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IRB No. 00-273-1 (Dr. Jeffrey Wasser, PI): R9811: A Phase III Randomized Study of 5-Fluorouracil, Cisplatin, and Radiotherapy Vs. 5 Fluorouracil, Mitomycin-C and Radiotherapy in Carcinoma of the Anal Canal

Study description not available

IRB No. 08-296-2 (Dr. Kevin Claffey, PI): Establishing Primary Cancer Cell Lines

This project is designed to improve our tools for the study of cancer. The evaluation of cancer cell phenotypes and resistance to treatment is limited by the availability of cell lines to study these events in the laboratory. This study will attempt to collect unique cancer cell types and culture them in the laboratory for future studies investigating mechanisms of cancer initiation, progression and response to treatment.

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

Study description not available

IRB No. 14-017-2 (Dr. Arvind Chhabra, PI): Generation of Customized Anti-Tumor T Cells From Human Pluripotent Stem Cells (hPS) Derived Embryoid Bodies (EB) For Immunotherapy of Human Melanoma.

Our study aims to combine the self-renewable potential of human pluripotent stem cells (hPS) with the TCR engineering technology to create a large reservoir of patient specific, immunologically matched, customized anti-tumor T cells with defined functional characteristics. The central hypothesis driving our study is that “the hPS derived EB can be utilized as an efficient model to study the differentiation of HSC precursors into T cells, in situ. Understanding the molecular mechanism of in-situ T cell generation in EB, in combination with the TCR engineering approach, could be utilized to generate naive, patient specific, customized anti-tumor T cells, for an effective cancer immunotherapy”.

IRB No. 14-024-2 (Dr. Jeffrey Wasser, 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. 09-185J-2 (Dr. Bijay Mukherji, PI): TCR Engineered T Cells in Tumor Immunity

simple blood draw. no risk to study subject.

IRB No. 14-129-6 (Dr. Biree Andemariam, PI): Sickle Cell Trait-related Blood Cell Adhesion as a Determinant of Disparate Cancer Treatment Outcomes

SPECIFIC AIMS The research objective of this proposal is to determine if blood cells from persons who are sickle cell trait carriers react adversely to standard chemotherapy compared to blood cells from persons without this genotype. African-American women have disparate breast cancer survival rates compared to white women that cannot be fully explained by either socio-economic or tumor marker expression differences. While sickle cell trait (SCT) is rare in the white population, nearly 10% of African-Americans carry SCT and most are unaware. Several case reports in the literature have described adverse reactions to systemically administered chemotherapy in African-Americans with SCT raising the possibility that chemotherapy-induced intravascular sickling may occur. Subsequent vaso-occlusion (overt or sub-clinical) may give rise to symptoms such as pain and nausea, or clinical signs such as unexplained anemia and renal insufficiency. These signs and symptoms may lead to treatment delays, dose-reductions and in some cases, cessation of therapy altogether--- all of which can impact efficacy and, most importantly, survival. We have previously shown that red blood cells (RBCs) from individuals with SCT are more adhesive to vascular endothelium than normal RBCs and that this adhesion is enhanced under physiologic stress conditions. We aim to compare the effect of chemotherapy on RBC adhesion to endothelial proteins in white women and in African-American women with and without SCT. The results are expected to lead to novel approaches to reverse disparities in cancer treatment outcomes among African-Americans. Our central hypothesis is that RBCs from African-American women with SCT are more adherent to vascular endothelium in the presence of chemotherapy than are healthy RBCs from both white and African-American women without SCT. To test the hypothesis, we will pursue the following two specific aims: Assess for baseline differences in RBC adhesion to endothelial proteins among white women as compared to African-American women– We will measure the change in quantity and strength of adhesive interactions between single RBCs and endothelial proteins. The influence of race and SCT-status will be examined. Test the in vitro effect of chemotherapy on RBC adhesion to endothelial proteins among white women as compared to African-American women – We will measure the in vitro effect of chemotherapy on single RBC adhesion to endothelial proteins. The influence of race and SCT-status will be examined.

IRB No. 14-162-2 (Dr. Patricia Diaz, PI): The prevalence of culturable and non-culturable fungi among patients with cancer undergoing chemotherapy treatment alone or in combination with head neck radiotherapy and non-cancer controls

To conduct a pilot comparison of the prevalence and abundance of culturable and non-culturable fungi among individuals diagnosed with cancer (during the course of chemotherapy alone or combined with head and neck radiation therapy) and non-cancer subjects.

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. 15-073-3 (Dr. Bruce Liang, PI): Circulating Markers and Advanced Noninvasive Cardiac Imaging Techniques That Predict Subsequent Cardiotoxicity in Cancer Patients Treated with Anthracyclines

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. 15-077-1 (Dr. Jeffrey Wasser, 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. 10-068OSJ-3 (Dr. Thomas Devers, PI): Identifying Early Clinical and Molecular Markers of Colon Cancer Risks

Study description not available

IRB No. 16-007-1 (Dr. Upendra Hegde, PI): A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Head and neck cancer describes a range of tumors that arise in the head and neck region, which includes the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, and salivary glands. The worldwide incidence of head and neck cancer exceeds half a million cases annually, ranking it as the fifth most common cancer worldwide, and accounts for 5% of all malignancies. A large number of patients with head and neck cancer initially present with locally advanced, stage III/IV disease that is initially treated with combinations of chemotherapy, radiation and/or surgery. This initial treatment is generally designated as "definitive" therapy, which typically combines chemoradiation and surgery and can result in disease control rates ranging between 33 and 86% of patients. Patients who progress after initial definitive therapy require subsequent treatment for recurrent (R) disease. Patients who initially present with metastatic (M) disease generally receive the same therapy as those with recurrent disease after definitive treatment. In this trial, subjects with oropharynx cancer will be stratified by HPV status (positive or negative). The favorable prognostic significance of HPV-positive head and neck cancers in the oropharynx has been increasingly established. Preliminary data of single agent pembrolizumab in head and neck cancer patients in KEYNOTE-012 demonstrate efficacy in both HPV-positive and HPV-negative patients. Investigator site assessment of HPV using immunohistochemistry (IHC) staining for the p16 protein will be used for the subjects with oropharyngeal cancer prior to randomization. Study design This is a randomized, active-controlled, multi-site, open-label trial of pembrolizumab, or pembrolizumab plus platinum plus 5-FU chemotherapies versus platinum plus 5-FU plus cetuximab in subjects with advanced head and neck cancer. Study population and sample size Subjects with recurrent or metastatic Head and Neck Squamous Cell Carcinoma. Approximately 750 subjects will be enrolled. Major Study Interventions (1) Pembrolizumab (MK-3475) 200 mg every 3 weeks; or (2) Pembrolizumab (MK-3475) 200 mg every 3 weeks + Platinum + 5- Fluorouracil (5-FU); or (3) Cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 (weekly) + Platinum + 5FU (Platinum is either Cisplatin 100 mg/m2 Q3W or Carboplatin AUC 5 Q3W; 5FU is 1000 mg/m2 continuous from Day 1 to Day 4 Q3W) Main Outcome Measures/Analyses Primary Objectives (1) Objective: To compare the Progression Free Survival (PFS) per RECIST 1.1 as assessed by central radiologists' review in a subgroup of first line recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) subjects with strongly positive PD-L1 expression, treated with Pembrolizumab monotherapy versus standard treatment cetuximab with chemotherapy. (2) Objective: To compare the Progression Free Survival (PFS) per RECIST 1.1 as assessed by central radiologists' review in subjects with first line R/M HNSCC treated with pembrolizumab monotherapy or a combination of Pembrolizumab with chemotherapy versus standard treatment cetuximab with chemotherapy.

IRB No. 16-124-1 (Dr. Jessica Clement, 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. 16-227-3 (Dr. Jeffrey Wasser, PI): PROTOCOL FULL TITLE A phase 1, Open-Label, Dose Escalation Study of PF-04518600 as a single agent and in combination with PF-05082566 in Patients with Selected Locally Advanced or Metastatic Carcinomas

Background: PF-04518600 and PF-05082566 are antibodies (a type of protein) which have been shown to stimulate the immune system. Research has shown that an immune response like this can work against tumor cells to slow tumor growth by causing tumor cells to die. PF-04518600 alone and in combination with PF-05082566 are being investigated as possible treatments for patients with advanced liver, skin (melanoma), kidney, head and neck, stomach, cervical, gastric, bladder or lung cancer. Rationale for this study: The ability to escape immune recognition is a hallmark of cancer progression. By manipulating the immune system and restoring immune surveillance, immunotherapy offers the opportunity to not only eradicate or stop tumor growth, but also the opportunity to decrease the rate of recurrence.1 One strategy for increasing tumor immunity would be to activate and expand tumor-associated antigen T cells. It has long been recognized that T cell activation is not mediated by antigen stimulation alone. Indeed, tumor antigens may induce T-cell anergy, rendering T cells unable to proliferate in response to antigen, and hypo-responsive to further antigen encounter. Instead, co-stimulatory receptors are required to complete the process of T cell activation and expansion. Thus, co-stimulatory receptors may have the potential to prevent tumor-induced immune tolerance. PF-04518600 is a fully human Immunoglobulin G2 (IgG2) agonistic monoclonal antibody that is highly selective for human OX40 (CD134). PF-04518600’s agonistic potential was revealed in a 293 luciferase reporter assay, whereby induced OX40 mediated NFkB activation, and luciferase activity increased dose proportionally to increasing concentrations of PF-04518600. Selectivity studies using a biacore assay also revealed PF-04518600 to be highly selective for OX40, with no cross activity with other members of the TNFR super-family, including CD40 receptor, 4-1BB receptor (CD137) and glucocorticoid-induced TNFR family related gene (GITR). Study Design: This is a Phase 1, open label unblinded manner, multi-center, multiple dose, dose escalation, safety,pharmacokinetic, and pharmacodynamic study of PF-04518600 monotherapy (Part A) and PF-04518600 plus PF-05082566 combination therapy (Part B). Both Part A and Part B will be further divided into a dose escalation phase, and a dose expansion phase. Study Population and Sample Size: Adults (men and women) age 18 years and over. Patients with histological or cytological diagnosis of HNSCC, HCC, melanoma, clear cell RCC urothelial bladder carcinoma (including renal pelvis, ureters, urinary bladder, and urethra), gastric or squamous cell carcinoma of the uterine cervix. A maximum of approximately 190 patients are expected to be enrolled into the study. Major Study Interventions: For monotherapy, patients will be dosed at 0.01 mg/kg PF-04518600 in the first cohort. For combination therapy, patients will be dosed at 0.1 mg/kg PF-04518600 and 20 mg PF-05082566 in the first dose combination level. Main Outcome measures /Analyses: To assess safety, and tolerability at increasing dose levels of PF-04518600 in patients with selected advanced or metastatic solid tumors in order to establish the MTD. Primary Objectives: -To establish the RP2D of PF-04518600 in patients with selected advanced or metastatic solid tumors. To further characterize the safety and tolerability of PF-04518600 in patients with selected advanced or metastatic solid tumors. Secondary Objectives: -To assess preliminary anti-tumor clinical activity of PF-04518600 in patients with selected advanced or metastatic solid tumors solid tumors. To characterize the single dose and multiple dose PK of PF-04518600 following IV administration. -To characterize the degree of TE by PF-04518600 at multiple doses

IRB No. 14-041HO-1 (Dr. Rajesh Lalla, PI): Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (ORARAD)

The ORARAD study is a prospective cohort study to document dental and other oral outcomes in patients who receive radiation therapy as part of treatment for a head and neck cancer. Seven hundred and fifty-six participants will be enrolled nationally over a three year period. Of these, 135 will be enrolled at UCHC. All participants will be seen for the study before starting radiation therapy then at six-month intervals for up to two years after the start of radiation therapy. The primary outcome will be the two-year rate of tooth loss after radiation therapy. Secondary outcomes will include measures of dental caries, periodontal health, salivary flow, and exposed bone/osteoradionecrosis.