthracycline-taxane-targeted agents-based chemotherapy).

          -  Previous malignant disease being disease-free for less than 5 years (except CIS of the
             cervix and non-melanomatous skin cancer).

          -  6. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart
             disease, angina pectoris requiring antianginal medication, previous history of
             myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or
             poorly controlled arterial hypertension (i.e. BP >140 / 90 mm Hg under treatment with
             at maximum two antihypertensive drugs), rhythm abnormalities requiring permanent
             treatment, clinically significant valvular heart disease.

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Bazett's Correction

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis)

          -  History of primary immunodeficiency

          -  History of allogeneic organ transplant

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, active peptic ulcer disease or gastritis, active bleeding diatheses
             including any subject known to have evidence of acute or chronic hepatitis B,
             hepatitis C or human immunodeficiency virus (HIV).

          -  Known history of previous clinical diagnosis of tuberculosis

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving MEDI4736

          -  Autoimmune disease and conditions (i.e. inflammatory bowel disease)

          -  History of significant neurological or psychiatric disorders including psychotic
             disorders, dementia or seizures that would prohibit the understanding and giving of
             informed consent

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Pre-existing motor or sensory neuropathy of a severity >= grade 2 by NCI-CTC criteria
             v 4.0.

          -  Currently active infection.

          -  Incomplete wound healing or unhealed bone fracture.

          -  Definite contraindications for the use of corticosteroids

          -  Known hypersensitivity reaction to one of the compounds or incorporated substances
             used in this protocol;

          -  Concurrent treatment with:

          -  chronic corticosteroids prior to study entry with the exceptions of intranasal and
             inhaled corticosteroids or systemic corticosteroids at physiological doses, which are
             not to exceed 10 mg/day of prednisone, or equivalent corticosteroid.

          -  other immunosuppressive medication (e.g. low dose MTX)

          -  sex hormones (including hormonal contraception) prior treatment must be stopped before
             study entry.

          -  other experimental drugs or any other anti-cancer therapy.

          -  Participation in another clinical trial with any investigational, not marketed drug
             within 30 days prior to study entry.

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736

          -  Male patients.