Neoplasms

All Conditions

Neoplasms, Glandular and Epithelial

Carcinoma

Neoplasms by Histologic Type

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Interleukin-2

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Analgesics, Non-Narcotic

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Subjects will receive a therapy based on Tumor-infiltrating Lymphocyte (NEXTGEN-TIL product) preceded by a preparative non-myeloablative lymphodepleting (NMA-DL) regimen and followed by IL-2 infusion. Patients will be followed-up for 2 years, assessed at weeks 2, 3, 4, 6, 9, 12, 18, 24, 30, 36 (9 months), and then at 1 year, 1,5 and 2 years.

NEXTGEN-TIL product is a cellular investigational product comprising a live cell suspension of autologous tumor-infiltrating lymphocytes derived from the patient's own tumor.

Each dose contains at least 5 x 10\^8 total viable lymphocytes, and a maximum of 1.11x10\^11. It will be administered IV on Day 0 (24h after the last dose of Fludarabine).

NEXTGEN-TIL

Patients will receive a NMA-LD chemotherapy based on Cyclophosphamide 60 mg/kg IV (once daily on Days -5 and -4) and Fludarabine 25 mg/m2 IV (once daily on Days -5 to -1).

Non-myeloablative Lymphodepletion (NMA-LD) Regimen

Patients will receive sequential doses of 720,000 IU/kg IV IL-2 every 8-24 hours depending on patient tolerance. It will be administered on Days 0 to 2, starting between 3 and 24 hours after the completion of NEXTGEN-TIL infusion.

IL-2 doses may be skipped in case of toxicity. If 2 sequential doses or more than 2 non-sequential doses of IL-2 are skipped due to patient intolerance or the discretion of the investigator, IL-2 administration must be stopped.

Elena Garralda

Susana Muñoz

Elena Garralda, MD

Vladimir Galvão de Aguiar, MD

Background:

The presence of T-lymphocytes in resected tumor samples derived from long-term survival patients and the fact that reinvigoration of their functionality through the administration of specific immune-therapies can lead to remarkable antitumor responses supports that lymphocytes play a critical role in cancer immunity.

Adoptive cell therapy using tumor-infiltrating lymphocytes product (TIL-ACT) is a well-established combination therapy currently under study in several world reference centers, using an autologous cell product without genetic modifications. This cell product consists of tumor-infiltrating lymphocytes (TIL), which are collected from the patient and expanded in the lab under specific conditions to enhance its antitumoral efficacy before reinfusion in the same patient. However, this cell product alone does not achieve adequate efficacy, and a combination of both previous non-myeloablative lymphodepleting (NMA-LD) chemotherapy and subsequent cytokine therapy (specifically IL-2) is needed to support the expansion of the infused cells.

The investigators hypothesize that TILs enriched for neoantigen recognition are superior to unselected TILs at mediating tumor regression in patients with epithelial tumors and even other solid tumors where immune checkpoint blockade (ICB) is approved and used as part of standard therapy. The investigators propose to manufacture a T-cell product composed of TILs that are selected based on their ability to recognize patient-specific neoantigens and to use these to treat patients with metastatic, refractory, epithelial cancers, as well as ICB-resistant solid tumors. Furthermore, it also proposed to study the tumor and T cells at baseline and after treatment to investigate whether specific phenotypic and functional traits may be associated with clinical outcome.

Primary objective:

To evaluate the safety and the tolerability of ex vivo next generation neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) in patients with metastatic or unresectable epithelial tumors and immune checkpoint blockade (ICB) resistant solid tumors.

Secondary objectives:

* To determine the success in producing active specific TILs from our target patients.
* To evaluate the initial clinical activity of the NEXTGEN-TIL products in our target patients.

Methods:

This study is a first-in-human, open-label, non-controlled, single-centre, phase I trial to assess the safety and tolerability of NEXTGEN-TIL-ACT. Given the exploratory nature of the study, there is no formal hypothesis testing and no formal sample size calculation was carried out.

A sample size of 10 patients has been selected to provide information about the frequency of treatment-limiting toxicity (TLT).

Study treatment:

The main study therapy is the Tumor-infiltrating Lymphocyte (NEXTGEN-TIL) product, which is preceded by a preparative non-myeloablative lymphodepleting (NMA-DL) regimen and followed by IL-2 infusion.

NEXTGEN-TIL product is a cellular investigational product comprising a live cell suspension of autologous tumor-infiltrating lymphocytes derived from the patient's own tumor.

First-in-human, open-label, non-controlled, single-centre, phase I trial. Sequential recruitment: The first six patients will be included for safety assessment. If no more than one treatment-limiting toxicity (TLT) is observed, four additional patients will be included for the final safety population analysis (a total of 10 patients).

Assessment of the Safety and Tolerability of ex Vivo Next-generation Neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) Therapy in Advanced Epithelial Tumors and Immune Checkpoint Blockade (ICB) Resistant Solid Tumors

A Phase I Study to Assess the Safety and Tolerability of ex Vivo Next-generation Neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) Therapy in Advanced Epithelial Tumors and Immune Checkpoint Blockade (ICB) Resistant Solid Tumors

Nature and frequency of AE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Nature and frequency of SAE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Toxicities related to treatment administration that, if recurrent at high enough frequency (≥2 patients treated), should trigger review by the Independent Data Safety Monitoring Board (IDSMB), which could lead to recommendations for treatment modifications for subsequent patients.

Nature and frequency of abnormalities found in clinical laboratory test results

Nature and frequency of abnormalities found in electrocardiogram

Nature and frequency of abnormalities found in vital signs.

Nature and frequency of abnormalities found in the physical examination.

Patient performance status assessed as per Eastern Cooperative Oncology Group (ECOG) score, where grade 0 is for fully active and capable patient and grade 5 is death.

Rate of successful neoantigen-selected TIL (NEXTGEN-TIL) generation from biopsied patients and frequency of neoantigen-specific TILs in all TILs produced from biopsied patients included in this trial.

ORR per RECIST v1.1 as assessed by investigator, defined as proportion of patients who have a partial or complete response to therapy.

DOR per RECIST v1.1 as assessed by investigator, defined as the time elapsed between the initial response to therapy and subsequent disease progression or relapse.

PFS per RECIST v1.1 as assessed by investigator, defined as the time from the date of treatment administration to the date of first documentation of disease progression or death due to any cause, whichever occurs first. For a patient who has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is stable disease (SD) or better.

Banc de Sang i Teixits

Vall d'Hebron Institute of Oncology

Rare Diseases

Sarcoma

Neoplasms, Connective and Soft Tissue

Soft Tissue Sarcoma

Malignant Mesenchymoma

Interleukin-12

NHS-IL12 escalating doses on a 4 week schedule (Completed).

NHS-IL12 escalating doses on a 2 week schedule

NHS-IL12 expansion group on a 4 week schedule (Completed).

NHS-IL12 is an investigational agent supplied to investigators by the manufacturer EMD Serono, Inc.

NHS-IL-12

James L Gulley, M.D.

Background:

- The experimental drug NHS-IL12 may help the immune system become more active and kill cancer cells that have not responded to standard treatments. NHS-IL12 has been designed to cause less severe side effects than other anticancer drugs, and may be more effective. More research is needed to test NHS-IL12 in people who have solid tumors that have not responded to treatment.

Objectives:

- To test the safety and effectiveness of NHS-IL12 as a treatment for solid tumors which have not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age with solid tumors that have not responded to standard treatments.

Design:

* Participants will be screened with a medical history, physical exam, blood and urine tests, and imaging studies.
* Participants will receive NHS-IL12 injection every 4 weeks, and will stay in the hospital for at least one day to be monitored with frequent blood tests.
* Participants will have periodic blood samples taken before treatment and during the first week after treatment for the first two cycles. They will then have blood samples taken before treatment for the rest of the cycles.

Background:

* Interleukin-12 (IL-12) is a proinflammatory cytokine produced by activated phagocytes and dendritic cells (DCs) that plays a critical role in regulating the transition from innate to adaptive immunity.
* IL-12 has shown some promising clinical activity in phase I trials, including stabilization of disease in renal cancer patients with partial regression of a metastatic lesion, but has not proceeded further in clinical development due to toxicity.
* The NHS-IL12 concept is a strategy to reduce the toxicity associated with systemic administration of recombinant human IL-12 by selectively targeting delivery to tumors. The NHS-IL12 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and doublestranded DNA. Thus, NHS-IL12 targets delivery to regions of tumor necrosis where DNA has become exposed.

Objectives:

-To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of NHS-IL12 administered subcutaneously every 4 weeks and subcutaneously every 2 weeks in participants with metastatic or locally advanced solid epithelial or mesenchymal tumors.

Eligibility:

* Adults with histologically or cytologically proven metastatic or locally advanced solid epithelial or mesenchymal tumors, except unstable brain metastases, for which standard curative or palliative measures do not exist or are no longer effective.
* Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
* Participants with acquired immune defects, systemic autoimmune disease, history of organ transplant, history of chronic infections, or history of active inflammatory bowel disease will be excluded.

Design:

* With amendment D, this is a phase I, open-label, dose-escalation study designed to assess the safety, tolerability, PK, and biological and clinical activity of NHS-IL12. Goals are to determine the MTD of every 4-week doses at a starting dose level of 2 mcg/kg of NHS IL12 and to define the biologically optimal treatment schedule.
* Participants will be enrolled in cohorts of 3 to 6 participants using a standard 3+3 approach until MTD is reached.
* The trial will include a planned schedule-optimization amendment with up to 12 participants at each of the 2 dose levels that are of greater biologic interest (MTD and dose below MTD), which will be submitted as soon as a clear biological response (changes in circulating cytokine levels) is measured in at least 3 participants at a given dose level. With amendment L, a cohort will be enrolled evaluating NHS-IL12 at 12 mcg/kg every 2 weeks with dose escalation to 16.8 mcg/kg every 2 weeks if 0 of 3 or 1 of 6 DLTS are observed.
* With a maximum accrual ceiling of 83 participants, this study will be completed within 1year, enrolling up to 2-3 participants per month.

NHS-IL12 for Solid Tumors

First In-Human Phase I Trial of NHS-IL12 in Patients With Metastatic Solid Tumors

Determination of safety, immune response and pharmacokinetic parameters

National Cancer Institute (NCI)

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Pleural Effusion

Neoplasm Metastasis

Pleural Effusion, Malignant

Mesothelioma

Mesothelioma, Malignant

Disease Progression

Adenoma

Neoplasms, Mesothelial

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Pleural Diseases

Malignant Mesothelioma

LMB-100

Immunotoxins

Immunoconjugates

LMB-100 at escalating/de-escalating doses + MSLN testing

Cytoreductive surgery: minimally invasive (VATS/robotic) or open (thoracotomy)

Cytoreductive surgery

1000 mcg/mL (DL1) post-operative dose as a single 90-minute normothermic intrathoracic perfusion using a closed circuit and roller pump with a heat exchanger following maximal cytoreductive surgery

Performed at screening to determine mesothelin expression; separate testing of tumor mesothelin expression will be assessed retrospectively in resected tumor tissues. The device is not diagnostic; protocol assessment of mesothelin expression status will only be used to help to increase the possibility that all persons enrolling on the study might derive benefit from therapy.

Immunohistochemical Assay for Mesothelin

David S Schrump, M.D.

Background:

Cancers that spread into the thin tissue lining your lungs (pleura) cause serious illness. They often recur when removed. These tumors include malignant pleural mesothelioma (MPM), caused by exposure to asbestos and related fibers. Malignant pleural effusions (MPEs) are caused when cancers in other parts of the body spread to the lungs and pleura. Many people diagnosed with pleural tumors survive less than a year.

Objective:

To test the safety of a study drug (LMB-100) in people. LMB-100 may help stop pleural tumors from recurring after surgery.

Eligibility:

People aged 18 years or older diagnosed with MPM or related cancer that has spread into the pleura.

Design:

Participants will undergo screening. They will have a physical exam with blood and urine tests. They will have CT scans. They will have tests that measure the how their heart and lungs function. They will provide a sample of tumor tissue to determine if their tumor expresses a protein called mesothelin.

Participants will undergo standard surgery to maximally remove the plural tumors. Then they will have LMB-100 pumped into their chest. The liquid will rinse the chest wall, diaphragm, heart sac, and surface of the lungs for 90 minutes. Then the liquid will be drained and the surgical incisions closed. The participants will be under anesthesia during this procedure.

Participants will remain in the intensive care unit for a least 48 hours. They will remain in the hospital for up to a week or more until recovered enough to be safely discharged.

Participants will return for regular follow-up visits for 2 years.

Background

* Malignant pleural mesotheliomas (MPM) are aggressive cancers with a high predilection for intrapleural recurrences despite potentially curative resections.
* Pleural metastases and associated malignant pleural effusions (MPE) cause considerable morbidity and mortality in patients with lung and esophageal cancers, gastrointestinal, pancreatic, and ovarian carcinomas, as well as sarcomas.
* Mesothelin (MSLN), a tumor differentiatio antigen, is expressed in over 95% of epithelioid MPM, as well as 80% of thymic carcinomas, 50% of lung and gastroesophageal cancers, 75% of pancreatic carcinomas, and 30% of ovarian carcinomas and synovial sarcomas.
* Mesothelin is an attractive target for cancer therapy due to its limited expression in normal human tissues and effects on invasion and metastasis of cancer cells.
* LMB-100 is a novel recombinant anti-mesothelin immunotoxin containing a humanized fragment of an anti-mesothelin Fab conjugated to a de-immunized Pseudomonas exotoxin A (PEA) which exhibits broad activity against cancer lines and tumor xenografts expressing mesothelin.
* Despite de-immunizing modifications, LMB-100 still induces neutralizing antibodies that prevent repeated systemic administration of this immunotoxin.
* Local (intraperitoneal) administration of LMB-100 can eradicate low-volume carcinomatosis in a murine model of minimal residual disease.
* Conceivably, intracavitary administration of LMB-100 following cytoreductive surgery may enhance local control of pleural-based malignancies that express mesothelin while minimizing systemic exposure of the immunotoxin.

Primary Objective

-To identify maximum tolerated dose (MTD) and evaluate the toxicities of LMB-100 administered by 90-minute normothermic, intrapleural perfusion in participants with mesothelin-positive MPM, or MPE from cancers that express mesothelin.

Eligibility

* Age \>= 18 years
* Histologically confirmed mesothelioma, or other mesothelin-positive malignancy metastatic to the pleura, potentially amenable to cytoreductive surgery and subsequent intrapleural perfusion.
* No systemic or local therapy for their malignancy within 3 weeks prior to protocol treatment.
* Adequate organ function and cardiopulmonary reserve to tolerate intended resection.
* No active infections.
* No active central nervous system (CNS) metastases.

Design

* Participant s will undergo maximal cytoreductive surgery for their malignancies by open or minimally invasive procedures as dictated by histologic, anatomic, and physiologic parameters.
* Thereafter, LMB-100 will be administered by 90-minute normothermic intrathoracic perfusion using a closed circuit and roller pump with a heat exchanger.
* LMB-100 levels will be measured in pulmonary lavage and plasma.
* The dose of LMB-100 will be increased using a 3 plus 3 design to define MTD.
* Once the MTD has been defined, the enrollment will be expanded to more fully define toxicities and evaluate time to disease progression and overall survival (OS) using 2 separate cohorts of participants with MPM and pleural effusions from other malignances (MPE).
* The accrual ceiling will be set at 42.

Phase I Evaluation of Immunotoxin LMB-100 Administered by Normothermic, Intrapleural Perfusion Following Cytoreductive Surgery in Participants With Pleural Mesotheliomas, or Pleural Effusions From Cancers Expressing Mesothelin

.All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

List of adverse event frequency, type, and grade Safety data based on toxicity grades and types of toxicity will be reported by dose level during dose escalation.

Cytoreductive surgery until time of documented clinical recurrence (radiographically or pathologically) Progression free survival (PFS): 2 year PFS probability will be calculated from the on-study date through 2 years after initiation of study therapy using the Kaplan-Meier method. Overall Survival (OS): 3 year OS probability from the on-study date through 3 years after initiation of study therapy

Pharmacokinetic accumulation of free and total plasma concentrations of LMB-100 will be measured using validated ligand-binding assays analyzed in the blood (plasma)and pulmonary lavage at protocol time points. Analyses will be performed retrospectively in batched samples or at the end of the trial.

Participants will receive intravenous (IV) infusion of MEHD7945A in escalating doses Q2W until MTD is reached or up to disease progression as determined by the investigator, intolerable toxicity, withdrawal of consent, or death, whichever occurs first. Approximately 5 dose levels between 1 and 30 mg/kg will be evaluated.

Participants will receive IV infusion of MEHD7945A Q2W at or below the MTD (decided from dose escalation part) up to disease progression as determined by the investigator, intolerable toxicity, withdrawal of consent, or death, whichever occurs first.

MEHD7945A will be administered as specified in the individual arms.

MEHD7945A

Andrea Pirzkall, M.D.

This is a Phase I, multicenter, open-label study of MEHD7945A in participants with incurable, locally advanced, or metastatic epithelial malignancies that have progressed despite standard therapy or for which no standard therapy exists. The study will be conducted in two stages: a dose escalation stage and an expansion stage. The dose-escalation stage is designed to evaluate the safety, tolerability, and PK of MEHD7945A administered (at five dose levels from 1 to 30 milligrams per kilogram \[mg/kg\]) every 2 week (Q2W). An expansion stage will be initiated after establishment of maximum tolerated dose (MTD) in dose escalation stage. Participants with refractory or recurrent metastatic colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and pancreatic cancer will be enrolled in an expansion stage to better characterize the safety, tolerability, PK and preliminary assessment of the anti-tumor activity of MEHD7945A.

A Study of the Safety and Pharmacokinetics (PK) of MEHD7945A in Participants With Locally Advanced or Metastatic Epithelial Tumors

A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of MEHD7945A Administered Intravenously to Patients With Locally Advanced or Metastatic Epithelial Tumors

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Assessment of the Safety and Tolerability of ex Vivo Next-generation Neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) Therapy in Advanced Epithelial Tumors and Immune Checkpoint Blockade (ICB) Resistant Solid Tumors	NCT05141474	Epithelial Tumo... Malignant Solid...	NEXTGEN-TIL Non-myeloablati... Interleukin-2	18 Years -	Vall d'Hebron Institute of Oncology
NHS-IL12 for Solid Tumors	NCT01417546	Epithelial Neop... Epithelial Tumo... Malignant Mesen...	NHS-IL-12	18 Years -	National Institutes of Health Clinical Center (CC)
Phase I Evaluation of Immunotoxin LMB-100 Administered by Normothermic, Intrapleural Perfusion Following Cytoreductive Surgery in Participants With Pleural Mesotheliomas, or Pleural Effusions From Cancers Expressing Mesothelin	NCT05375825	Malignant Pleur... Malignant Pleur... Epithelial Tumo... Pleural Effusio... Mesothelin (Msl...	Cytoreductive s... LMB-100 Immunohistochem...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Study of the Safety and Pharmacokinetics (PK) of MEHD7945A in Participants With Locally Advanced or Metastatic Epithelial Tumors	NCT01207323	Epithelial Tumo...	MEHD7945A	18 Years -	Genentech, Inc.
Phase I Evaluation of Immunotoxin LMB-100 Administered by Normothermic, Intrapleural Perfusion Following Cytoreductive Surgery in Participants With Pleural Mesotheliomas, or Pleural Effusions From Cancers Expressing Mesothelin	NCT05375825	Malignant Pleur... Malignant Pleur... Epithelial Tumo... Pleural Effusio... Mesothelin (Msl...	Cytoreductive s... LMB-100 Immunohistochem...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
NHS-IL12 for Solid Tumors	NCT01417546	Epithelial Neop... Epithelial Tumo... Malignant Mesen...	NHS-IL-12	18 Years -	National Institutes of Health Clinical Center (CC)
NHS-IL12 for Solid Tumors	NCT01417546	Epithelial Neop... Epithelial Tumo... Malignant Mesen...	NHS-IL-12	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for epithelial tumors, malignant