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IRB No. 03-203-2 (Dr. Daniel Rosenberg, PI): Identification and Analysis of Aberrant Crypt Foci in Colonoscopy Patients

Study description not available

IRB No. 08-310-1 (Dr. Marilyn Sanders, PI): UCONN Health Center Research Tissue Registry/Repository

The objective of this project is to develop a research repository for the purpose of performing cancer studies. Information will be gathered form UCHC medical records, molecular and pathological analysis of blood collected and tissue gathered during surgical procedures. The tissue will be obtained during surgical procedures the patient may have elected to have performed at the Health Center in the future. The collection of data will also permit review of relevant information to identify patients who may be eligible for future studies, and to seek permission of patients to be contacted to determine their interest in taking part in future studies. De-identified information will be used for approved research studies and to gather pilot data for extra-mural grant applications.

IRB No. 11-027-2 (Dr. Susan Tannenbaum, PI): UCHC Cancer Center Research Screening

Study description not available

IRB No. 11-191-1 (Dr. Rajesh Lalla, PI): Quality Assessment of Pre-Radiation Dental Management in Head and Neck Cancer Patients

Oral Medicine Quality Assurance Study

IRB No. 14-024-2 (Dr. Adam Adler, PI): In vitro characterization of cancer related immune impairment and its reversal by the use of cytokines, costimulatory molecules and a blocker of immune suppression used singly or in combination

The trial will include patients with advanced malignancy and an estimated survival of 6 months or less, based on the judgment of their oncologist, the type of malignancy, ECOG performance status, stage of disease and pre-existing co-morbidities. This is an exploratory in-vitro study which is being performed to determine optimal combinations of cytokines, costimulatory agonists and inhibitors of immune-suppressive factors to restore immune responsiveness in patients with advanced malignancy. Patients meeting the “inclusion and exclusion criteria” will be solicited by their physician or designee to allow a venipuncture and withdrawal of 20cc of blood. The samples will be obtained, as much as feasible, along with routine blood work, so as to minimize the need for additional venipuncture. The lymphocytes will be isolated and exposed to cytokines, including, but not limited to, members of the IL1 family of cytokines [IL 1, IL 18, and IL 33. IL 36]. The cells will also be exposed to agonists for costimulatory molecules of the TNF family, including but not limited to, OX-40 and 4-1-BB. Costimulatory agonists and antagonists to B7 family will also be used, including but not limited to PD1, PD2, PD1L and CD28. An inhibitor of IDO will also be used to reduce the suppressive effects of Tregs and MDSC. The T-cells will be stimulated by vaccine recall antigens, such as tetanus toxoid and influenza antigen. Mitogens such as PMA plus Ionomycin and/or anti-CD3 monoclonal antibody will also be employed. Ki-67 staining, a marker of cell proliferation will be done to determine a Ki-67 labeling index on the study and control specimens before and after experimental manipulations. Measurements of T cell cytotoxicity and quantification of expression levels of cytotoxic effector molecules will be performed before and after experimental manipulations. RNA-Seq will be done before and after experimental manipulations of the study and control specimens to determine which genes are being transcribed in response to experimental measures. Control samples will be obtained from de-identified blood purchased from the GRC. These control specimens will be stimulated and activated in a similar fashion to the specimens obtained from the experimental subjects. If possible, the same study patients will be requested to allow a second venipuncture no sooner than 6 weeks after the first venipuncture, and in no case, no sooner than six weeks after the last antineoplastic therapy.

IRB No. 14-056-6 (Dr. Pamela Taxel, PI): Investigation of the Ability of the UCONNS (University of Connecticut OsteoNecrosis Numerical Scale) to Predict the Risk for the Developing Osteonecrosis of the Jaw in Women Receiving Bone-Modifying Therapies for Cancer

The purpose of this proposal is to investigate the risk factors for osteonecrosis of the jaw (ONJ), a known complication of several bone-modifying therapies used in the treatment of advanced cancers. When this complication occurs, it can lead to the discontinuation of important therapy that often impacts the quality of life in skeletal-related events in this population. With the use of a weighted scale that we have devised, the University of Connecticut OsteoNecrosis Numerical Scale (UCONNS), based on known risk factors for ONJ, we aim to validate this scale as a potential predictor of patients at risk, so they may be appropriately monitored and preventative treatment can be initiated. As the medical community has limited guidelines regarding ONJ, we anticipate that this scale, if validated, will foster better communication among providers, as well as improve patient outcomes. This proposal represents a unique collaboration between two investigators in the dental and medical schools at the University of Connecticut Health Center. We hypothesize that the UCONNS can aid in the identification of cancer patients who may be at increased risk for the development of ONJ associated with the use of bisphosphonates and the newer bone modifying therapy, denosumab.

IRB No. 09-185J-2 (Dr. Upendra Hegde, PI): TCR Engineered T Cells in Tumor Immunity

simple blood draw. no risk to study subject.

IRB No. 14-179-1 (Dr. Rajesh Lalla, PI): Oral Microbiome in Head and Neck Cancer Patients

This research study is about the community of germs that live in the mouth (the oral microbiome) and its relationship to oral complications of radiation therapy such as dryness, mouth sores, tooth loss, cavities, gum disease or poor healing of bone. The purpose of this study is to look at changes in the oral microbiome from before radiation therapy until 18 months after radiation therapy to see if certain characteristics of the oral microbiome relate to mouth problems that may occur after radiation therapy. An optional sub-study is about future genetic testing of saliva samples to look for genes that may affect the risk of oral complications of radiation therapy..

IRB No. 15-027-2 (Dr. Susan Tannenbaum, PI): S1207, "Phase III Randomized, Placebo-Controlled Clinical Trial Evaluating the Use of Adjuvant Endocrine Therapy +/- One Year of Everolimus in Patients with High-Risk, Hormone Receptor-Positive and HER2/neuNegative Breast Cancer."

Primary Objective: The primary objective of this study is to compare whether the addition of one year of everolimus (10 mg daily) to standard adjuvant endocrine therapy improves invasive disease-free survival (IDFS) in patients with high-risk, hormone-receptor (HR) positive and HER2-negative breast cancer. Secondary Objectives: a. To compare whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves overall survival (OS) and distant recurrence-free survival (DRFS) in this patient population. b. To evaluate the safety, toxicities and tolerability of one year of everolimus in combination with standard adjuvant endocrine therapy and compare it with standard adjuvant endocrine therapy plus placebo in this patient population. c. To determine whether the benefit of one year of everolimus use in addition to standard adjuvant endocrine therapy varies by recurrence score (RS), nodal status, or other commonly used prognostic factors. d. To evaluate adherence to 1-year treatment of everolimus in comparison to placebo in addition to standard adjuvant endocrine therapy in this patient population. e. To collect specimens in order to evaluate biomarkers of therapeutic efficacy.

IRB No. 15-077-1 (Dr. Susan Tannenbaum, PI): A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination with INCB024360 in Subjects with Selected Solid Tumors (Phase 1) Followed by a Randomized, Double-Blind, Placebo-Controlled Study in Subjects with Advanced Non-Small Cell Lung Cancer (Phase 2)

The INCB 24360-202 study is a randomized, double-blind, placebo-controlled Phase 1/2 study of INCB024360 or placebo administered in combination with MK-3475. Phase 1 will be open-label and will include subjects with Stage IIIB, IV, or recurrent non--small cell lung cancer (NSCLC), melanoma, transitional carcinoma of the genitourinary (GU) tract, renal cell cancer, triple negative breast cancer, adenocarcinoma of the endometrium, or squamous cell carcinoma of the head and neck, and Phase 2 will be randomized, double-blind, and placebo-controlled in subjects with Stage IIIB, IV, or recurrent NSCLC. INCB024360 represents a novel, potent, and selective inhibitor of the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) in both human tumor cells and human dendritic cells (DCs). MK-3475 is a potent and highly selective humanized monoclonal antibody of the immunoglobulin (Ig) G4/kappa isotype directed against programmed death receptor 1 (PD-1). For a thorough discussion of the pharmacology of MK-3475 and INCB024360, refer to the INCB024360 Investigator’s Brochure (iIB) and the MK-3475 Investigator’s Brochure (mIB). The goal of cancer immunotherapy is to initiate or reinitiate a self-sustaining cycle of cancer immunity, enabling it to amplify and propagate. Cancer immunotherapies must overcome the negative feedback mechanisms inherent in most cancers. The current approach will attempt to further amplify an immune response by targeting multiple nonredundant immune checkpoints. Expression of IDO1 represents an early checkpoint that results in a diminished immune response and tolerance to tumor antigen. Many recent clinical results suggest that another common rate-limiting step is the expression of PD-L1 as a distal immune modulator expressed in 20% to 50% of human cancer (Hiraoka 2010, Herbst et al 2013), including but not limited to the ones selected for investigation in the Phase 1 portion of this study: advanced or metastatic NSCLC, melanoma, transitional carcinoma of the GU tract, renal cell cancer, triple negative breast cancer, endometrial cancer, or squamous cell carcinoma of the head and neck. Expression of IDO and PD-1/L1 have been found to be increased in NSCLC as the disease progresses, and expression of these markers in tumor cells has been associated with shorter subject survival (Iversen et al 2013). Anti-PD-L1 and anti-PD-1 monotherapy response rates of 17% to 24% have been reported in refractory NSCLC (Garon et al 2013, Brahmer et al 2013) with survival medians of 8 to 18 months; however, MK-3475 has not yet reached the median in its study (Garon et al 2013). Thus, there is a strong rationale for therapies aimed at restoring antitumor immunocompetence in NSCLC and establishing a rationale for inhibiting IDO1 and the PD-1/L1 pathways in this disease. 2. STUDY OBJECTIVES AND PURPOSE 2.1. Primary Objectives ? Phase 1: To evaluate the safety, tolerability, and DLTs of a pharmacologically active dose (PAD) of INCB024360 administered in combination with MK-3475 in advanced or metastatic solid tumors, and to select doses for further evaluation. ? Phase 2: To evaluate and compare the PFS of subjects with Stage IIIB, IV, or recurrent NSCLC when treated with INCB024360 in combination with MK-3475 versus MK-3475 alone as determined by investigator assessment of objective radiographic disease assessments per modified RECIST v1.1. 2.2. Secondary Objectives (Phase 2) ? To evaluate and compare the efficacy of the 2 treatment groups with respect to ORR utilizing modified RECIST v1.1 ? To evaluate and compare the efficacy of the 2 treatment groups with respect to ordinal categorical response score, calculated as the following: - 1 = Complete response per modified RECIST v1.1 - 2 = Very good response, defined as > 60% tumor reduction - 3 = Minor response, defined as > 30% to 60% tumor reduction

IRB No. 16-124-1 (Dr. Upendra Hegde, PI): A Prospectively Designed Study to Assess the Relationship between Tumor Mutation Burden and Predicted Neo-antigen Burden in Patients with Advanced Melanoma or Bladder Cancer Treated with Nivolumab or Nivolumab plus Ipilimumab (CA209-260)

A Prospectively Designed Study to Assess the Relationship between Tumor Mutation Burden and Predicted Neo-antigen Burden in Patients with Advanced Melanoma or Bladder Cancer Treated with Nivolumab or Nivolumab plus Ipilimumab (CA209-260) Background and rationale: Please refer to section 3.0 of the Protocol Study design: This is a prospectively designed, open label study. It includes 2 independent study populations (melanoma and bladder) Study population and sample size: Patients with histologically confirmed locally advanced or metastatic disease of the following tumor types who meet the eligibility criteria: 1. melanoma and 2. bladder cancer. 120 evaluable patients will be enrolled in two separate arms. In each arm, 60 evaluable patients will be enrolled. Major study interventions: All eligible patients with melanoma will receive ipilimumab at a dose of 3mg/kg combined with nivolumab at a dose of 1mg/kg. The ipilimumab and nivolumab will be dosed every 3 weeks for 4 doses. Thereafter, patients may be eligible to receive nivolumab monotherapy at a dose of 3mg/kg administered every 2 weeks for up to 2 years. All eligible patients with bladder cancer will receive nivolumab at a dose of 3mg/kg administered every 2 weeks for up to 2 years. Patients with bladder cancer who have confirmed disease progression after treatment with nivolumab monotherapy may be treated with the combination of nivolumab and ipilimumab. Main outcome measures/analyses: Please refer to section 2.0 of the Protocol

IRB No. 01-127H-2 (Dr. Kazuya Machida, PI): Signalosome-oriented Phosphotyrosine Profiling of B-cell Malignancies

Study description not available

IRB No. 15-073-3.2 (Dr. Agnes Kim, PI): Circulating Biomarkers and Noninvasive Cardiac Imaging Techniques That predict Cancer Therapy Cardiotoxicity

The primary goal of this pilot study is to identify early signs of cardiotoxicity in patients with a wide range of cancers who are treated with anthracycline chemotherapy, alone or in conjunction with other chemotherapeutic or molecularly targeted cancer drugs, before there is irreversible cardiac dysfunction or clinical heart failure. We hypothesize that an elevation in apoptotic and inflammatory biomarkers and early changes in myocardial deformation as measured by strain imaging after exposure to anthracycline chemotherapy predict future development of cardiac dysfunction. By checking the levels of these biomarkers before chemotherapy, then at 3 months and at one year in cancer patients receiving anthracyclines, our goal is to determine whether those patients with a ""spike"" in level develop left ventricular dysfunction and/or clinical heart failure. Similarly, strain imaging by echocardiography will be performed at baseline, then every 3 months and at one year. We hypothesize that a decrease in global longitudinal strain can predict future reduction in LVEF. Our goal is to identify early those patients who are at a high risk for anthracycline-related cardiac toxicity. Early identification may lead to early institution of cardioprotective therapies (i.e. beta blockers and ACE inhibitors), which may prevent irreversible cardiac dysfunction and clinical congestive heart failure. Objectives: To determine the potential utility of biomarkers for the early identification of patients with cancer who are at risk for cardiac dysfunction. To determine whether biomarker levels, or serial changes in biomarker levels, or combination of biomarkers (activated caspase-3, troponin I, IL-6, TNF alpha, CRP, caspase-1, BNP) could predict subsequent cardiotoxicity in patients treated with anthracycline chemotherapy. To determine the utility of strain imaging in the identification of early cardiotoxicity. To determine whether cleaved caspase-3 and caspase-1 show serial changes over time during the course of cancer treatment with chemotherapy. Hypotheses: A serial increase in biomarker levels from baseline to post-chemotherapy may predict subsequent development of systolic or diastolic cardiac dysfunction. Caspase-3 as an apoptotic marker, caspase-1 as an inflammatory marker upstream of IL-1beta, IL-6 and CRP, and troponin I as cardiac injury marker can be quantified in human circulation. An elevation in the levels of these markers may indicate anthracycline-related cardiac apoptosis/ injury and associated inflammation. Strain imaging by echocardiography can identify early sub-clinical imaging evidence of cardiotoxicity. Taken together, the advanced strain imaging and novel biomarkers may identify those who are at risk of developing clinical cardiac dysfunction or heart failure. In the future, we will test whether prevention of overt heart failure can be achieved by institution of medications such as beta blocker and angiotensin converting enzyme inhibitor or angiotensin receptor blocker in these at-risk individuals.

IRB No. 13-087-3.2 (Dr. Susan Tannenbaum, PI): Factors Influencing Fatigue in Breast Cancer Patients Undergoing Breast Irradiation

Study description not available

IRB No. 14-056SF-6.1 (Dr. Pamela Taxel, PI): Investigation of the Ability of the UCONNS (University of Connecticut OsteoNecrosis Numerical Scale) to Predict the Risk for the Developing Osteonecrosis of the Jaw in Patients Receiving Bone-Modifying Therapies for Cancer

The purpose of this proposal is to investigate the risk factors for osteonecrosis of the jaw (ONJ), a known complication of several bone-modifying therapies used in the treatment of advanced cancers. When this complication occurs, it can lead to the discontinuation of important therapy that often impacts the quality of life in skeletal-related events in this population. With the use of a weighted scale that we have devised, the University of Connecticut OsteoNecrosis Numerical Scale (UCONNS), based on known risk factors for ONJ, we aim to validate this scale as a potential predictor of patients at risk, so they may be appropriately monitored and preventative treatment can be initiated. As the medical community has limited guidelines regarding ONJ, we anticipate that this scale, if validated, will foster better communication among providers, as well as improve patient outcomes. This proposal represents a unique collaboration between two investigators in the dental and medical schools at the University of Connecticut Health Center. We hypothesize that the UCONNS can aid in the identification of cancer patients who may be at increased risk for the development of ONJ associated with the use of bisphosphonates and the newer bone modifying therapy, denosumab.

IRB No. 21-001-1 (Dr. Daniel Rosenberg, PI): Determining the Role of Peanut Consumption on Dietary Habits, Gut Microbiome, and Colon Biomarkers in a Healthy Population

Colorectal cancer (CRC) is the second cancer-related cause of death among men and women in the United States. Dietary lifestyle is a contributing factor to CRC risk, and it plays a role in changing the bacteria living in the gut. Current research are now focusing on studying the effects of these bacteria and the compounds they produce, and how it is affecting cancer progression. Peanuts are part of the American diet, a food that is rich in nutrients such as protein, fiber, healthy fats, bioactive compounds, vitamins and minerals. The objective of this study is to determine if increasing peanut intake influences other dietary habits and gut bacteria composition. Secondary aims are as follows: 1) to understand if changes in dietary habits and gut bacteria affect biomarkers in the colon, and 2) to study possible mechanisms in early CRC prevention. Therefore, a dietary intervention will test the effects of peanut intake on dietary habits, gut microbiota, and colon biomarkers. Healthy participants (50-65 years old) scheduled for a screening colonoscopy will be recruited and start a 1-week washout period where they will be asked to avoid peanuts/nuts and other foods provided in a list throughout the study period. Then, they will be randomized into peanut or control group, where control gorup is gender and body mass index matched to peanut group. For 3 weeks, the peanut group will be consuming 2 ounces of roasted peanuts daily, while the control group will not consume peanuts. At baseline and end of clinical trial, blood, stool and 3-day dietary records will be collected. After the intervention, participants will have the colonoscopy done and eight colon biopsy samples will be collected. The hypothesis is that peanut consumption will increase intake of other healthy foods (increase in dietary fiber) and change the bacteria in the gut to a more diverse and rich community when compared to baseline and matched controls. We also expect an increase anti-inflammatory colon biomarker since peanuts contain fiber, unsaturated fats, and antioxidants that may help prevent cancer.