Evaluation of an Anti-cancer Immunotherapy Combined With Standard Neoadjuvant Treatment in Patients With WT1-positive Primary Invasive Breast Cancer

The purpose of this study is to evaluate the safety, immunogenicity and clinical activity of a new WT1 anti-cancer immunotherapy in patients with WT1-positive Stage II or III breast cancer. The treatment will be given before surgery in combination with standard therapy.

The study will be conducted in two consecutive segments (Phase I and Phase II), each with specific objectives. Active follow-up will be for three years.

Patients in this study will be allocated to cohorts as below. Cohort A will include postmenopausal patients with hormone receptor-positive breast cancer who receive aromatase inhibitor (AI) as neoadjuvant therapy concurrently with administration of 6 or 8 doses of WT1 anti-cancer immunotherapy (WT1 ASCI)/placebo starting on Day 0. AI treatment will be administered daily for duration of either 18 (if 6 doses of WT1 ASCI/placebo) or 24 weeks (if 8 doses of WT1 ASCI/placebo).

Cohort B will include breast cancer patients who will receive neoadjuvant chemotherapy concurrently with administration of WT1 ASCI/placebo starting on Day 0. Neoadjuvant chemotherapy in Cohort B will consist either 1) if 6 doses of WT1 ASCI/placebo: 6 cycle-treatment chemotherapy regimens consist of 6, three-weekly cycles of anthracycline/taxane-based therapy, or 2) if 8 doses of WT1 ASCI/placebo: 8 cycle-treatment regimens consisting of 4 three-weekly cycles of anthracycline-based therapy followed by 4 three-weekly or 12-weekly taxane administrations without trastuzumab.

Cohort C will include patients with Human Epidermal Growth Factor Receptor 2 (HER2)-overexpressing breast cancer who will receive neoadjuvant trastuzumab (Herceptin) therapy combined with chemotherapy concurrently with administration of WT1 ASCI/placebo starting on Day 0. Neoadjuvant chemotherapy in Cohort C will consist either 1) if 6 doses of WT1 ASCI/placebo: 6 cycle-treatment chemotherapy regimens consist of 6, three-weekly cycles of anthracycline/taxane-based therapy, or 2) if 8 doses of WT1 ASCI/placebo: 8 cycle-treatment regimens consisting of 4 three-weekly cycles of anthracycline-based therapy followed by 4 three-weekly or 12-weekly taxane administrations with trastuzumab.

Cohorts D and E will include patients with hormone receptor-positive and HER2 non-overexpressing breast cancer who will receive neoadjuvant chemotherapy. For patients in these Cohorts D and E, WT1 ASCI/placebo (placebo applicable only for Cohort E patients) will be administered on Day 14 of each three-weekly cycle of chemotherapy. Neoadjuvant chemotherapy in Cohorts D and E will consist either 1) if 6 doses of WT1 ASCI/placebo: 6 cycle-treatment chemotherapy regimens consist of 6, three-weekly cycles of anthracycline/taxane-based therapy, or 2) if 8 doses of WT1 ASCI/placebo: 8 cycle-treatment regimens consisting of 4 three-weekly cycles of anthracycline-based therapy followed by 4 three-weekly taxane administrations without trastuzumab. Enrolment in Cohort E will be conditional on the absence of a safety signal and on the adequate induction of an immune response by the WT1 ASCI in Cohort D (defined as \>= 40% response rate based on post-Dose 4 anti-WT1 antibody responses in at least six patients). If this criterion is met, 60 patients (40 receiving WT1 ASCI and 20 placebo) with identical eligibility criteria will be enrolled into Cohort E. In case no adequate safety and/or immunogenicity will be obtained in Cohort D, recruitment in Cohort E will not be initiated.

The protocol has been updated following Protocol Amendment 4, April 2013, leading to the update of the study design.

Eligibility Criteria:
Inclusion Criteria:

* The patient is ≥ 18 years of age at the time the informed consent to screening has been obtained.
* The patient has proven T1 with lymph node involvement or T2-T4c, any N, M0 primary invasive breast cancer, histologically confirmed by core needle biopsy.

Isolated supraclavicular lymph node involvement is allowed.

* The patient's tumor shows WT1 antigen expression.
* The patient has one of the following histologically confirmed breast cancer subtypes:

  * Estrogen receptor and/or progesterone positive tumor.
  * Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer.
  * HER2-negative breast cancer.
* Eastern Cooperative Oncology Group (performance status of 0 or 1 at the time of study treatment allocation.
* Baseline left ventricular ejection fraction of ≥ 50% as measured within six weeks prior to study treatment allocation by echocardiography or multi-gated acquisition(MUGA)scan.
* The patient shows normal organ function according to the following parameters(as measured within six weeks prior to treatment allocation)::

  * Hemoglobin: Within normal range according to institutional standards.
  * Absolute leukocyte count: Within normal range according to institutional standards.
  * Absolute lymphocyte count: Within normal range according to institutional standards.
  * Platelet count: Within normal range according to institutional standards
  * Alanine aminotransferase: ≤ 2.5 x Upper Limit of Normal (ULN)
  * Aspartate aminotransferase: ≤ 2.5 x ULN
  * Total bilirubin: ≤ 1.5 x ULN. In the case of known Gilbert's syndrome ≤ 2 x ULN
  * Serum creatinine: 1.5 x ULN
  * Calculated creatinine clearance: \> 50 mL/min
* A female patient of childbearing potential may be enrolled in the study, if the patient:

  * has practiced adequate contraception for 30 days prior to study product administration, and
  * has a negative pregnancy test within one week prior to treatment allocation and
  * has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the study product administration series.In view of the investigator, the patient can and will comply with the requirements of the protocol.
* Written informed consent has been obtained from the patient prior to performance of any study specific procedure.

Exclusion Criteria:

* The patient has inflammatory breast cancer, which is defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion.
* Diagnosis established by incisional biopsy.
* Prior and concomitant neoadjuvant anti-breast-cancer treatments such as chemotherapy, immunotherapy / biological response modifiers, endocrine therapy, and radiotherapy, unless authorized specifically by the protocol.
* The patient is known to be human immunodeficiency virus -positive.
* The patient has symptomatic autoimmune disease such as, but not limited to multiple sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not excluded.
* The patient is known to have difficult-to-control hypertension, coronary artery disease, arrhythmia requiring treatment, clinically significant valvular disease, cardiomegaly on chest X-ray, ventricular hypertrophy on electrocardiogram or previous myocardial infarction or congestive heart failure.
* The patient has a history of allergic reactions likely to be exacerbated by any component of the investigational product used in the study.
* The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
* The patient has (or has had) previous or concomitant malignancies at other sites, except effectively treated malignancy that is considered by the investigator highly likely to have been cured.
* The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the study procedures.
* The patient has received any investigational or non-registered product within 30 days preceding the first dose of study products or planned use during the study period.
* The patient requires concomitant treatment with any immunosuppressive agents or with systemic corticosteroids prescribed for chronic treatment.
* The patient has a significant disorder of coagulation or receives treatment with warfarin derivatives or heparin. Patients receiving individual doses of low molecular weight heparin outside of 24 hours prior to WT1-A10 + AS15 ASCI/placebo administration are eligible. Patients receiving prophylactic antiplatelet medications e.g. low-dose aspirin, and without a clinically-apparent bleeding tendency are eligible.