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NCT05375825 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: 10000062000062-C
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Malignant Pleural Mesotheliomas (Mpm); Malignant Pleural Effusions (Mpe); Epithelial Tumors, Malignant; Pleural Effusions, Malignant; Mesothelin (Msln)

Keywords

Pleural Metastases; Malignant Pleural Mesotheliomas (Mpm); Malignant Pleural Effusions (Mpe); Anti-Mesothelin; Mesothelin-Positive Malignancy; Progression Free Survival (Pfs); Overall Survival (Os)

Outcome Measures

Primary Outcomes (1)

• 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

  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.

  21 days

Secondary Outcomes (2)

• Determine 2 year progression free survival (PFS), and 3 year overall survival of participants following intrapleural LMB-100 perfusion

  at initial perfusion, every 3 months (+/- 2 weeks), to time of documented clinical recurrence and/or death

• Identify pharmacokinetics of LMB-100 administered by 90-minute normothermic, intrapleural perfusion

  Pre-dose, completion of perfusion, and 1, 3, 24 hours after start of perfusion

Study Arms (2)

1/ Dose Escalation

EXPERIMENTAL

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

Procedure: Cytoreductive surgery; Drug: LMB-100; Diagnostic Test: Immunohistochemical Assay for Mesothelin

2/ Dose Expansion

EXPERIMENTAL

LMB-100 at the MTD + MSLN testing

Procedure: Cytoreductive surgery; Drug: LMB-100; Diagnostic Test: Immunohistochemical Assay for Mesothelin

Interventions

Cytoreductive surgery PROCEDURE

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

1/ Dose Escalation; 2/ Dose Expansion

LMB-100 DRUG

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

1/ Dose Escalation; 2/ Dose Expansion

Immunohistochemical Assay for Mesothelin DIAGNOSTIC_TEST

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.

1/ Dose Escalation; 2/ Dose Expansion

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed by the Laboratory of Pathology (LP), CCR, NCI mesothelinpositive malignancy arising from or metastatic to the pleura that is potentially amenable to cytoreductive surgery (R0-R2) and subsequent intrapleural perfusion based on standard of care (SOC) imaging.
• Participants with biphasic MPM must have a \< 50% sarcomatoid component.
• Participants with MPE from extra-thoracic disease may be eligible provided these sites are controlled and are less threatening than the pleural involvement LENT score \>=2 .
• Participants with stage IV cancers affecting the pleura with MPE must have received firstline standard of care systemic treatment for their malignancies.
• MPM participants must not have received any local or systemic therapy for their disease.
• All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade \<= 1 except hemoglobin (Hgb) \<= Grade 2, alopecia (any grade), and \<= Grade 2 peripheral neuropathy.
• Age \>18 years.
• ECOG performance status of \< 2.
• Participants must have adequate pulmonary reserve evidenced by post-operative predicted FEV1 and adjusted DLCO \>= 40% predicted.
• Room air oxygen saturation \>= 90%; otherwise pCO2 \<= 45 and pO2 \>= 60 on room air arterial blood gas (ABG).
• Adequate organ and marrow function as defined below:
• leukocytes \>= 3,000/mcL
• absolute neutrophil count \>= 1,500/mcL (without transfusion or cytokine support)
• absolute lymphocyte count \> 800/mcL
• platelets \>= 100,000/mcL

You may not qualify if:

• Active smokers.
• Participants receiving systemic steroids other than physiologic replacement doses or inhaled corticosteroids (\<= 20 mg of dexamethasone a day \[or equivalent\]) for \<= 7 consecutive days prior to treatment initiation).
• Treatment with chemotherapy, targeted therapy, immunotherapy, radiation, or surgery to an index lesion within three weeks prior to commencing protocol therapy, excluding minor surgical procedures (i.e. VATS/thoracentesis/PleurX catheter placement to palliate
• MPE).
• Treatment with another investigational agent within four weeks prior to commencing protocol therapy.
• History of allergic reactions attributed to compounds of chemical or biologic composition similar to LMB-100 or SS1P including pseudomonas endotoxin.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (within 6 months prior to treatment initiation) or myocardial infarction (within 6 months prior to treatment initiation) unless revascularized, unstable angina, congestive heart failure (New York Heart Association Classification Class \>= II), serious cardiac arrhythmia, abnormal ejection fraction (echocardiogram \[ECHO\]) \<= 40%, clinically significant bleeding or clinically significant pulmonary embolism.
• History of pneumonitis (idiopathic or drug-induced) unless cleared by pulmonary consultants.
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
• HIV-infected participants. Participants on stable doses of antiretroviral therapy whose HIV RNA is below level of quantification are eligible.
• Active COVID-19 infection.
• Active infections requiring systemic therapy.
• An additional malignancy that is progressing or requires active treatment.
• Pregnancy
• Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mesothelioma, Malignant; Pleural Effusion, Malignant; Myeloproliferative Disorder, Chronic, with Eosinophilia; Carcinoma

Interventions

Cytoreduction Surgical Procedures; LMB-100

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Pleural Effusion; Pleural Diseases

Intervention Hierarchy (Ancestors)

Surgical Procedures, Operative

Study Officials

• David S Schrump, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2022
• First Posted: May 17, 2022
• Study Start: January 31, 2024
• Primary Completion: January 31, 2024
• Study Completion: January 31, 2024
• Last Updated: February 2, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. @@@@@@@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)