Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Substance Related Disorders

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Drug-Related Side Effects and Adverse Reactions

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Chemically-Induced Disorders

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

All Drugs and Chemicals

Antineoplastic Agents

Autoantibodies

Axitinib

Nivolumab

Ipilimumab

Sunitinib

Sorafenib

Tivozanib

Immunologic Factors

Patients treated for metastatic renal cell carcinoma in Denmark over a 6-year period.

Medical treatment for metastatic renal cell carcinoma with axitinib, cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, ipilimumab and nivolumab.

Measurement of concentration of active metabolite in cancer treatment.

Niels Fristrup, MD, PhD

Jakob N Henriksen, MD

Anne Kirstine H Moller, MD, PhD

The purpose of this observational study is to assess the role of plasma concentration monitoring of treatment drugs for patients with metastatic renal cell carcinoma (mRCC) in terms of efficacy and side effects.

Furthermore, the investigators examines the role of anti-drug antibodies and receptor polymorphisms in CTLA-4 and PD-1 receptors in treatment failure among patients with mRCC treated with check point immunotherapy. Moreover, polymorphisms in the UGT1A1 gene will be correlated with the pazopanib treatment dose.

BACKGROUND:

Treatment of metastatic renal cell carcinoma (mRCC) is ineffective among 25 % of patients. However, treatment still reduces patients' quality of life.

From clinical experience, interindividual dose requirements vary greatly among patients with mRCC treated with tyrosine kinase inhibitors.

The investigators expect this to partly be explained by great variation in the plasma concentration of treatment drugs. Furthermore, treatment failure among patients with mRCC treated with check point immunotherapy has not been fully investigated.

RATIONALE:

The few studies concerning plasma concentration measurement of tyrosine kinase inhibitors in patients with mRCC have found that a certain level of drug concentration is necessary for treatment efficacy. The role of plasma concentration in side effects is yet unknown.

Anti drug antibodies against the check point inhibitor ipilimumab has been shown to reduce efficacy and lead to treatment failure among patients with malignant melanoma. Receptor polymorphism in CTLA-4 and PD-1 receptors in terms of efficacy have not yet been studied.

A therapeutic drug interval for TKI treatment will allow for quicker and more precise dosing, and early signs of treatment failure of checkpoint immunotherapy will allow for quicker change of therapy, or define a subgroup of patients who will not benefit from checkpoint immunotherapy and therefore should be offered another effective treatment instead.

HYPOTHESIS:

1. Patients treated with TKIs for more than 6 months have an optimal plasma trough concentration. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicity in these patients are favorable compared with pivotal phase III study results.
2. Patients treated with CPI obtaining response have a higher plasma trough concentration value of ipilimumab and nivolumab than patients with progressive disease (PD). Patients treated with CPI who develop PD have a higher amount of ADA than patients with response to treatment.
3. Certain polymorphisms in CTLA-4 and PD-1 are associated with poor outcome.
4. UGT1A1 polymorphism is associated with improved survival despite dose reductions in patients treated with pazopanib.

MATERIALS AND METHODS:

All eligible TKI-patients will have blood samples drawn at each clinical visit during a 6-months period.

The plasma concentration of TKIs will be measured with liquid chromatography-mass spectrometry at the Department of Clinical Biochemistry at Aarhus University Hospital.

All eligible CPI-patients will have blood samples drawn from start CPI-treatment and during treatment until treatment failure or full treatment (2 years).

Analysis of checkpoint immunotherapy will be be done using in-house bead-based assays, anti-human IgG detection antibody and in-house developed flow cytometry-based assay at the Institute for Inflammation Research at Rigshospitalet.

Overall survival, progression free survival and quality of life using FKSI-19 questionnaire will be recorded for each patient.

This is an observational study among Danish patients treated for mRCC over a 6 year year period.

TDM for Optimized Outcome in Patients With mRCC.

Therapeutic Drug Monitoring for Optimized Outcome in Patients With Metastatic Renal Cell Carcinoma

Calculated from the date of inclusion, to the date of death of any cause or censored at the date at last follow-up.

National Comprehensive Cancer Network/ Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (NCCN-FACT FKSI-19).

19 items, each item scored on a 5 point Likert-scale, covering cancer quality of life.

In patients treated with ipilimumab/nivolumab

Herlev Hospital

Rigshospitalet, Denmark

Aarhus University Hospital

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Obesity

Lipoma

Neoplasms, Adipose Tissue

Neoplasms, Connective and Soft Tissue

Pharmaceutical Solutions

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Cardiotonic Agents

Respiratory System Agents

Prednisolone

Methylprednisolone

Cortisone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Adrenergic Agents

Adrenergic Agonists

Isoproterenol

Adrenergic beta-Agonists

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Protective Agents

Neurotransmitter Agents

Bronchodilator Agents

Anti-Asthmatic Agents

Sympathomimetics

Beta-adrenergic agonists and corticosteroid

Approximately 0.2 to 0.4cc of isoproterenol-prednisolone solution (0.04 - 0.08 mg isoproterenol and 0.07 - 0.14 mg prednisolone) in one or more sites in the lipoma depending on its size, 5 days a week for 4 weeks.

Prednisolone synthetic cortisone and Isoproterenol together

Leanne Redman, Ph.D.

Frank Greenway, M.D.

The purpose of this study is to test whether injected medications will increase the amount of fat released by a fat cell. We will compare prednisolone (a synthetic cortisone) combined with isoproterenol (a drug given for asthma) versus using isoproterenol alone. We will also test if injections of isoproterenol and prednisolone will shrink the size of lipomas, which are benign fatty tumors.

Lipomas are benign, non-cancerous fatty tumors that occur under the skin and make a bump that can be easily felt and often seen. The current treatment for lipomas is surgery. Isoproterenol, a medication used for the treatment of asthma and approved for injection under the skin, is known to cause fat cells to give up their fat. The fat cells become resistant to isoproterenol with repeated use. Prednisolone, a synthetic cortisone medication used to treat immune problems like allergy and approved for injection under the skin, keeps the fat cells from becoming resistant to isoproterenol. It is not known, if the fat cells in lipomas act like other fat cells or if the combination of isoproterenol and prednisolone injections would shrink lipomas without surgery. This study is designed to test this possibility.

Subjects will have a screening visit, 2 microdialysis visits a week apart, 20 treatment visits 5 days per week for 4 weeks, and up to 12 follow-up visits a year after treatment visits. During screening, subjects will have a history, physical exam, blood testing, electrocardiogram and a pregnancy testing if female with reproductive capacity. The first microdialysis visit will consist of placing two microdialysis catheters under the skin after the area is numbed. One microdialysis catheter will be in the lipoma and the other under the skin 2 inches away. The microdialysis catheter will connect to a pump, isoproterenol will be infused and the amount of fat breakdown measured. One week later prednisolone will be injected into the lipoma and under the skin 2 inches away. The microdialysis visit will be repeated 24 hours later.

Treatment will consist of injecting the lipoma 5 days a week with a mixture of isoproterenol and prednisolone in the Pennington clinic as a diabetic would inject insulin. Each week the blood pressure, pulse and lipoma will be measured and subjects will be asked how they feel. At the end of the treatment period the physical examination, blood test and electrocardiogram will be repeated.

The insertion of the microdialysis probes under the skin into the fat tissue could be uncomfortable, but numbing medication will be injected first to prevent this problem. At higher doses, isoproterenol could lower blood pressure and increase pulse rate. This should not happen at the doses used, but blood pressure and pulse will be monitored throughout the study. Prednisolone, at higher doses, could decrease the body's production of cortisone. This should not happen at the doses being used, but cortisone in the body will be measured during the trial. Blood tests involve the discomfort of a needle going through the skin of the arm, possible bruising and rarely fainting or infection. Trained technicians and sterile needles will minimize these risks.

Association of Beta-2 Adrenergic Agonist and Corticosteroid Injection in the Treatment of Lipomas

A Pilot Study: Association of Beta-2 Adrenergic Agonist and Corticosteroid Injection in the Treatment of Lipomas

Lipothera

Pennington Biomedical Research Center

Principal Investigator

Prednisolone and Isoproteronol

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

The single case that did not have an increase in lipoma volume showed variability which may have been because of a small lipoma making accurate measurement difficult.

Leanne Redman

The Average Percent Volume Reduction in the Lipoma.

The Number of Lipoma Increased in Volume.

The Number of Subjects Elected to Have the Lipoma Removed.

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Pembrolizumab

Immunomodulating Agents

Atezolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Lung cancer patients receiving one of three standard of care immunotherapy drugs including nivolumab, pembrolizumab or atezolizumab. 3D-EX will be performed on biopsies from patients enrolled in the study to correlate with the patient's evaluation of response by RECIST.

Nivolumab, pembrolizumab or atezolizumab will be administered as per the established standard of care for the eligible population.

Analysis of drug-mediated changes in the tumor microenvironment.

3D-EX

Evaluation of tumor response using the set of published rules to determine if a tumor has responded, is stable or progressed during treatments.

Evaluation of Response by RECIST

Soner Altiok, MD, PhD

Igor Rybkin, MD

Subjects will be eligible for this study if they are about to start on a drug called nivolumab for lung cancer. Some patients' cancers respond to nivolumab but a majority of patients do not. To better determine which patients will most likely respond to nivolumab or not, the investigators are testing an assay that tests biopsy tissue to determine if the subject's tumor will likely respond to nivolumab.

The main purpose of this research study is to see if this specialized test can help identify people with locally advanced or metastatic non-small cell lung cancer who are more likely to benefit from treatment with nivolumab. The results of the tests will not affect whether or not subjects receive nivolumab but may help identify future patients who are more likely to benefit from nivolumab. The study assay is extra and experimental.

Overview of PD-1 inhibition for locally advanced or metastatic NSCLC Lung cancer (LC) is the most common malignancy-related death in the United States (causing deaths in \~ 86,380 men and \~71,660 women in 2015. Fifteen percent of LC patients present with Stage I disease, which is treated primarily with surgery, leading to a 5-year survival rate of 54%. Approximately 57% of LC patients are initially diagnosed with metastatic disease (Stage IV) with a corresponding 5-year survival rate of 4.2%.

More recently, major treatment responses have been observed with the use of immune checkpoint inhibitor proteins expressed on the surface of lymphocytes and other immune cells, most notably on cytotoxic T-cells. When bound to their specific ligand, often another surface-bound protein on a neighboring cell, they can transmit stimulatory or inhibitory signals to activate or inhibit the cellular adaptive immune response. Several studies showed that the predominant mechanism by which NSCLC evades detection and elimination by the immune system is by exploiting one such inhibitory pathway through the expression of programmed death ligand 1 (PD-L1, B7-H1). PD-L1 then binds to its receptor, programmed cell death protein 1 (PD1), on surveilling lymphocytes and initiates a signaling cascade which leads to lymphocyte exhaustion, a state of impaired function. The most successful immune checkpoint inhibitors so far are anti PD1 or anti-PD-L1 monoclonal antibodies that prevent PD1-PD-L1 interaction at the tumor-immune interface. In this pilot study, the investigators will investigate if Nilogen's functional ex vivo bioassay can predict therapeutic response to anti PD1 (nivolumab, pembrolizumab) or anti PD-L1 (atezolizumab) in advanced non-small cell lung cancer (NSCLC).

Functional bioassay as a potential predictive biomarker. The intent of using anti-PD-1/PD-L1 as an anti-cancer therapeutic is to block one of the ways that tumors inhibit T cell function within the tumor microenvironment, allowing restoration of T cell function. Therefore, the investigators hypothesize that a bioassay that directly measures restoration of T cell function in the context of all of the elements of the tumor microenvironment could accurately predict whether or not a patient will be clinically responsive to a particular immunotherapeutic agent that is designed to target the tumor microenvironment. A tumor biopsy from a patient who will be clinically responsive to anti-PD-1 will contain inactive T cells that may have their functional activity restored by the provision of anti-PD-1/PD-L1 ex vivo, much like what is seen in the ex vivo experiments performed at Nilogen using the 3D-EX platform (www.nilogen.com). To assess tumor response to nivolumab, pembrolizumab or atezolizumab the investigators will use their proprietary immune cell function analysis in tumor samples obtained by FNA biopsy upon treatment with nivolumab, pembrolizumab or atezolizumab, pembrolizumab or atezolizumab ex vivo.

Hypothesis

1. In 80% of patients, FNA samples will provide a sufficient number of viable tumor cells to perform ex vivo functional bioassays with nivolumab, pembrolizumab or atezolizumab.
2. Patients whose tumor FNA samples fail to respond to nivolumab, pembrolizumab or atezolizumab, in the 3D Ex-Vivo assays will likely not show a clinical response to systemic nivolumab, pembrolizumab or atezolizumab treatment.

Study Objectives

Primary Objective To test whether it is feasible to perform the 3D-EX functional response bioassay in the context of patients with advanced NSCLC receiving treatment with nivolumab, pembrolizumab or atezolizumab in a standard clinical setting.

Overall study design Eligible patients will have a histologic or cytologic diagnosis of NSCLC; advanced-stage disease who are appropriate candidates for therapy with nivolumab, pembrolizumab or atezolizumab, and age greater than 18 years. Prior surgery, chemotherapy and/or radiotherapy are allowed. Inclusion and exclusion criteria are outlined in the appropriate section. All inclusion and exclusion criteria will be assessed within 6 weeks prior to the first dose of nivolumab, pembrolizumab or atezolizumab. Baseline radiographic studies should be performed within 30 days of screening. This clinical study will require central IRB approval. Informed consent will be obtained from each patient prior to screening and enrolling in the study.

Nivolumab, pembrolizumab or atezolizumab will be administered as per the established standard of care for the eligible population.

Prediction of Response to Nivolumab, pembrolizumab or atezolizumab by Nilogen's 3D-EX Bioassay.

In previous preclinical and clinical studies the investigators showed that FNA samples provide a sufficient number of viable tumor cells to perform drug sensitivity assays ex-vivo. The assay protocol is optimized to process tumor FNA samples, where the tumor microenvironment is intact and contains tumor cells and all other tumor-infiltrating inflammatory cells as well as specialized tumor stroma. Prior to initiation of therapy, tumor samples will be collected by FNA from accessible tumor tissue. For the ex vivo assays, aspirates will be obtained from each patient after collection of biopsy samples required for SOC. The FNA samples will be immediately shipped to the Nilogen Laboratory. All proposed assays will be performed at the Nilogen Oncosystems laboratory in Tampa, FL according to CLIA standards.

Patients who do not have a site of disease that will provide enough tumor cells for analyses will be taken off study. In adequate samples, tumor FNA samples will be treated nivolumab, pembrolizumab or atezolizumab at clinically relevant concentrations. At the end of incubation T-cell activation will be assessed by a proprietary approach including evaluation of drug-mediated changes in three parameters: (1) T-cell activation, (2) cytokine release and (3) gene expression profiles. The response rate to treatment will be scored for T-cell activity and correlated with patient outcome.

The investigators hypothesize that tumors that fail to respond ex vivo will not be likely to be responsive in vivo in cancer patients.

Pilot Study of Nilogen 3D-EX and Its Ability to Predict Therapeutic Response to Anti-PD1 or Anti-PDL1 in NSCLC

Pilot Study of the Nilogen Ex-Vivo Assay (3D-EX) and Its Ability to Predict Therapeutic Response to Anti-PD1 (Nivolumab, Embrolizumab) or Anti-PDL1(Atezolizumab) in Advanced Non-small Cell Lung Cancer (NSCLC)

Participant data will not be shared but the results of the clinical trial will be published in a peer-reviewed journal.

Complete Response (CR) is defined as disappearance of all target lesions Partial Response (PR) is defined as at least a 30% decrease in the sum of longest dimension (LD) of target lesions taking as reference the baseline sum LD Progressive Disease (PD) is defined as at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD since the treatment started

Henry Ford Health System

Nilogen Oncosystems

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TDM for Optimized Outcome in Patients With mRCC.	NCT04659343	Kidney Cancer Renal Cell Carc... Drug Toxicity Drug Side Effec... Drug Mechanism	Measurement of ...	18 Years -	University of Aarhus
TDM for Optimized Outcome in Patients With mRCC.	NCT04659343	Kidney Cancer Renal Cell Carc... Drug Toxicity Drug Side Effec... Drug Mechanism	Measurement of ...	18 Years -	University of Aarhus
Association of Beta-2 Adrenergic Agonist and Corticosteroid Injection in the Treatment of Lipomas	NCT00624416	Lipoma	Prednisolone sy...	18 Years - 60 Years	Pennington Biomedical Research Center
Pilot Study of Nilogen 3D-EX and Its Ability to Predict Therapeutic Response to Anti-PD1 or Anti-PDL1 in NSCLC	NCT03371992	Non Small Cell ...	Nivolumab 3D-EX Evaluation of R...	18 Years -	Nilogen Oncosystems
Association of Beta-2 Adrenergic Agonist and Corticosteroid Injection in the Treatment of Lipomas	NCT00624416	Lipoma	Prednisolone sy...	18 Years - 60 Years	Pennington Biomedical Research Center

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