Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

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Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Adenocarcinoma

Adenocarcinoma of Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Lung Adenocarcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Pembrolizumab

Immunomodulating Agents

Immunoglobulins

Mitogens

LMB-100

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Immunoconjugates

Immunologic Factors

Participants will receive LMB-100 on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles.

Participants will receive pembrolizumab on day 1 of each subsequent 21-day cycle.

pembrolizumab

Testing for mesothelin expression performed at screening

Mesothelin Expression

Testing for ROS oncogene 1 (ROS1) gene, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) variations performed at screening.

TrueSight Oncology 500

Azam Ghafoor, M.D.

Background:

Over 230,000 new lung cancer cases are diagnosed every year in the United States (U.S.) About 80% of lung cancers are non- small cell lung cancer (NSCLC). Most people have a more advanced stage of the disease that doesn't respond well to standard treatment. Researchers want to see if a combination of drugs may be able to help.

Objective:

To find out if LMB-100 followed by pembrolizumab can help tumors to shrink in people with NSCLC.

Eligibility:

People ages 18 and older with NSCLC that has not responded to standard therapies

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Tumor sample. If one is not available, they will have a biopsy.
* Assessments of ability to perform normal activities
* Lung function tests
* Blood, heart, and urine tests
* Computed tomography (CT) and positron emission tomography (PET). They will lie in a machine that takes pictures of the body.

Participants will take LMB-100 in 21-day cycles for up to 2 cycles. They will take the drug by injection into an arm vein on days 1, 3, and 5 of each cycle. They will stay in the hospital 7-10 days each cycle. Then they will get pembrolizumab by injection into an arm vein every 3 weeks for up to 2 years. They may be able to take pembrolizumab an additional year if their cancer gets worse.

Participants will have repeats of the screening tests throughout the study.

About 30 days and 90 days after they stop treatment, participants will have follow-up visits. Then they will have visits every 6-12 weeks. They will be followed for the rest of their life through phone calls and emails.

Background:

* Mesothelin is expressed in approximately half of all lung adenocarcinomas.
* LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor models including non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-1) is an Ig superfamily member related to cluster of differentiation (CD28) and cluster of differentiation 152 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands.
* Pembrolizumab, an immunoglobulin G4 (IgG4) monoclonal antagonist antibody to PD-1, is Food and Drug Administration (FDA) approved in the frontline for advanced non-squamous NSCLC as a single agent with high programmed death-ligand 1 (PD-L1) expression \[tumor proportion score (TPS) \>=50%\] or in combination with platinum-based doublet chemotherapy (PD-L1 unselected). It also approved in the second-line for high PDL1 expressing tumors (TPS \>=1%).
* Combination treatment with LMB-100 plus pembrolizumab results in greater anti-tumor efficacy in murine lung cancer model.

Objectives:

-To determine the objective response rate of LMB-100 followed by pembrolizumab in the treatment of subjects with mesothelin-expressing non-squamous non-small cell lung cancer (NSCLC) previously treated with immune checkpoint inhibitors.

Eligibility:

* Histologically confirmed locally advanced or metastatic non-squamous, non-small cell lung cancer lacking an EGFR sensitizing mutation, anaplastic lymphoma kinase (ALK) or ROS oncogene 1 (ROS1) gene rearrangement and not amenable to potentially curative surgical resection or chemoradiation.
* Tumor mesothelin expression of at least 25% of tumor cells as determined by the Laboratory of Pathology at the NCI.
* Subjects must have at least progressed after one prior platinum-based doublet chemotherapy AND standard immune checkpoint inhibitor (ICI) with either frontline single-agent pembrolizumab, or in combination with platinum-based doublet chemotherapy, or second-line single-agent nivolumab, pembrolizumab, or atezolizumab.
* Age \>= 18 years.

Design:

* This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab in subjects with mesothelin expressing NSCLC who have progressed on standard therapies
* Subjects will receive LMB-100 at the single agent maximum tolerated dose (MTD) (140mg/kg) on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles and pembrolizumab 200 mg on day 1 of cycle 3 of a 21- day cycle (or cycle 2 if disease progression is observed after 1 cycle) onwards until disease progression (on or after pembrolizumab) or intolerable toxicity for a maximum of 2 years (unless second course initiated).
* The total accrual ceiling for the screening will be set at 100 total patients in order to treat 23 subjects.

LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

A Phase II Study of LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Participants with a partial response or complete response is reported with an 80% confidence interval. Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Participants with a partial response or complete response is reported with an 95% confidence interval. Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria. Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression (on or after pembrolizumab) or death, whichever occurs first, calculated from the on-study date using the Kaplan-Meier method.

Overall survival is defined as the duration of time from start of treatment to death from any cause.

Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 3 is severe. Grade 4 is life-threatening.

Participants who are treated who are unable to tolerate the treatment other than development of adverse events

National Cancer Institute (NCI)

Principal Investigator

3/6 participants were analyzed because 3 were screen failures. There were 3 deaths due to progression and not related to the study.

LMB-100 + Pembrolizumab

LMB-100: Participants will receive LMB-100 140mcg/kg on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles.

Pembrolizumab: Participants will receive 200 mg pembrolizumab on day 1 of each subsequent 21-day cycle for up to 2 years or until disease progression.

Mesothelin Expression: Testing for mesothelin expression performed at screening.

TrueSight Oncology 500: Testing for ROS oncogene 1 (ROS1) gene, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) variations performed at screening.

Mesothelin Expressing Non-Small Cell Lung Cancer Participants

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Although 3 participants were screen failures, data collected for all (6) participants enrolled is shown here.

Dr. Azam Ghafoor

3/6 participants were analyzed because 3 were screen failures.

Proportion of Participants With Partial Response or Complete Response Reported With an 80% Confidence Interval

Proportion of Participants With Partial Response or Complete Response Reported With an 95% Confidence Interval

Complete Response

Partial Response

Stable Disease

Progressive Disease

Overall Response (OR)

Number of Participants With a Response

Progression Free Survival (PFS)

LMB-100 + Pembrolizumab

LMB-100: Participants will receive LMB-100 on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles.

pembrolizumab: Participants will receive pembrolizumab on day 1 of each subsequent 21-day cycle.

Mesothelin Expression: Testing for mesothelin expression performed at screening

TrueSight Oncology 500: Testing for ROS oncogene 1 (ROS1) gene, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) variations performed at screening.

Spots Global Cancer Trial Database for truesight oncology 500