Mesothelin-Targeted Immunotoxin LMB-100 in People With Malignant Mesothelioma

NCT02798536 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16012716-C-0127
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Background: LMB-100 is a man-made protein. It is attracted to the mesothelin protein. This is found in many tumors, including mesothelioma. But it is found in only a very small number of normal tissues. After binding to mesothelin on tumors, LMB-100 attacks and kills cancer cells. Researchers want to test LMB-100 in people with advanced mesothelioma. Objective: To find a safe dose and anti-tumor activity of LMB-100 for people with advanced mesothelioma. Eligibility: Adults ages 18 and older with: Advanced pleural or peritoneal mesothelioma that has not responded to platinum-based therapy Adequate organ function Design: Participants will be screened with: Samples of tumor tissue or tumor fluid. These can be new or from a previous procedure. Medical history Physical exam Blood, urine, and heart tests Chest x-rays Computed tomography (CT) or magnetic resonance imaging (MRI) scans Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans Participants will get LMB-100 on days 1, 3, and 5 of each 21-day cycle. It will be given through an intravenous (IV) catheter, a tube inserted in an arm vein. They will get standard medicines before each infusion to help prevent side effects. Each infusion lasts about 30 minutes. They will be monitored for up to 2 hours after. During each cycle, participants will repeat the screening tests. Participants will get the study drug for up to 4 cycles or until their disease worsens or they have intolerable side effects. About 4-6 weeks after their last infusion, participants will have a follow-up visit. They will repeat the study tests. Participants will have follow-up scans every 6 weeks until their disease gets worse. Participants will be called about once a year to see how they are doing.

Conditions

Mesothelioma

Keywords

Immunotoxin; Mesothelin; Targeted Therapy

Outcome Measures

Primary Outcomes (1)

• Recommended Phase 2 Dose (RP2D) of LMB100 + Nab-paclitaxel

  Highest administered dose of LMB-100 + nab-paclitaxel at which no more than 1 of 6 participants experiences a dose limiting toxicity (DLT). A DLT is any of the following events attributed to LMB-100 and occurring within 21 days after the first dose of LMB-100 such as Grade 4 neutropenia, Grade 3 and 4 febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia associated with bleeding episodes. Grade ≥ 3 non-hematological toxicity with the exception of alopecia (any grade), Grade 3 nausea and vomiting without appropriate treatment, Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration.

  3 weeks after initial dose

Secondary Outcomes (7)

• Number of Participants at Recommended Phase 2 Dose (RP2D) With Partial or Complete Response by the Response Evaluation Criteria in Solid Tumors (RECIST)

  End of treatment, an average of 57.6 days

• Median Progression Free Survival (PFS)

  At progression, up to 3.6 months

• Median Overall Survival (OS)

  At death, up to 60.8 months

• Number of Participants With LMB-100 Maximum Observed Serum Concentration (Cmax) of >100ng/mL

  Cycle 1 and Cycle 2 (each cycle is 21 days), approximately 42 days

• Number of Participants With Anti-drug Antibodies (ADAs) Formation to LMB-100

  Cycle 1 and Cycle 2 (each cycle is 21 days), approximately 42 days

Other Outcomes (2)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

  Date treatment consent signed to date off study, approximately 34 months and 19 days for Dose Level 1, 52 months for Dose Level -1, and 42 months and 3 days for Dose Level -2.

• Number of Participants With Dose-limiting Toxicities (DLT)

  First 21 days after first dose of LMB-100

Study Arms (4)

A1/LMB-100 dose escalation (closed)

EXPERIMENTAL

De-escalating doses of LMB-100 in up to 18 subjects

Drug: LMB-100

A2/LMB-100 dose expansion (closed)

EXPERIMENTAL

Fixed dose of LMB-100 as determined in Arm A1 in up to 16 subjects

Drug: LMB-100

B1/LMB-100+ nab- paclitaxel dose escalation

EXPERIMENTAL

De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects

Drug: LMB-100; Drug: nab-paclitaxel

B2/LMB-100+ nab- paclitaxel dose expansion

EXPERIMENTAL

Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects

Drug: LMB-100; Drug: nab-paclitaxel

Interventions

LMB-100 DRUG

Administered intravenous (IV) on days 1, 3 and 5 of a 21 day cycle for up to 4 cycles (Arms A1 and A2) or 2 cycles (Arms B1 and B2)

A1/LMB-100 dose escalation (closed); A2/LMB-100 dose expansion (closed); B1/LMB-100+ nab- paclitaxel dose escalation; B2/LMB-100+ nab- paclitaxel dose expansion

nab-paclitaxel DRUG

Arms B1 and B2 only. Administered intravenous (IV) on days 1 and 8 of each 21 day cycle for up to 6 cycles

B1/LMB-100+ nab- paclitaxel dose escalation; B2/LMB-100+ nab- paclitaxel dose expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed epithelial or biphasic mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a more than or equal to 50% sarcomatoid component will be excluded. The diagnosis will be confirmed by the Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI).
• Archival sample or fresh biopsy or tumor effusion must be available for confirmation of diagnosis.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to10 mm with spiral computed tomography (CT) scan.
• Patients must have had at least one prior chemotherapy regimen that includes pemetrexed and cisplatin or carboplatin. There is no limit to the number of prior chemotherapy regimens received.
• The last dose of previous therapy must have occurred at least 3 weeks prior to the start of study therapy. Palliative radiotherapy is allowed up to 2 weeks before the first LMB-100 infusion.
• Patients for whom no standard curable therapy exists
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of LMB-100 in patients \<18 years of age, children are excluded from this study
• All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade less than or equal to 1, except alopecia (any grade) and Grade 2 peripheral neuropathy.
• Eastern Cooperative Oncology (ECOG) performance status (PS) 0 or1
• Adequate hematological function: neutrophil count of more than of equal to 1.5x10\^9 cells/L, platelet count of greater than or equal to 100,000/microl, (transfusion independent, defined as not receiving platelet transfusions within 7 days prior to laboratory sample) hemoglobin more than or equal to 9 g/dL
• Adequate Liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 X upper limit of normal alkaline phosphate less than 2.5 X upper limit of normal unless bone metastasis is present (less than 5 X upper limit of normal) in the absence of liver metastasis.
• Bilirubin less than or equal to 1.5 mg/dL (excluding Gilbert's Syndrome, see below).
• Unconjugated hyperbilirubinemia noted on several occasions
• No evidence of hemolysis (normal hemoglobin, reticulocyte count, and lactate dehydrogenase (LDH)
• Normal liver function tests

You may not qualify if:

• Known or clinically suspected central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases. History or clinical evidence of CNS metastases unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days.
• Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically significant pericardial effusion)
• Active or uncontrolled infections.
• Human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. HIV positive patients will be excluded due to a theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
• Patients with prior pneumonectomy
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
• Major surgery or significant traumatic injury greater than or equal to 28 days prior to the first LMB-100 infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment
• Dementia or altered mental status that would prohibit informed consent
• Live attenuated vaccinations 14 days prior to treatment
• Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LMB-100, breastfeeding should be discontinued if the mother is treated with LMB-100. These potential risks may also apply to other agents used in this study.
• Known hypersensitivity to any of the components of LMB-100
• High doses of systemic corticosteroids within 7 days prior to first dosing. High dose is considered as \> 20 mg of dexamethasone a day (or equivalent) for \> 7 consecutive days.
• Subjects must not have received paclitaxel nor nab-paclitaxel within 4 months prior to initiation of study therapy.
• Participants with contra-indication and/or history of sever hypersensitivity reactions to nab-paclitaxel.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mesothelioma

Interventions

LMB-100; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

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

Results Point of Contact

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

hassanr@mail.nih.gov

240-760-6232

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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 10, 2016
• First Posted: June 14, 2016
• Study Start: July 27, 2016
• Primary Completion: July 20, 2017
• Study Completion: April 21, 2022
• Last Updated: August 23, 2022
• Results First Posted: August 23, 2022

Record last verified: 2022-07

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)