Phase II Trial of SAHA & Tamoxifen for Patients With Breast Cancer

Study Overview
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Brief Summary
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Phase II trial to explore the efficacy of vorinostat and tamoxifen combined.

Detailed Description
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Phase II trial to explore the efficacy of vorinostat and tamoxifen combined. Tamoxifen will be given once daily, continuously. Vorinostat will be given daily for 3 out of 4 weeks (a cycle). Responses will be assessed (restaged) after 2 cycles and toxicities will be captured continuously. Eligible patients will receive treatment in consecutive 4-week cycles, until progression of disease or unacceptable toxicity. Patients will be followed for evaluation of safety for at least 30 days after the last dose of the study drug. Tests will be obtained pre-and post vorinostat treatment and correlated with plasma levels of vorinostat at the time of tumor biopsy and vorinostat doses; the tests will consist of: Patient history Physical exam (including height and weight) Toxicity assessment Pharmacokinetic (PK) sample Tumor fine needle aspirate (FNA) Peripheral Blood Mononuclear Cells (PBMC) Standard labs and Chemistry Profile Carcinoembryonic antigen (CEA), cancer antigen (Ca) 15-3, Ca 125 (If clinically indicated) Pregnancy Test Computed tomography (CT) scans, and magnetic resonance imaging (MRI) Documentation of response and progression will be evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST).

Official Title
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Phase II Trial of Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat) in Combination With Tamoxifen for Patients With Advanced Breast Cancer Who Have Failed Prior Anti-hormonal Therapy.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: suberoylanilide hydroxamic acid (SAHA, Vorinostat)
* Drug: tamoxifen citrate (Tamoxifen)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have cytologically/histologically documented locally advanced or metastatic breast cancer with either: Progression on treatment with any aromatase inhibitor for metastatic disease; Recurrence while on adjuvant aromatase inhibitors or within 12 months of completion; Recurrence after having completed adjuvant tamoxifen for at least 12 months; Patient who are not candidates for or are intolerant of aromatase inhibitor treatment; Patients are allowed (but not required) to have one prior chemotherapy regimen for metastatic disease. Tumors must express estrogen or progesterone receptor. Patients are eligible regardless of the menopausal status. Age > 18 years old Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Patients must be able to give informed consent and able to follow guidelines given in the study. Patients must have acceptable organ function, as defined by the following laboratory parameters: white blood count (WBC) >3.0 x 10^9/L; absolute neutrophil count (ANC) >1.5 x 10^9/L; hemoglobin (Hgb) >10.0g/dL; platelets (PLT) >100 x 10^9/L, Bilirubin < 2.0 mg/dl, aspartate aminotransferase/alanine aminotransferase (AST/ALT) < 2.5 X upper limit of normal (ULN), Creatinine <1.8 mg/dl (Creatinine clearance >60 ml/min). Women of childbearing age must have a negative pregnancy test. All patients of reproductive potential must use an effective method of contraception during the study and 6 months following termination of treatment. (Not applicable to patients with bilateral oophorectomy and/or hysterectomy or to female patients who are older than 50 years and have not had a menstrual cycle in more than one year. Patients must have measurable disease by RECIST criteria by staging studies performed within 30 days of enrollment. For patients with bone only disease: For this protocol isolated bone lesions can be classified as target lesions if they are measurable by MRI at screening and must be followed by MRI. Both men and women of all races and ethnic groups are eligible for this trial. Exclusion Criteria: Patients must not have received tamoxifen for metastatic disease. Patients must not have evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) at time of study entry. Patients must be disease-free of prior invasive malignancies for > 5 years with the exception of: curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix. Pregnant and breast-feeding women are excluded from the study because effects on the fetus are unknown and there may be a risk of increased fetal wastage. Patients with uncontrolled central nervous system (CNS) metastasis or a history of seizures are excluded. Patients with stable CNS metastasis (either surgically resected, treated with gamma knife or stable for 3 months following whole brain radiation therapy [WBRT] are eligible). Patients with stable brain metastases will need an MRI within 4 weeks prior to start of therapy. Patients may not be receiving any other investigational agents and must have stopped all other histone deacetylase inhibitors (including Valproic acid) or other hormonal therapies. Patients must have discontinued their prior therapies for breast cancer and radiation therapy for a minimum of 3 weeks, patient is excluded if radiation therapy was given to a single measurable lesion and the disease is otherwise not measurable. Patients are excluded if they have any known hypersensitivity reaction to tamoxifen. Patient with a history of blood clots are not eligible. Women who have abnormal vaginal bleeding and/or endometrial hyperplasia or cancer are not eligible. Patients with evidence of visceral crisis are not eligible for this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorinostat and Tamoxifen<br>As outlined in Intervention descriptions | Drug: suberoylanilide hydroxamic acid (SAHA, Vorinostat)<br>* Vorinostat will be used to potentiate the effects of tamoxifen or overcome tamoxifen resistance. All patients will receive vorinostat at 400 mg by mouth (po) daily for 3 out of 4 weeks. Responses will be assessed after 2 cycles (8 weeks + 4 days).<br>* Other names: NSC #701852;Drug: tamoxifen citrate (Tamoxifen)<br>* Tamoxifen will be given once daily at 20 mg. Tamoxifen will be given continuously. Responses will be assessed after 2 cycles (8 weeks + 4 days).<br>* Other names: Tamoxifen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response (OR) | The Objective Response Rate. Response and progression were evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST). Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. For the purposes of this study, patients were evaluated for response every 8 weeks. In addition to a baseline scan, confirmatory scans were also obtained ≥ 4 weeks following initial documentation of objective response. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | The median response duration in months. Response and progression were evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST). | Up to 30 months | 
| Number of Participants With Serious Adverse Events (SAEs) | Safety evaluation according to descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | 4 years, 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Suberoylanilide hydroxamic acid (SAHA), Vorinostat, Tamoxifen, Anti-hormonal therapy, Estrogen receptor positive, Progesterone receptor positive, Metastatic disease, Aromatase inhibitors (Ais), Histone deacetylase (HDAC) inhibitors, Selective estrogen receptor modulators(SERMS)