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

Phase 1

Terminated

Conditions: Mesothelioma

Interventions: 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

Registration Number: NCT04840615

Lead Sponsor: National Cancer Institute (NCI)

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....

Detailed Description: Background:

LMB-100, and a closely related immunotoxin, SS1P, also targeting mesothelin, given intravenously, have been studied in Phase 1 clinical studies for mesothelioma and pancreatic cancer.

LMB-100 given intravenously results in systemic inflammation in patients, but as a single agent has limited anti-tumor efficacy.

Almost all patients develop neutralizing anti-LMB-100 antibodies after 2 cycles of therapy.

Intra-tumoral delivery of LMB-100 has been shown to induce immune cell infiltration in immune-competent mice, bearing murine malignant mesothelioma tumors. Combination with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blockage eradicates murine tumors by promoting anti-cancer immunity.

Ipilimumab is a fully human anti CTLA-4 monoclonal antibody, that is approved for treatment of melanoma and in combination with nivolumab for many solid tumors.

It is hypothesized that intra-tumoral delivery of anti-mesothelin immunotoxin LMB-100 in combination with ipilimumab will result in greater anti-tumor efficacy in patients with mesothelioma.

Objective:

To determine the safety and feasibility of intra-tumoral LMB-100 injection plus ipilimumab infusion in patients with mesothelioma

To identify the recommended phase 2 dose (RP2D) of intratumorally administered LMB-100 + ipilimumab in patients with malignant mesothelioma

Eligibility:

Histologically confirmed pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection.

Have locally accessible disease suitable for intra-tumor injection of LMB-100. This includes superficial or visceral 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.

Adequate organ and bone marrow function

Subjects with clinically significant pericardial effusion are excluded.

Chemotherapy within 3 weeks or radiotherapy within 2 weeks prior to start of study therapy, is prohibited.

Subjects with active central nervous system (CNS) metastasis are excluded.

Subjects with active autoimmune disease for which they have received systemic immunosuppressive medications during the previous 2 years (excluding daily glucocorticoid-replacement therapy for conditions such as adrenal or pituitary insufficiency) are excluded.

Subjects with active interstitial lung disease, or a history of pneumonitis or interstitial lung disease for which they had received glucocorticoids are excluded.

Design:

This is an open-label, single center phase I dose escalation study of intratumorally administered LMB-100 followed by ipilimumab in subjects with malignant mesothelioma.

Subjects will receive intratumorally administered LMB-100, beginning at dose level 1, in 21-day cycles. LMB-100 will be given on days 1 and 4 of cycle 1, and ipilimumab is given on day 1 of cycles 2-4.

Tumor biopsies will be performed prior to each administration of LMB-100, on day 1 of cycle 2 and after completion of ipilimumab therapy to evaluate changes in the tumor immune microenvironment.

Up to 14 evaluable subjects will be enrolled.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1/Intra-tumoral LMB-100 Administration	LMB-100	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	Biopsy	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	FDG-PET	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	CT CAP	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	MRI	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	ECG	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	Echocardiogram	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	ipilimumab	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	Diphenhydramine	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	Acetaminophen	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	Famotidine	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.
1/Intra-tumoral LMB-100 Administration	Dexamethasone	Those with pleural or peritoneal mesothelioma receiving intra-tumoral administration of LMB-100 + ipilimumab for up to 4 cycles.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Grades 1-5 Serious and/or Non-serious Toxicity Related (= Possibly + Probably + Definitely) to LMB-100	Median follow-up: 3.4 months (1.9 months and 5.0 months)	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.
Recommended Phase 2 Dose (RP2D) of Intratumorally Administered LMB-100 in Participants With Mesothelioma	21 days after first LMB-100 administration	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.
Number of Participants Who Experienced Grades 1-5 Serious and/or Non-serious Toxicity Related (= Possibly + Probably + Definitely) to Ipilimumab	Median follow-up: 3.4 months (1.9 months and 5.0 months)	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Response	Median follow-up: 3.4 months (1.9 months and 5.0 months)	Duration of response is defined as the median time criteria are met for partial or complete response to the first date that recurrence or progression is documented. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Partial response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Complete response is disappearance of all target lesions. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.
Progression Free Survival	Median: 1.4 months (95% CI: 0.6-2.3 months)	Progression free survival is defined as the median time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.
Overall Survival	Median 3.4 months (1.9 months and 5.0 months).	Overall survival is defined as the median time from start of treatment to death from any cause.
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).	Proportion of participants who experienced an objective response defined as either a partial or complete response assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Partial response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Complete response is disappearance of all target lesions.