Addition of Vismodegib to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Patients

Study Overview
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Brief Summary
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To evaluate safety and efficacy of vismodegib with standard neoadjuvant chemotherapy in breast cancer patients based on the CTCAE v4 2010 To study changes in biomarkers involved in the Hedgehog (HH) pathway in the first biopsy as compared to the later one To detect predictive factors among patients who reached pathological complete response (pCR) as compared to those with no pCR To evaluate the role of the addition of vismodegib in the pCR rate To evaluate clinical responses by breast MRI and rates of breast conservative surgery after neoadjuvant chemotherapy To evaluate QOL with EORTC QLQ-C30 scale

Official Title
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A Randomized Phase II Pilot Study to Evaluate Safety and Efficacy of the Addition of Vismodegib to Standard Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: vismodegib
* Drug: Paclitaxel
* Drug: Epirubicin
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female sex Ability to give informed agreement and to carry out the whole study protocol during the study period The patient should be able to carry out the needs of the clinical trial and have measurable disease The patient should be 18-75 year-old Triple negative breast cancer (ER<1%, Progesteron Receptor (PR)<1%, non-overexpressing HER2). 1. Patients with oligometastatic disease (1-2 resectable metastases) could be included No previous systemic therapies Patients who are going to benefit from neoadjuvant chemotherapy Eastern Cooperative Oncology Group (ECOG)<2 or Karnofsky≥70% Blood tests and biochemistry suitable: (absolute neutrophil count> 1500/uL; haemoglobin>9 gr/dL; platelets>100000/uL (microliters); total bilirubin≤ 1.5 the upper normal limit; GOT and GPT (transaminases)≤twice the upper normal limit; fasting glucose≤150 gr/dL; HbA1c≤8%, serum creatinine≤2 mg/dL. Exclusion Criteria: Severe diseases or infectious diseases or liver, kidney or bone marrow failure that advise not to participate in the study according to investigator criteria Pregnancy or breast feeding period or fertility women who are not agree with contraception methods Other primary tumors except for breast in situ carcinoma (CIS), cervical neoplasia(CIN) or localized skin tumors Inflammatory breast cancer or bilateral breast cancer Bone fractures, peptic ulcus or healing disorders Any local or systemic therapy for breast cancer To be maintained on immunosuppressants (prednisone > 10 mgr daily or others), aspirin> 325 mgr per day or clopidogrel > 75 mgr daily Cardiomyopathy by New York Heart Association (NYHA) class II-IV; heart stroke in the previous 6 months; uncontrolled blood pressure (systolic > 150 mm Hg and /or diastolic > 100 mm Hg), coagulopathy or hemorrhagic diseases Previous lung diseases Personal history of abdominal perforation, abdominal abscess, or abdominal fistula. Inability to swallow pills Intolerance to galactose, malabsorption to galactose or/and glucose, or primary hypolactasia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vismodegib plus chemotherapy<br>Vismodegib 150 mg orally during paclitaxel and then dose dense epirubicin + cyclophosphamide (EC) therapy (see active comparator arm) | Drug: vismodegib<br>* Smo inhibitor<br>* Other names: GDC0449;Drug: Paclitaxel<br>* Paclitaxel (80 mg/m2) weekly x 12 doses followed by sequential dose dense Epirubicin (90 mg/m2) plus Cyclophosphamide (600 mg/m2) each 2 weeks x 4 doses with granulocyte macrophage colony stimulating factors (GM-CSF) support<br>Drug: Epirubicin<br>* dose dense Epirubicin (90 mg/m2) plus Cyclophosphamide each 2 weeks x 4 doses with GMCSF after Paclitaxel<br>Drug: Cyclophosphamide<br>* dose dense Cyclophosphamide (600 mg/m2) together with Epirubicin each 2 weeks x 4 doses with GMCSF after Paclitaxel<br>|
| Active Comparator: chemotherapy<br>Paclitaxel 80 mg/m2 weekly on days 1, 8 and 15 each 21 days x 12 doses and then dose dense E (90 mg/m2) plus cyclophosphamide (CPA) 600 mg/m2 each 2 weeks x 4 doses | Drug: Paclitaxel<br>* Paclitaxel (80 mg/m2) weekly x 12 doses followed by sequential dose dense Epirubicin (90 mg/m2) plus Cyclophosphamide (600 mg/m2) each 2 weeks x 4 doses with granulocyte macrophage colony stimulating factors (GM-CSF) support<br>Drug: Epirubicin<br>* dose dense Epirubicin (90 mg/m2) plus Cyclophosphamide each 2 weeks x 4 doses with GMCSF after Paclitaxel<br>Drug: Cyclophosphamide<br>* dose dense Cyclophosphamide (600 mg/m2) together with Epirubicin each 2 weeks x 4 doses with GMCSF after Paclitaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with treatment-related adverse events as assessed by CTCAE v4.0 |  | 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular changes in breast |  | 30 months | 
| Pathologic complete response (pCR) |  | 30 months | 
| Clinical complete response (cCR) |  | 21 months | 
| European Organisation for Research and Treatment of Cancer Quality of Life questionnaire C30 (EORTC QOL-C30) | We will consider data related to quality of life such as weakness, appetite, physical health, physiological health, social relationships, environment etc | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, triple negative, neoadjuvant