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
- Conditions
- Malignant Pleural Mesotheliomas (Mpm)Malignant Pleural Effusions (Mpe)Epithelial Tumors, MalignantMesothelin (Msln)Pleural Effusions, Malignant
- Interventions
- Procedure: Cytoreductive surgeryDiagnostic Test: Immunohistochemical Assay for Mesothelin
- Registration Number
- NCT05375825
- Lead Sponsor
- National Cancer Institute (NCI)
- 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 2/ Dose Expansion LMB-100 LMB-100 at the MTD + MSLN testing 1/ Dose Escalation Cytoreductive surgery LMB-100 at escalating/de-escalating doses + MSLN testing 1/ Dose Escalation Immunohistochemical Assay for Mesothelin LMB-100 at escalating/de-escalating doses + MSLN testing 2/ Dose Expansion Cytoreductive surgery LMB-100 at the MTD + MSLN testing 2/ Dose Expansion Immunohistochemical Assay for Mesothelin LMB-100 at the MTD + MSLN testing 1/ Dose Escalation LMB-100 LMB-100 at escalating/de-escalating doses + MSLN testing
- Primary Outcome Measures
Name Time Method 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 21 days 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.
- Secondary Outcome Measures
Name Time Method 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 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.
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 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
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States