LMB-100 / National Cancer Institute - LARVOL DELTA

Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers. (PubMed, Front Oncol) - P1 | "Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. https://www.clinicaltrials.gov/study/NCT04034238."

Journal • Metastases • Appendix Cancer • Biliary Cancer • Cardiovascular • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • IL10 • MSLN • TNFA

LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P2 | N=6 | Terminated | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2024 ➔ Dec 2023 | Active, not recruiting ➔ Terminated; Study was terminated due to slow accrual.

Trial completion date • Trial termination • Lung Adenocarcinoma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CTLA4 • EGFR • KRAS • MSLN • PD-L1 • ROS1

Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers (Front Oncol) - P1 | N=19 | NCT04034238 | "The study was closed early due to occurrence of drug-induced pericarditis in 2 patients....Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred."

P1 data • Cholangiocarcinoma • Mesothelioma • Pancreatic Adenocarcinoma

Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma (clinicaltrials.gov) - P1 | N=2 | Terminated | Sponsor: National Cancer Institute (NCI) | Completed ➔ Terminated; Study was closed early due to slow accrual.

Trial termination • Mesothelioma • Oncology • Solid Tumor

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 (clinicaltrials.gov) - P1 | N=42 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2027 ➔ Dec 2024 | Trial primary completion date: Dec 2026 ➔ Dec 2024

Surgery • Trial completion date • Trial primary completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • MSLN

Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma (clinicaltrials.gov) - P1 | N=2 | Completed | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Completed | N=20 ➔ 2

Enrollment change • Trial completion • Mesothelioma • Oncology • Solid Tumor

Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors (clinicaltrials.gov) - P1 | N=19 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Lung Cancer • Mesothelioma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

Analysis of systemic immune changes in patients with advanced cancer treated with immunotoxin LMB-100 and tofacitinib. (ASCO 2023) - P1 | "Combination of LMB-100 with tofacitinib is not safe. An insufficient number of patients was treated to conclusively assess the ability of tofacitinib to stop or delay ADA formation. Increases in circulating Tregs were observed in patients with early neutralizing ADA formation."

Clinical • Metastases • Appendix Cancer • Biliary Cancer • Cardiovascular • Cholangiocarcinoma • Gastrointestinal Cancer • Heart Failure • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD4 • CXCL8 • IL10 • MSLN • TNFA

Systemic immune changes accompany combination treatment with immunotoxin LMB-100 and nab-paclitaxel. (PubMed, Cancer Med) - P1/2 | "In summary, LMB-100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • CXCL8 • HAVCR2 • IFNG • MSLN

Anti-Tumor Efficacy of Mesothelin Targeted Immunotoxin LMB-100 Plus Pembrolizumab in Mesothelioma Patients and Mouse Models (IASLC-WCLC 2019) - P2; "Pembrolizumab following LMB-100 is associated with durable tumor response in mesothelioma patients as well as pre-clinical models of mesothelioma and lung cancer. This combination is currently being evaluated in a prospective clinical trial in patients with mesothelioma (clinicaltrials.gov # NCT03644550)."

IO biomarker • PD(L)-1 Biomarker • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

[VIRTUAL] Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with pancreatobiliary cancer or other mesothelin expressing solid tumors. (ASCO-GI 2021) - P1 | "Participants will receive tofacitinib 10 mg twice daily on days 1-10 and LMB-100 at 65, 100, or 140 mcg/kg on days 4, 6 and 8 of a 21-day cycle. The dose escalation phase has been completed and enrollment onto dose expansion phase is ongoing."

Combination therapy • P1 data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • JAK1 • MSLN

A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer. (ASCO-GI 2019) - P1/2; "MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued."

Clinical • Combination therapy • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

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 (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting

Enrollment open • Surgery • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • MSLN

Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Jan 2023 ➔ Jan 2024

Trial primary completion date • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

Anti-mesothelin immunotoxin induces mesothelioma eradication, anti-tumor immunity, and the development of tertiary lymphoid structures. (PubMed, Proc Natl Acad Sci U S A) - "LMB-100 treatment upregulates genes associated with tertiary lymphoid structures (TLS) development and induces TLS formation in tumors. In sum, immunotoxin-mediated cell death induces anti-tumor immunity and the development of TLS, which provides insights into how immunotoxins cause tumor regressions."

Journal • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • CD4 • CD8 • MSLN

MSLN-targeted immunotoxin LMB-100 induces development of tertiary lymphoid structures and tumor regressions of orthotopic mesothelioma (SITC 2022) - "The regression of the primary tumor requires CD8 + T cells, CD4 + T cells as well as B cells. LMB-100 mediated tumor cell death induces the development of TLS in the solid tumor, probably by upregulating chemotaxis chemokines and cytokines that are associated with TLS formation."

Lung Cancer • Mesothelioma • Oncology • Solid Tumor • CCL20 • CCL21 • CD4 • CD8 • CXCL13 • MSLN

LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P2 | N=6 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | N=100 ➔ 6

Enrollment change • Enrollment closed • Lung Adenocarcinoma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • KRAS • MSLN • PD-L1 • ROS1

Mesothelin-Targeted Immunotoxin LMB-100 in People With Malignant Mesothelioma (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2021 ➔ Apr 2022

Trial completion date • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

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 (clinicaltrials.gov) - P1 | N=42 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1 trial • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • MSLN

Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors (clinicaltrials.gov) - P1/2 | N=40 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Jan 2022 ➔ Jun 2021

Combination therapy • Trial completion • Trial completion date • Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

NCI Opens New Immunotherapy Clinical Trial for Mesothelioma (Asbestos) - "The National Cancer Institute has opened a promising clinical trial aimed at increasing the effectiveness of immunotherapy treatment for patients with unresectable malignant mesothelioma. This latest study involves combining LMB-100, a manmade protein designed to kill cancer cells, with ipilimumab, an immunotherapy drug recently approved for use by the U.S. Food and Drug Administration."

Trial status • Mesothelioma • Oncology

Anti-Mesothelin Immunotoxin LMB-100 Followed by Pembrolizumab in Malignant Mesothelioma (clinicaltrials.gov) - P2; N=18; Terminated; Sponsor: National Cancer Institute (NCI); Completed ➔ Terminated; Due to the Food and Drug Administration's recent approval of Nivolumab plus Ipilimumab as first line treatment for Mesothelioma, the principal investigator decided to end the study early (prior to reaching enrollment goal).

Trial termination • Lung Cancer • Mesothelioma • Oncology • Solid Tumor

Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors (clinicaltrials.gov) - P1; N=16; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Recruiting ➔ Active, not recruiting; N=45 ➔ 16

Combination therapy • Enrollment change • Enrollment closed • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Lung Cancer • Mesothelioma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

[VIRTUAL] Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer. (ASCO 2021) - P1 | "LMB-100 was unable to be co-administered safely with tofacitinib . ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence."

Clinical • Combination therapy • P1 data • Appendix Cancer • Biliary Cancer • Cardiovascular • Cholangiocarcinoma • Gastrointestinal Cancer • Heart Failure • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer. (ASCO-GI 2019) - P1/2; "MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued."

Clinical • Combination therapy • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor