Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Bruno SEGUI, Pr

Cutaneous melanoma is a bad prognosis skin cancer, which can be treated with immune checkpoint inhibitors (ICI), such as anti-PD-1 (nivolumab, nivo) and anti-CTLA-4 (ipilimumab, ipi). However, about 50% of patients do not respond or relapse within 3 years post therapy induction, and immune-related adverse events (irAEs), such as colitis, are triggered and can be treated with TNF inhibitor (TNFi; ie, infliximab, inflix). The pharmacodynamic impact of TNFi on the immune and clinical responses remain to be clarified. The investigators previously demonstrated that TNFi enhance the efficacy of ICI in mouse melanoma models. Based on preclinical findings, the investigators implemented two clinical trials in advanced melanoma patients, TICIMEL and MELANFalpha. In TICIMEL, patients are concomitantly treated with TNFi \[certolizumab (certo) or inflix\] and ICI (ipi+nivo). In MELANFalpha, patients are treated with ICI alone. Preliminary results show both tritherapies promote systemic MART-1 specific CD8 T cell responses and that certo but not inflix may improve ICI efficacy and Th1 responses. In mouse melanoma models, TNFi enhance the response to ICI. Investigators' primary objective is to decipher how certolizumab and infliximab influence ICI-dependent anti-tumor immune responses in advanced melanoma patients. The secondary objectives are to analyse the cellular and molecular impact anti-TNF have on ICI-dependent anti-melanoma immune responses and clinical activities (irAEs and efficacy). By combining mouse and human data as well ex vivo functional assays, the investigators will dissect the impact treatments have on anti-melanoma immune responses by flow cytometry and transcriptomic analyses. The investigators expect to clarify (i) the mechanisms by which TNFi enhance ICI efficacy, (ii) identify the best TNFi to be combined with ICI in advanced melanoma patients and (iii) discover TNF-dependent biomarkers of resistance.

Background and originality of the project with regards to the state of the art

Despite the tremendous breakthrough immune checkpoint inhibitors (ICI) such as anti-PD-1 and anti-CTLA-4 brought for the treatment of advanced melanoma patients, 60% of them do not respond or relapse within 5 years following treatment initiation. Severe immune-related adverse events (irAEs) are triggered upon ICI therapy, such as colitis, which can be treated with inhibitors (TNFi) of the Tumor Necrosis Factor alpha (TNF) such as infliximab. The pharmacodynamic impact of TNFi on the immune and clinical responses remains to be clarified.

Although TNF has been identified as a soluble factor able to trigger tumor necrosis in mice, the chronic production of TNF in the tumor microenvironment was shown to contribute to cancer progression. The investigators and others have shown this cancer promoting property relies on multiple mechanisms, including immune escape. For instance, the investigators showed that TNF triggers activation-induced cell death (AICD) in CD8 T cells, thereby limiting the infiltration of CD8 T cells in mouse melanoma tumors. In mouse models of melanoma, breast and colon cancers, TNFi enhance ICI (anti-PD-1, anti-CTLA-4) efficacy and reduce the severity of irAEs such as colitis. Hence, combining TNF-blocking antibodies to ICI promotes therapy efficacy and tolerance in vivo.

Investigators' unpublished data show all treatments promoted the differentiation of circulating T cells towards an effector memory phenotype (data not shown) between baseline (before treatment induction, week 0 \[W0\]) and week 6 (W6) post-treatment induction. They also significantly 1- Background and originality of the project with regards to the state of the art Despite the tremendous breakthrough immune checkpoint inhibitors (ICI) such as anti-PD-1 and anti-CTLA-4 brought for the treatment of advanced melanoma patients, 60% of them do not respond or relapse within 5 years following treatment initiation. Severe immune-related adverse events (irAEs) are triggered upon ICI therapy, such as colitis, which can be treated with inhibitors (TNFi) of the Tumor Necrosis Factor alpha (TNF) such as infliximab. The pharmacodynamic impact of TNFi on the immune and clinical responses remains to be clarified. Although TNF has been identified as a soluble factor able to trigger tumor necrosis in mice, the chronic production of TNF in the tumor microenvironment was shown to contribute to cancer progression. The investigatorsand others have shown this cancer promoting property relies on multiple mechanisms, including immune escape. For instance, the investigators showed that TNF triggers activation-induced cell death (AICD) in CD8 T cells, thereby limiting the infiltration of CD8 T cells in mouse melanoma tumors. In mouse models of melanoma, breast and colon cancers, TNFi enhance ICI (anti-PD-1, anti-CTLA-4) efficacy and reduce the severity of irAEs such as colitis. Hence, combining TNF-blocking antibodies to ICI promotes therapy efficacy and tolerance in vivo. Based on preclinical studies, the investigators implemented two clinical trials (TICIMEL and MELANFalpha) in advanced melanoma patients (stage IIIc/IV) treated with ICI \[anti-PD-1, nivolumab (nivo) + anti-CTLA-4, ipilimumab (ipi)\] in combination (TICIMEL) or not (MELANFalpha) with TNFi \[certolizumab (certo) or infliximab (inflix)\]. Whereas inflix is a bivalent anti-TNF chimeric IgG1 monoclonal antibody, certo is a monovalent PEGylated Fab' fragment of a humanized anti-TNF monoclonal. All patients (i.e., 92) have been enrolled between 2018 and 2021. TICIMEL (n=32) is a phase 1b clinical trial aiming at evaluating the safety and tolerability of co-administering ipi, nivo and TNFi (certo or inflix). Investigators' first data, obtained from 14 patients, indicate that both tritherapies are safe in humans, with a promising high response rate in the certo cohort. MELANFalpha (n=60) is a pilot study aiming at discovering predictive biomarkers of response/resistance to ICI. It notably shows high TNF levels are detected upon ipi/nivo treatment in plasmas from non-responders. Investigators' unpublished data show all treatments promoted the differentiation of circulating T cells towards an effector memory phenotype between baseline (before treatment induction, week 0 \[W0\]) and week 6 (W6) post-treatment induction. They also significantly increased the proportion of Th1 T cells in patients' blood. However, those effects were significantly amplified in the certolizumab cohort as compared to the ipi/nivo one. Accordingly, the investigators observed increased IFN-gamma plasma concentrations in the certolizumab cohort. Proportions of Th2, Th17 and Th1/17 T cells were not significantly affected by the three treatment regimens. Moreover, TNFi combination with ICI was associated with increased proportions of circulating MART-1-specific CD8 T cells. These cells mainly exhibited a central/effector memory phenotype and show increased expression of CXCR3 (Fig. 1D-F). The investigators performed CiteSeq single cell RNA sequencing (scRNAseq) on peripheral blood mononuclear cells (PBMCs) obtained before (W0) and at W6 from 4 advanced melanoma patients enrolled in each of the 3 cohorts. Signs of activation and maturation of immune responses were obvious in all patients from TICIMEL, but one, at W6. This indicates TNFi unlikely compromise the immune boost observed in patients treated with ipi/nivo. Moreover, the investigators show in a mouse melanoma model (B16Ova) whereby treatment conditions mimic that of TICIMEL and MELANFalpha (alphaPD-1+alphaCTLA-4+/- TNFi \[anti-mouse TNF, clone XT3.11\]), that the tritherapy increased the frequency of total tumor regressions and overall survival, as compared to the bitherapy. Mice, cured upon tritherapy, developed anti-melanoma memory responses, as evidenced by a rechallenge experiment. Understanding how TNF blockade increases the awakening of patients' anti-melanoma immune responses upon ICI and how the properties of TNFi may differentially modulate these responses is pivotal to:

* (i) get a better understanding of the cellular and molecular pathways, which need to be engaged to overcome some of the mechanisms responsible for ICI resistance.
* (ii) identify new and potentially better strategies to promote these responses.
* (iii) identify patients who might benefit the most from such therapies.

Hypothesis, main objective(s) and endpoint(s) of the project

Considering investigators' recently published and unpublished data, the investigators hypothesize that TNF blockade may promote ICI efficacy in patients. This effect may however be affected by the structural properties of the TNF blocking agent used. To evaluate this hypothesis, the investigators will compare the clinicobiological responses of patients from the TICIMEL (ipi+nivo+certo or inflix) and MELANFalpha (ipi+nivo, without TNFi) clinical trials. To clarify the molecular mechanisms by which certo and inflix differently impact on immune responses, the investigators will perform ex vivo and in vivo experiments in co-culture systems as well as in a unique mouse melanoma model, respectively.

Project plan describing the methodology and work to be performed To reach the primary and secondary objectives, the proposal is divided into three main WPs.

WP1: To decipher how certolizumab and infliximab influence the ICI-dependent systemic immune responses in advanced melanoma patients.

WP2: To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in tumors in advanced melanoma patients. The investigators already performed immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) melanoma biopsies from patients enrolled in the first part of TICIMEL to evaluate the tumor-infiltrating leukocytes before and along therapy (CD3, CD8, CD4, FOXP3, CD68).

WP3: To analyse the impact TNFi have on ICI-dependent anti-melanoma immune responses in co-culture experiments and in mice.

Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma

In patients from the MELANFalpha trial as well as in patients from the second phase of TICIMEL, influence of the different therapies on the capacity of circulating CD4 and CD8 T cells to produce IFNgamma, TNF and IL-17 ex vivo will be counted by flow cytometry in PBMCs.

In patients enrolled in the second part of TICIMEL and in the ipi/nivo cohort of MELANFalpha, the evaluation of poucentage of HLA-A2 positive melanoma patients displaying circulating CD8 T cells reactive towards the tyrosinase and/or MART-1 antigens will be evaluate after staining.

CiteSeq scRNAseq on PBMCs from patients from the 3 cohorts, including two non-responders of the ipi/nivo/certo cohort will be realise. PBMC's RNA obtained at W0 and W6 will be compared.

To evaluate the tumor-infiltrating leukocytes before and along therapy (CD3, CD8, CD4, FOXP3, CD68), immunohistochemistry (IHC) on tumor samples on biopsies from patients enrolled in the second part of TICIMEL and on FFPE biopsies from MELANFalpha patients will be realised.

To further characterize immune responses in tumors from patients enrolled in TICIMEL and MELANFalpha, RNAseq analyses on RNA extracted from pre-treatment and, when possible, matched post-treatment FFPE tumor biopsies will be performed. Differential immune signatures according to treatment and response will be assessed.

To combine all biological and clinical data from patients by biostatistical and bioinformatic analyses. Flow cytometry, CiteSeq scRNAseq data obtained on circulating immune cells as well as IHC and RNAseq data from tumor biopsies will be combined to clinical data using machine learning methods.

The baseline PBMCs proliferation and the production of IFNgamma will be measured in presence of autologous CD14+ monocytes and antigenic peptides from tyrosinase or MART-1. IFNgamma plasma concentration is determined by mesoscale (pg/mL). Proliferation is measured by flow cytometry.

Institut National de la Santé Et de la Recherche Médicale, France

Institut Claudius Regaud

Nervous System Diseases

Breast Neoplasms

Brain Neoplasms

Breast Diseases

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Yi-Hua YH Liao, PhD

Yao-Chen YC Tseng, Master

Yi-Hua Liao

The goal of this clinical trial is to develop an imaging platform for intraoperative tumor margin delineation in 250 cases of tumor-suffered patients. The main questions it aims to answer are:

• to develop the protocol of rapid assessment of surgical specimens without need for fixation, embedding, and cryosectioning required for conventional histopathology.

Participants will provide a small piece of their surgical specimens from tumor removal surgery .

If there is a comparison group: Researchers will compare normal specimens to see if we can observe the difference.

Microscopy Imaging of Whole-mount Stained Human Tissues

Microscopy Imaging of Whole-mount Stained Human Tissues: Development of an Imaging Platform for Intraoperative Tumor Margin Delineation

Do comparison with images acquired by our microscopy (with the whole-mount staining method) and bright field microscopy (with standard FFPE method) and do assessment to interpret tumor characteristics

National Taiwan University Hospital

Melanoma, Cutaneous Malignant

Patients who will receive definitive surgery for a primary malignancy of the skin, will have their tumor injected with India ink for tumor marking and will be given oxygen during the measurement sessions.

Patients who will receive definitive radiation (+/- concurrent systemic therapy) for a primary malignancy of the skin, will have their tumor injected with India ink for tumor marking and will be given oxygen during the measurement sessions.

Patients who will receive palliative radiation (+/- concurrent systemic therapy) for any tumor involving the skin, will have their tumor injected with India ink for tumor marking and will be given oxygen during the measurement sessions.

Patients who will receive systemic therapy alone (without radiation) for any tumor involving the skin, will have their tumor injected with India ink for tumor marking and will be given oxygen during the measurement sessions.

Patients will be given oxygen via a facemask during the measurement session

Oxygen

Todd Tenenholz, MD

Malcolm Mattes, MD

Andrey Bobko, PhD

Timothy Eubank, PhD

Geraldine Jacobson, MD

Valery Khramtsov, PhD

Mark Tseytlin, PhD

This protocol will take measurements of a variety of tumors involving the skin in order to assess changes in tumor oxygen from hyperoxygenation therapy and standard cancer-directed treatments, to demonstrate the clinical feasibility of using in vivo Electron Paramagnetic Resonance (EPR) Oximetry to obtain clinically useful measurements of tumor oxygen levels from cancer patients.

All patients in this study will receive standard of care therapy for their cancer at the discretion of their treating physician(s). All subjects will be assigned to one of the four cohorts for which they qualify; there is no randomization and no stratification within the cohorts.

Cohort 1 - Patients who will receive definitive surgery for a primary malignancy of the skin

Cohort 2 - Patients who will receive definitive radiation (+/- concurrent systemic therapy) for a primary malignancy of the skin

Cohort 3 - Patients who will receive palliative radiation (+/- concurrent systemic therapy) for any tumor involving the skin

Cohort 4 - Patients who will receive systemic therapy alone (without radiation) for any tumor involving the skin

All patients enrolled in this study will undergo two initial measurements of their tumor oxygen level. On the first day, a small metal disc (less than 1 cm in diameter) called a SPOTChip will be placed on the surface of the tumor, and held in place using an adhesive. The patient will then be positioned (lying down or sitting) between a set of two magnets that are used to measure the oxygen level in the tumor. A small plastic oxygen detector will be placed on the skin over the tumor. These devices will be used to take a measurement of the tumor's oxygen level at baseline, then while breathing oxygen through a clear plastic facemask, and then a final time after the oxygen facemask has been removed.

After the measurements are taken, a small amount (20-50 microliters) of India ink will be injected into the tumor using a small (28-gauge) needle. The India ink will make a permanent, dark blue/black colored mark on the tumor. The ink leaves a permanent tattoo in the spot where it is injected, unless it is physically removed surgically.

The patient will return for another measurement, at least 2 days later. This measurement will use the India ink that was previously injected (described above) and there will no longer be a need to use the SPOTChip. For the India ink tumor oxygen measurement a small piece of wire (called a loop resonator) will be placed over the tumor and held in place using medical honey and saran wrap or tape. The Investigator will first take a measurement of the tumor's oxygen level at baseline, then while breathing oxygen through a clear plastic facemask, and then the mask will be taken the tumor's oxygen level will be measured as it returns to baseline.

Patients who have surgical excision of the tumor (cohort 1) will not have any further measurements after this point.

Patients who are being treated with radiation therapy (cohorts 2 \& 3), will come back for weekly measurements of the tumor during treatment, followed by one additional measurement one month after they have completed the course of radiation therapy.

Patients being treated with chemotherapy, immunotherapy, or other systemic therapies without radiation (cohort 4), will come back for measurements every 3-4 weeks around the time of their regular infusion, followed by one additional measurement one month after they complete the course of systemic therapy.

Four cohorts based on standard treatment will be given the same intervention

Measurement of the Partial Pressure of Oxygen in Cutaneous Tumors Using Electron Paramagnetic Resonance (EPR) Oximetry

Tumor oxygen kinetics will be measured by EPR oximetry under ambient conditions, during hyperoxygenation therapy (100% O2 administered via a non-rebreather face mask), and immediately after hyperoxygenation therapy.

Patients will undergo weekly tumor oxygen measurements by EPR during a radiation therapy course and every 3-4 week measurements during cycles of systemic therapy. Changes in tumor oxygen will be correlated with standard measures of response to therapy using RECIST criteria.

West Virginia Clinical and Translational Science Institute

Mary Babb Randolph Cancer Center at West Virginia University Hospitals

West Virginia University

Radiation Oncologist, Assistant Professor

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antirheumatic Agents

Natriuretic Agents

Anticonvulsants

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Acetazolamide

Participants will receive conditioning therapy prior to administration of OBX-115 regimen.

A tumor sample is obtained from each participant for autologous OBX-115 manufacture.

After lymphodepletion including cyclophosphamide and fludarabine, participant will receive OBX-115 infusion, followed by a short course of acetazolamide.

OBX-115

Obsidian Therapeutics

Estefania Bobe Cortes

Sajeve Thomas, MD

Melissa B. Hall

Jason Chesney, MD, PhD

NSCLC

Alexander Shoushtari, MD

Lindsay Brown

Yazan Samhouri, MD

This is a study to investigate the safety and efficacy of an investigational OBX-115 regimen in adult participants with advanced solid tumors.

Primary Objective (Phase 1):

• Assess the safety and tolerability of OBX-115 regimen

Primary Objective (Phase 2):

• Evaluate preliminary efficacy of OBX-115 regimen as measured by the investigator using objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary (Phase 1):

• Assess preliminary efficacy of OBX-115 regimen by evaluating ORR

Secondary (Phase 2):

• Evaluate safety and tolerability of OBX 115 based on the collected AE data

Secondary (both Phase 1 and Phase 2):

* Evaluate duration of response (DOR): To evaluate the duration from the time that criteria are met for CR or PR per RECIST v1.1 as assessed by the investigator until disease progression or death due to cancer.
* Evaluate disease control rate (DCR): To evaluate the percentage of participants with a best overall confirmed response of CR or PR at any time plus stable disease (SD) for at least 4 weeks per RECIST v1.1 as assessed by the investigator.
* Evaluate progression-free survival (PFS): To evaluate the time from the date of OBX-115 infusion until disease progression per RECIST v1.1 as assessed by the investigator or death due to any cause.
* Evaluate overall survival (OS): To evaluate the time from the date of OBX-115 infusion to death due to any cause
* Evaluate feasibility of the manufacturing process: Evaluated as the proportion of OBX-115 products initiated for manufacturing that pass release criteria for infusion.

Safety and Efficacy of OBX-115 in Advanced Solid Tumors

A Phase 1/2, Open-Label Study to Investigate the Safety and Efficacy of Membrane Bound IL15 Expressing Tumor-Infiltrating Lymphocytes (OBX-115) In Participants With Advanced Solid Tumors

• Incidence of dose-limiting toxicities (DLTs) during the first 28 days after OBX-115 infusion (Phase 1).

• The proportion of participants who have a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 as assessed by the Investigator from the date of OBX-115 infusion until disease progression, death, start of a new anticancer therapy, withdrawal of consent, or end of study, whichever comes first (Phase 2)

• The proportion of participants who have a confirmed CR or PR per RECIST v1.1 as assessed by the Investigator from the date of OBX-115 infusion until disease progression, death, start of a new anticancer therapy, withdrawal of consent, or end of study, whichever comes first (Phase 1)

• Incidence of treatment-emergent adverse events (TEAEs), including SAEs, study intervention related AEs, and AEs leading to early discontinuation of study intervention or withdrawal from the Assessment Period or death up to 2 years after initiation of study intervention

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Blocking TNF to Potentiate the ICI-dependent Immune Awakening in Melanoma	NCT05867004	Melanoma Immune Defect Tumor Skin		18 Years -	Institut Claudius Regaud
Microscopy Imaging of Whole-mount Stained Human Tissues	NCT05689112	Tumor, Brain Tumor, Breast Tumor Skin		20 Years -	National Taiwan University Hospital
Microscopy Imaging of Whole-mount Stained Human Tissues	NCT05689112	Tumor, Brain Tumor, Breast Tumor Skin		20 Years -	National Taiwan University Hospital
Measurement of the Partial Pressure of Oxygen in Cutaneous Tumors Using Electron Paramagnetic Resonance (EPR) Oximetry	NCT03716193	Skin Lesion Skin Cancer Skin Melanoma Tumor Skin	Oxygen	18 Years - 90 Years	West Virginia University
Microscopy Imaging of Whole-mount Stained Human Tissues	NCT05689112	Tumor, Brain Tumor, Breast Tumor Skin		20 Years -	National Taiwan University Hospital
Safety and Efficacy of OBX-115 in Advanced Solid Tumors	NCT06060613	Tumor Skin Metastatic Mela... Melanoma Lung Cancer Metastatic Lung... Non Small Cell ... Metastatic Non ...	OBX-115	18 Years -	Obsidian Therapeutics, Inc.

Spots Global Cancer Trial Database for tumor skin

Every month we try and update this database with for tumor skin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for tumor skin

Every month we try and update this database with for tumor skin cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for tumor skin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.