NOV-002, Doxorubicin, Cyclophosphamide, and Docetaxel in Women With Newly Diagnosed Stage II or IIIC Breast Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Oxidized glutathione (NOV-002) may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Giving NOV-002 together with chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying how well giving oxidized glutathione (NOV-002) together with doxorubicin and cyclophosphamide followed by docetaxel works in treating women with newly diagnosed stage II or stage III breast cancer.

Detailed Description
-----------------
OUTLINE: This is a multicenter study. Patients receive oxidized glutathione (NOV-002) IV twice on day -1 of course 1 and once on day 1 of courses 2-8. Patients receive NOV-002 subcutaneously once daily on days 2-21 of courses 1-8. Patients also receive chemotherapy comprising doxorubicin hydrochloride IV and cyclophosphamide IV on day 1 of courses 1-4 followed by docetaxel IV on day 1 of courses 5-8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo definitive surgery 3-6 weeks after completion of neoadjuvant therapy. Blood samples are obtained at baseline and periodically during study to measure serum and plasma protein glutathionlylation. Additional blood samples are collected from some patients for immunological correlative studies. After completion of study therapy, patients are followed at 30 days.

Official Title
-----------------
Phase II Study of Neoadjuvant Treatment With NOV-002 in Combination With Doxorubicin and Cyclophosphamide Followed by Docetaxel in Patients With Stages IIB-IIIC Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Docetaxel
* Drug: Doxorubicin
* Drug: NOV 002


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Females age 18 years or older. The ability to provide written informed consent prior to study specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time. Histologically confirmed infiltrating (invasive) breast cancer by core needle biopsy, with no evidence of metastatic disease except to the ipsilateral axillary lymph nodes. Clinical stage IIB - IIIC (T2-4, N0 or N1, M0 or - any T, N1-3, M0) breast cancer. The primary tumor must be greater than or equal to 2 cm (T2-4) or with pathologically proven axillary nodal involvement (N1-3). Patients with inflammatory breast cancer (T4) are permitted into the study. Clinically palpable tumor that meets the criteria of RECIST for palpable measurable disease. The primary tumor must be greater than or equal to 2 cm (T2-4) or with pathologically proven axillary nodal involvement (N1-3). Bilateral synchronic breast cancers are allowed but one of the primary tumors should be selected as the target tumor. Primary tumor may be estrogen or progesterone receptor negative or positive, and human epidermal growth factor receptor 2 (HER-2/neu) negative as determined by either Fluorescent In Situ Hybridization (FISH) or 0-2+ staining by immunohistochemistry (IHC) (Hercept™). Normal cardiac ejection fraction (EF ≥ 50%) as determined by screening multigated acquisition scan (MUGA) or echocardiogram. No prior history of myocardial infarction, congestive heart failure, symptomatic coronary artery disease, or cardiac arrhythmias. Patients must be ambulatory with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. The patient or her caregiver must be able to self administer daily subcutaneous injections. Life expectancy greater than 6 months. Exclusion Criteria: Prior therapy of any modality for the treatment of breast cancer Any prior therapy with an anthracycline or a taxane for any other indication HER-2 positive breast cancer defined as either gene amplification by Fluorescent In Situ Hybridization (FISH) or 3+ staining by IHC (Hercept™). Women who have a positive pregnancy test, no pregnancy test available, who are pregnant or who are lactating. Women of childbearing potential must agree to use a reliable and appropriate contraceptive method, which could include a double barrier method (condom plus diaphragm), an intrauterine device or oral contraceptives. Women with ER or PR positive breast cancer, should not, however, use oral contraceptives as a method of contraception. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Women with breast cancer that do not have palpable breast tumors at screening. History of another malignancy within the last 5 years except curatively treated basal cell carcinoma of the skin or cervical intraepithelial neoplasia. Clinically significant (i.e. active) cardiac disease (NYHA Grade II or greater congestive heart failure, symptomatic coronary artery disease, unstable angina, and cardiac arrhythmia not well-controlled with medication), myocardial infarction within the last 6 months prior to study start, or screening ejection fraction of < 50%. Any of the following abnormal laboratory values: Absolute neutrophil count < 1.5 x 109/L Platelet count < 100 x 109/L Serum bilirubin > 1.5 x upper limit of normal (ULN) Serum alanine transaminase (ALT), aspartate transaminase (AST) > 2.5 x ULN Serum creatinine > 2.0 mg/dL or 177mmol/L or calculated creatinine clearance by the method of Cockcroft and Gault < 50mL/min). Any severe or poorly controlled systemic disease (e.g., hypertension; clinically significant cardiovascular, pulmonary, or metabolic disease, disorders of wound-healing, ulcer or bone fracture). Patients who have received any investigational treatment within 4 weeks of study start. Known infection with HIV, Hepatitis B virus (HBV), or Hepatitis C virus (HCV). Known hypersensitivity to any of the components of NOV-002 or to any of the study drugs. Patients assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NOV-002 and Chemotherapy<br>NOV-002: Cycle 1, Day -1 only: 60 mg intravenously (IV) x 2, 3 hours (+/- 30 minutes) apart Cycles 1 - 8, Day 1: 60 mg IV, 1 hour (+/- 30 minutes) prior to chemotherapy administration Cycle 1 - 8, Days 2 - 21: 60 mg subcutaneous injections Cyclophosphamide: 600 mg/m2 IV, Cycles 1 - 4, Day 1 Doxorubicin: 60 mg/m2 IV, Cycles 1 - 4, Day 1 Docetaxel: 100 mg/m2 IV, Cycles 5 - 8, Day 1 | Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: Docetaxel<br> <br> * Other names: Cytoxan;Drug: Doxorubicin<br> <br> * Other names: Adriamycin;Drug: NOV 002<br> <br> * Other names: Oxidized glutathione;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pathologic Complete Response in the Affected Breast After Protocol Therapy | The primary objective of this study is to define the rate of pathologic complete response rate (pCR) in the affected breast after the preoperative administration of NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with stage IIB-IIIC breast cancer. Pathologic complete response (pCR) is defined according to Hankoop et al [41] as either: the absence of any histological evidence of invasive breast cancer cells in the tissue specimen removed from the breast or the presence of invasive tumor equal to or less than 10mm after preoperative treatment, determined at definitive breast surgery. | About 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definition of the Safety Profiles of Protocol Therapy | Definition of the safety profiles of protocol therapy in study participants as shown by the number of study participants experiencing adverse events or other toxicity. | Up to 30 days Post-Last Dose of Protocol Therapy, About 7 months | 
| Correlation Between Myeloid Derived Suppressor Cell (MDSC) Levels and Pathologic Complete Response (pCR) and Non-Responders | The investigators hypothesized that patients with favorable responses, i.e. pCR, are more likely to have significantly lower levels of MDSCs than non-responders. MDSC levels will be measured at baseline and on day 1 of each treatment cycle, cycles 1 through 8. | Baseline, Day 1 of Cycles 1 through 8, about 7 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage II breast cancer, stage IIIC breast cancer, inflammatory breast cancer