Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma

NCT04840615 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 10000059000059-C
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Mesothelioma is a type of cancer. It originates in cells that line human body cavities. Most people have advanced disease when they are diagnosed. Researchers want to see if a combination of drugs can help. Objective: To find a safe dose of LMB-100 in combination with ipilimumab when LMB-100 is injected into tumors. Eligibility: Adults ages 18 and older with malignant pleural or peritoneal mesothelioma, that cannot be cured with surgery and has not responded to standard first-line treatments for mesothelioma. Design: Participants will be screened with:

• Tumor biopsy or effusion, if needed
• Medical history
• Physical exam
• Blood and urine tests
• Imaging scans
• Heart and lung function tests
• Pregnancy test, if needed Some screening tests will be repeated during the study. Participants will get LMB-100 on Days 1 and 4 for up to 2 cycles. Each cycle lasts 21 days. They will stay in the hospital for about 8 days each time they get LMB-100. It will be injected into their tumor with needles. Participants will get ipilimumab through a tube that is put in a vein. It will be given on Day 2 of the first 2 cycles and Day 1 of the next 2 cycles. Participants will be assessed for how well they do daily activities. They will give blood and tissue samples for research. Participants will have a safety visit 4 to 6 weeks after the last dose of the study drugs. Then they will have scans every 6 weeks until their disease gets worse. If their tumor gets bigger, they will have phone, video, or email follow-ups every 12 weeks. Participants will be on this study for life....

Conditions

Mesothelioma

Keywords

Immunotherapy; Checkpoint Inhibitor; anti CTLA-4

Outcome Measures

Primary Outcomes (3)

• Recommended Phase 2 Dose (RP2D) of Intratumorally Administered LMB-100 in Participants With Mesothelioma

  RP2D is defined as the highest dose at which fewer than 2 of 6 participants experience a dose-limiting toxicity. A dose-limiting toxicity is defined as any Grade 4 hematological toxicity lasting greater than 5 days. Grade 3 febrile neutropenia, Grade 3 thrombocytopenia associated with bleeding episodes, any Grade 3 or greater, non-hematological toxicity with the following exceptions: tumor lysis syndrome, Grade 3 electrolyte changes associated with clinically significant consequences, Grade 3 nausea and diarrhea which has not received appropriate treatment, isolated Grade 3 fever occurring within 48 hours of LMB-100 infusion and resolving within 48 hours to ≤ Grade 2 and fully resolved within 1 week, alopecia, infusion-related reactions up to and including Grade 3, asymptomatic ≥ Grade 3 lymphopenia, leukopenia, hypoalbuminemia, electrolyte abnormalities resolving within 24 hours, and increase in alkaline phosphatase.

  21 days after first LMB-100 administration

• Number of Participants Who Experienced Grades 1-5 Serious and/or Non-serious Toxicity Related (= Possibly + Probably + Definitely) to LMB-100

  Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.

  Median follow-up: 3.4 months (1.9 months and 5.0 months)

• Number of Participants Who Experienced Grades 1-5 Serious and/or Non-serious Toxicity Related (= Possibly + Probably + Definitely) to Ipilimumab

  Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.

  Median follow-up: 3.4 months (1.9 months and 5.0 months)

Secondary Outcomes (4)

• Proportion of Participants Who Experienced an Objective Response Defined as Either a Partial or Complete Response

  Median: 3.4 months (1.9 months and 5.0 months).

• Duration of Response

  Median follow-up: 3.4 months (1.9 months and 5.0 months)

• Progression Free Survival

  Median: 1.4 months (95% CI: 0.6-2.3 months)

• Overall Survival

  Median 3.4 months (1.9 months and 5.0 months).

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 7 months.

Study Arms (1)

1/Intra-tumoral LMB-100 Administration

EXPERIMENTAL

Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.

Biological: LMB-100; Drug: ipilimumab; Drug: Diphenhydramine; Drug: Famotidine; Drug: Acetaminophen; Drug: Dexamethasone; Procedure: Biopsy; Diagnostic Test: FDG-PET; Diagnostic Test: CT CAP; Diagnostic Test: MRI; Diagnostic Test: ECG; Diagnostic Test: Echocardiogram

Interventions

LMB-100 BIOLOGICAL

LMB-100 administered into lesion on days 1 and 4 during cycle 1.

1/Intra-tumoral LMB-100 Administration

ipilimumab DRUG

Administered intravenously once per cycle up to three 21-day cycles. Administration will occur during cycles 2,3,4.

Also known as: Yervoy

1/Intra-tumoral LMB-100 Administration

Diphenhydramine DRUG

Infusion related reactions precaution: All participants will be premedicated with 25-50 mg Diphenhydramine by mouth (PO) or intravenous (IV) (or alternative antihistamine at adequate dose) 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration.

Also known as: Benadryl

1/Intra-tumoral LMB-100 Administration

Famotidine DRUG

Infusion related reactions precaution: All participants will be premedicated with 20 mg Famotidine by mouth (PO) or intravenous (IV) (or alternative histamine H2- receptor antagonists (H2) blocker at adequate dose) 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration.

Also known as: Pepcid

1/Intra-tumoral LMB-100 Administration

Acetaminophen DRUG

Infusion related reactions precaution: All participants will be premedicated with 650 mg Acetaminophen by mouth (PO) or intravenous (IV) 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration.

Also known as: Tylenol

1/Intra-tumoral LMB-100 Administration

Dexamethasone DRUG

Additional infusion precaution at infusions of LMB-100 after Cycle 1 Day 1 (as appropriate): Dexamethasone 20 mg by mouth (PO), 6-12 hours prior to LMB-100 administration OR 10mg, intravenous (IV), 30-60 minutes prior to LMB-100 administration OR equivalent dose of another corticosteroid as clinically indicated.

Also known as: Ozurdex

1/Intra-tumoral LMB-100 Administration

Biopsy PROCEDURE

As feasible at screening, Cycle 1 Day 1 and 5, Cycle 2, 3, \& 4 Day 1, and Cycle 4 Day 21 (±7 days).

1/Intra-tumoral LMB-100 Administration

FDG-PET DIAGNOSTIC_TEST

At screening, at the end of cycles 2 \& 4 ± 7 days, Follow-Up Visit (4-6 weeks after end of treatment), and Long-Term Follow-Up (every 6-12 weeks).

Also known as: Fluorodeoxyglucose-positron emission tomography

1/Intra-tumoral LMB-100 Administration

CT CAP DIAGNOSTIC_TEST

At screening, at the end of cycles 2 \& 4 ± 7 days, Follow-Up Visit (4-6 weeks after end of treatment), and Long-Term Follow-Up (every 6-12 weeks).

Also known as: Computed tomography of the chest, abdomen and pelvis

1/Intra-tumoral LMB-100 Administration

MRI DIAGNOSTIC_TEST

At screening, at the end of cycles 2 \& 4 ± 7 days, Follow-Up Visit (4-6 weeks after end of treatment), and Long-Term Follow-Up (every 6-12 weeks).

Also known as: Magnetic resonance imaging

1/Intra-tumoral LMB-100 Administration

ECG DIAGNOSTIC_TEST

At screening, Cycle 1 Day 1, Cycles 2, 3, \& 4 Day 1 and Follow-Up Visit (4-6 weeks after end of treatment).

Also known as: Electrocardiogram

1/Intra-tumoral LMB-100 Administration

Echocardiogram DIAGNOSTIC_TEST

At screening.

Also known as: Echo

1/Intra-tumoral LMB-100 Administration

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 malignant pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection. The diagnosis will be confirmed by the Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI).
• Tumor must have epithelioid histology determined by the Laboratory of Pathology at the NCI. If the patient has biphasic histology, the epithelioid component must be \>50%
• Have provided archival tumor tissue sample or able to provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred, to slides. Newly obtained biopsies are preferred to archived tissue.
• Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
• Have disease locally, accessible disease to suitable for intra-tumoral injection of LMB- 100.
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Subjects must have received prior immune checkpoint therapy with anti-Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with anti-CTLA4 blocking antibodies, as well as platinum-based chemotherapy.
• Age \>= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Evaluation of ECOG is to be performed within 28 days prior to initiation of study therapy.
• Have adequate organ and marrow function as defined below:
• System and Laboratory Value
• Hematological -
• hemoglobin \>= 9 g/dL(a)
• absolute neutrophil count \>= 1,500/mcL
• platelets \>= 100,000/mcL

You may not qualify if:

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks prior to initiation of study therapy.
• Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks after the last dose of the previous investigational agent. Patients with active devices will be excluded from the study.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to initiation of study therapy.
• Has active systemic issues as bleeding diathesis or active infections
• Presence of a clinically significant pericardial effusion
• Has severe hypersensitivity (\>=Grade 3) anti-CTLA4 therapies and/or any of their excipients.
• Has received prior radiotherapy to the site of local administration
• Subjects who have received LMB-100 previously
• Has received prior systemic anti-cancer therapy including investigational agents within 3 weeks prior to initiation of study therapy. Patients who have received prior anti-PD-1/PD- L1 or CTLA4 antibodies are eligible. Any toxicity related to these agents must have resolved to grade 1 and they must not be on systemic immunosuppressive therapies (physiologic dose of steroids are permitted).
• Has received prior radiotherapy to site other than target lesion within 2 weeks prior to initiation of study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (\<=2 weeks of radiotherapy) to non-CNS disease.
• Has not recovered from all adverse events (AEs) due to previous therapies to \<=Grade 1 or baseline. Participants with \<=Grade 2 neuropathy may be eligible. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to initiation of study therapy.
• Has received a live vaccine within 30 days prior to initiation of study therapy. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist(R)) are live attenuated vaccines and are not allowed.
• Is receiving therapeutic anti-coagulation. Patients receiving prophylactic anticoagulation may be eligible if in the opinion of the study team, anti-coagulation may be stopped during the time of LMB-100 administration and tumor biopsies.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to initiation of study therapy.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Morhard R, Mauda-Havakuk M, Delgado JF, Kassin MT, Ghafoor A, Pastan I, Hassan R, Karanian JW, Pritchard WF, Wood BJ, Mikhail AS. Mapping drug distribution using CT imaging following direct tissue injection in ex vivo liver: informing clinical implementation. CVIR Oncol. 2025;1(1):27. doi: 10.1007/s44343-025-00027-x. Epub 2025 Dec 16.

  PMID: 41425223 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mesothelioma

Interventions

LMB-100; Ipilimumab; Diphenhydramine; Famotidine; Acetaminophen; Dexamethasone; Calcium Dobesilate; Biopsy; Magnetic Resonance Imaging; Electrocardiography; Echocardiography; Caves

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Ethylamines; Amines; Organic Chemicals; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acetanilides; Anilides; Amides; Aniline Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Tomography; Diagnostic Imaging; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Electrodiagnosis; Cardiac Imaging Techniques; Ultrasonography; Geological Phenomena; Physical Phenomena; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Environment and Public Health

Results Point of Contact

• Title: Dr. Raffit Hassan
• Organization: National Cancer Institute

rh276q@nih.gov

240760-6232

Study Officials

• Raffit Hassan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 9, 2021
• First Posted: April 12, 2021
• Study Start: June 11, 2021
• Primary Completion: December 6, 2021
• Study Completion: January 12, 2022
• Last Updated: February 2, 2024
• Results First Posted: February 2, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data in Biomedical Translational Research Information System (BTRIS) will be shared throughout the course of the study and indefinitely with the permission of the investigator.
• Access Criteria: Clinical individual participant data (IPD) will be shared through the Biomedical Translational Research Information System (BTRIS) database for open-ended analysis. All BTRIS subscribers, generally limited to the National Institutes of Health (NIH) Clinical Center, may request data.

Locations

US (1)