Clinical Trials

A total of 150 patients will be studied. Each patient will have a suspicious lesion on mammogram, ultrasound or breast magnetic resonance imaging (MRI) for which biopsy is scheduled. The lesion size on mammogram, ultrasound or breast MRI must be less than 2 cm in diameter and must be considered "suspicious" or "highly suspicious" for malignancy. Following injection of 8 mCi Tc-99m sestamibi, all patients will undergo craniocaudal (CC) and mediolateral oblique (MLO) views of each breast using a molecular breast imaging (MBI) system incorporating the latest hardware and software algorithms. Each image will be acquired for 10 minutes in dynamic mode as 4 x 2.5 minute images. Summation of a given number of frames from each acquisition will yield images of an increasing mCi dose. Hence with an 8 mCi injection and a dynamic acquisition mode, we can evaluate the sensitivity of MBI as a function of administered doses of Tc-99m sestamibi ranging from 2 to 8 mCi. The thickness of the breast will be recorded to determine its relevance to lesion detectability.

     Patient Selection

     The goal of this study is to enroll 150 female patients in this study. The rationale for a study number of 150 patients is given in Appendix D. Patients referred for a mammogram, ultrasound or breast MRI study at Mayo Clinic Rochester will be considered for the study if they meet the following criteria:

       -  Have a lesion on mammogram, ultrasound or breast MRI that measured < 2 cm and is considered suspicious or highly suggestive of malignancy according to the Breast Imaging Reporting and Data System Atlas criteria (BI-RADS 4 or 5). (Note: while 2 cm is larger than the desired lesion size that we wish to study, this limit was recommended by our radiology colleagues as estimates of lesion size from mammography, ultrasound and MRI are not exact)

       -  Are scheduled for biopsy (needle and/or surgical biopsy) of the suspicious lesion

       -  Are > 18 years of age

       -  Had a negative pregnancy test or must be postmenopausal or surgically sterilized

     Eligible patients will be offered enrollment if the time interval between mammogram, ultrasound or MRI and scheduled biopsy allows for performance of MBI. Patients with prior needle biopsy of the lesion will be excluded from this study, as such biopsies may effectively remove all or part of the lesion. Prospective patients will be identified by the radiologist based on findings in their mammographic, ultrasound or MRI studies.

OBJECTIVES:

       -  To examine the changes in the plasma concentrations of the hydroxylated metabolite, 4-hydroxy tamoxifen, and endoxifen in women with known or at high risk for developing breast cancer who are receiving selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor therapy comprising venlafaxine, citalopram hydrobromide, escitalopram oxalate, gabapentin, or sertraline hydrochloride for the treatment of hot flashes, depression, or any other medically indicated condition.

       -  To evaluate whether genetic variants known to affect the activity of CYP2D6, SULT1A1, and other drug metabolizing enzymes (e.g., UGT's) involved in the biotransformation of tamoxifen citrate affect the plasma concentrations of the hydroxylated metabolites, 4-hydroxy tamoxifen and endoxifen.

     OUTLINE: This is a multicenter study.

     Patients receive oral tamoxifen citrate and concurrent selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) therapy comprising oral venlafaxine, citalopram hydrobromide, escitalopram oxalate, sertraline hydrochloride, or gabapentin for 8-24 weeks. Treatment continues in the absence of disease progression.

     Blood samples are obtained at baseline and after completion of study therapy. Samples are evaluated by pharmacokinetic analysis to determine the effects of SSRI/SNRI study drugs on plasma concentrations of tamoxifen and its metabolites. Plasma levels of tamoxifen citrate, N-desmethyl tamoxifen, 4-OH tamoxifen, and endoxifen are measured using reverse phase high performance liquid chromatography. Blood samples are also analyzed by CYP2D6 genotyping to test for CYP2D6 gene variation (i.e., *3, *4, *6, *10, *17, and *41) in genes that encode tamoxifen-metabolizing enzymes. Additional CYP2D6 alleles, including gene duplication and gene deletion (*5) are assessed.

This proposal describes a community-based participatory research study to develop and pilot test a new behavioral intervention to promote mammography screening among Navajo women. From a public health perspective, the intervention has the potential to reach many Navajo women, as 80% of women scheduled for mammography appointments do not follow through.  These women (over 1,500 each year) are referred to the Nation Breast and Cervical Cancer Prevention Program (NNBCCPP).  A key barrier toward implementing cancer prevention and control efforts in the Navajo community is a lack of cancer literacy or cultural and conceptual knowledge regarding cancer.  Other barriers to screening are fear of cancer, stigma of cancer (even talking about cancer) often experienced by the patient, family and community, and lack of knowledge about the etiology of cancer and importance of early detection.  Therefore, communication about cancer is impeded within Navajo families and the community.

     This proposal builds on our successful partnership and collaboration with Diné College (the Navajo tribal college).  The proposed study is designed to assess the feasibility and potential efficacy of a cancer-literacy focused, family-based intervention on completion of mammography screening for Navajo women.  The intervention will include culturally and linguistically appropriate educational materials about cancer (e.g., the Navajo Cancer Glossary).  The project will be implemented in two phases.  During Phase 1, the investigators will develop the family cancer literacy intervention with feedback from our community advisory committee.  In addition, the Cancer Literacy Measure will be adapted for Navajo women through focus groups and individual interviews.  Phase 2 will consist of a formative evaluation of the intervention.  The NNBCCPP patient and a female family member will be randomly assigned in pairs to the control condition (existing NNBCCPP health education services, N=40 pairs) or to receive these health education services plus the family cancer literacy intervention (N=40 pairs).  The investigators  will assess the intervention's feasibility and acceptability as indicated by the recruitment and retention rates and qualitative ratings of treatment acceptability.  In addition, the investigators will examine the effect of the intervention compared with the control group on the proportion of women who complete mammography screening at 3-month follow-up documented by NNBCCPP records.   The investigators will also examine changes in Cancer Literacy Measure scores from baseline to 3-month follow-up among both patients and family members.  The investigators expect that as a result of this project, the investigators will have developed a replicable, feasible, and acceptable intervention, the efficacy of which can be tested in future large-scale randomized clinical trials.  In addition, the adapted Cancer Literacy Measure could be used in future cancer prevention and control projects within the Navajo Nation.  The overall objective is to reduce breast cancer morbidity and mortality among Navajo women.

PRIMARY OBJECTIVES: I. To assess the safety of administering a course of cyclophosphamide treatment followed by six subsequent monthly vaccinations with a peptide-based vaccine targeting folate receptor 1 (FR)-alpha (multi-epitope folate receptor alpha peptide vaccine). II. To assess the ability of this vaccination protocol to elicit an immune response as measured by activated FR-alpha-specific T lymphocytes or high-affinity antibodies. CORRELATIVE OBJECTIVES: I. To determine FR-alpha expression status of primary tumors when available as formalin-fixed, paraffin-embedded material and whether expression correlates with the ability to generate an immune response. II. To identify human lymphocyte antigen (HLA) class I binding peptides from FR-alpha that are recognized by lymphocytes from patients prior to and after vaccination. OUTLINE: Patients receive 100 mg cyclophosphamide orally daily for 1 week followed by a 1 week rest, and then another week of cyclophosphamide. Approximately 7-10 days after the last dose of cyclophosphamide, patients receive multi-epitope folate receptor alpha peptide vaccine intradermally (ID) on day 1. Vaccine treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, and 12 months.

Patients will be identified and enrolled from Thoracic Surgical Clinics. A preoperative bronchoscopy will be performed to obtain systematic bronchial biopsies from defined proximal airway sites. Patients will then undergo surgical resection and tumor tissue and normal lung specimens collected. For patients with bronchial dysplasia postoperatively, starting less than 90 days from the time of surgery, patients will be randomized to receive either 850 mg po BID of metformin or observation. Metformin dosing will include a 4 week ramp up of 850 mg po daily prior to starting the BID dose. Adjuvant platinum-based chemotherapy will be applied at the discretion of treating physicians.  Patients found to have bronchial dysplasia at the time of bronchoscopy will undergo follow up bronchoscopy and tissue sampling at 6 months follow up.

PRIMARY OBJECTIVES:

     I. To evaluate the efficacy of myo-inositol (inositol) 9 grams by mouth twice a day for 6 months versus placebo to revert bronchial dysplasia in current/former smokers with or without curatively treated Stage 0/I non-small cell lung cancer.

     SECONDARY OBJECTIVES:

     I. To further define the mechanism(s) of action of pharmacological doses of myo-inositol as a lung cancer chemopreventive agent by evaluating changes in: the number of dysplastic lesions, Ki-67, caspase-3, peroxisome proliferator-activated receptor (PPAR) gamma, cyclin D1, cyclin E and vascular endothelial growth factor (VEGF) immunostaining in bronchial biopsies; gene expression analysis of ribonucleic acid (RNA) from bronchial brush cells; and changes in inflammatory biomarkers (C-reactive protein [CRP], monocyte chemotactic protein-1 [MCP-1], myeloid progenitor inhibitory factor-1 [MPIF-1] and L-Selectin) levels in bronchoalveolar lavage (BAL) and plasma before and after treatment.

     II. To collect additional safety and adverse event profiles of participants enrolled in both intervention arms. III. To establish a biospecimen repository archive for future correlative studies.

     OUTLINE: Patients are stratified according to smoking status (current vs former), prior lung cancer (yes vs no), and number of dysplastic lesions at baseline (1 vs > 1). Patients are randomized to 1 of 2 treatment arms.

     ARM I: Patients receive oral inositol once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.

     ARM II: Patients receive oral placebo once daily for 2 weeks and then twice daily for up to 6 months in the absence of unacceptable toxicity.

     Patients undergo white light and autofluorescence bronchoscopy with bronchoalveolar lavage, bronchial brushings, and biopsies as well as optical coherence tomography imaging and blood sample collection at baseline and after completion of study treatment. Samples are analyzed for tissue biomarkers (e.g., PPAR gamma, Ki-67, caspase-3, cyclin D1, cyclin E, and VEGF) by immunohistochemistry (IHC); cytokine levels (e.g., CRP, MCP-1, MPIF-1, and L-selectin) by ELISA; and gene expression profiles of RNA by microarray.

     After completion of study treatment, patients are followed within 30 days.

PRIMARY OBJECTIVES:

     I. The proportion of subjects with an adenoma recurrence at the 1-year follow-up colonoscopy exam. This adenoma recurrence rate for difluoromethylornithine (DFMO) (eflornithine) + aspirin will be compared to double placebo to see if there is improvement in the adenoma recurrence rate in this patient population.

     SECONDARY OBJECTIVES:

     I. To determine the relative tolerability and safety of the treatment regimens administered for 12 months.

     II. To determine the effect of the study drugs (aspirin [acetylsalicylic acid] + DFMO) and placebo with respect to proliferation (Ki67 labeling index), apoptosis (caspase-3 expression assay), and drug effect markers (COX-1, -2, polyamines, PGE2) from adenomas, aberrant crypt focus (ACF) and normal-appearing mucosa using pre- and 12-month post-intervention tissue biopsy samples.

     III. To estimate the percentage change in rectal ACF number, as determined by magnifying colonoscopy in subjects treated for 12 months with placebo or study drugs (aspirin +DFMO) by comparing % change in drug versus placebo arms.

     IV. To characterize ACF based on three criteria (ACF size [crypt number < 50 or >= 50], crypt morphology characteristics, and histology) of ACF and to correlate such characteristics with the intervention (vs placebo). Also, to evaluate the natural history of ACF over 1-year on placebo.

     V. To correlate the 12-month measurements of ACF size (# crypts/ACF), number, morphology, and histopathology with the adenoma recurrence data at 12 and 36 months; correlate the 12-month % (and actual) change in ACF size and number with the 12- and 36-month adenoma recurrence rate; and correlate the adenoma recurrence data at 1 year with the adenoma recurrence data at 3 years.

     TERTIARY OBJECTIVES:

     I. To explore the effects of the study agents on a focused panel of tissue biomarkers in pre- and post-intervention biopsy samples from recurrent adenomas, rectal ACF, and adjacent normal-appearing mucosa among subjects enrolled in the phase II clinical trial.

     II. To determine if cleaved capase-3 expression can improve the detection of apoptotic cells by recognizing cellular commitment to apoptosis prior to late nuclear morphologic features and correlate with apoptotic regulatory proteins, histology, and treatment response.

     III. To determine the effects of aspirin on its biochemical targets COX-1, -2, and prostaglandin E2, and polyamine levels in subjects receiving DFMO.

     IV. To examine COX-2-dependent genes (i.e., Bcl-2 and DR5) in adenomas and ACF that have been shown to regulate the intrinsic mitochondrial and extrinsic death receptor-mediated apoptotic pathways in vitro and in vivo.

     V. To perform expression profiling of adenomas or ACF and to relate such date to ACF histology, size/morphology, modulation by chemopreventive agents, and subsequent adenoma recurrence rates.

     OUTLINE: Patients are randomized to 1 of 2 treatment arms.

     ARM I: Patients receive acetylsalicylic acid orally (PO) once daily and eflornithine PO twice daily on days 1-28.

     ARM II: Patients receive placebo PO three times daily on days 1-28.

     Treatment repeats every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed at 6, 12, and 36 months.

OBJECTIVES:

     Primary

       -  To evaluate change in mammographic density using the Boyd method after one year of vitamin D supplementation compared to placebo in premenopausal women.

     Secondary

       -  To explore changes in the serum biomarker IGF1 in response to one year of vitamin D or placebo supplementation in premenopausal women.

       -  To explore changes in cellular proliferation (atypia and Ki67) in response to one year of vitamin D or placebo supplementation in premenopausal women.

       -  To explore correlations between change in breast cancer biomarkers (density, IGF1, atypia, and Ki67) with each other and with change in vitamin D levels.

       -  To compare methods of mammographic density analysis.

       -  To validate a recently developed sunlight questionnaire.

     OUTLINE: This is a multicenter study. Patients are stratified according to baseline vitamin D (sufficient [≥ 30 ng/mL or ≥ 75 mmol/L] vs insufficient [< 30 ng/mL or < 75 mmol/L]) and institutional random periareolar fine-needle aspiration (RPFNA) status (performs RPFNA vs does not perform RPFNA). Patients are randomized to 1 of 2 treatment arms.

       -  Arm I: Patients receive oral placebo once daily for 12 months.

       -  Arm II: Patients receive oral vitamin D (2000 IU) once daily for 12 months. Tissue and blood samples are collected at baseline and at 12 months for laboratory biomarker analysis. Patients also complete questionnaires at baseline and at 12 months.

The purpose of this study is to compare two types of radioactive drugs to see if they provide the same or different information about any disease that may be present in the participants breast.

PRIMARY OBJECTIVES:

     I. To determine the safety profile of a peptide-based vaccine targeting HER-2/neu, in patients with stage II/III HER-2 positive breast cancer.

     II. To determine the ability of this vaccination protocol to elicit an immune response as measured by activated HER-2/neu-specific T lymphocytes or high-affinity antibodies.

     SECONDARY OBJECTIVES:

     I. To compile descriptive follow-up data regarding vital status and disease recurrence.

     II. To determine if HER-2/neu peptide 885 generates a T cell response that is specific to HER-2/neu or is cross-reactive with epidermal growth factor receptor (EGFR) protein.

     III. To determine if the human leukocyte antigen (HLA)-DR epitopes contain HLA class I embedded epitopes.

     OUTLINE:

     Patients receive HER-2/neu peptide vaccine intradermally (ID) every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed up for up to 2 additional years.