Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors

NCT04034238 | Completed Phase 1 Results FDA Drug FDA Device

• 2 other identifiers: 19012819-C-0128
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The protein mesothelin is found on many kinds of tumors. The drug LMB-100 targets cancer cells that make this protein. Researchers want to see if LMB-100 combined with another drug can help people with these tumors. Objective: To find a safe dose of LMB-100 plus tofacitinib in people with pancreatic cancer, bile-duct cancer, and other solid tumors that make mesothelin. Eligibility: People ages 18 and older with pancreatic cancer, bile-duct cancer, or any other solid tumor with mesothelin that worsened after treatment or they could not receive standard treatment Design: Participants will be screened with:

• Medical history
• Tumor tissue sample. If they do not have a sample, they will have a biopsy.
• Physical exam
• Blood and heart tests
• Scans and x-rays: They may have a dye injected for the scans. Participants will take the drugs in up to three 21-day cycles. They will take tofacitinib by mouth twice a day on days 1-10 of each cycle. They will have LMB-100 injected into the blood on days 4, 6, and 8 of every cycle. Patients that do not have a medi-port may need to have a central vein access line placed. Participants will take other drugs on the days they receive LMB-100. Participants will repeat screening tests during the study. They may have a biopsy at the start of the first 2 cycles. If participants must stop the study, they will have a safety visit 3-6 weeks after their last dose of the study drug. Some participants may then have visits every 6 weeks. After treatment, participants will be contacted about once a year. They will be asked about their cancer.

Conditions

Neoplasms With Mesothelin Expression; Epithelioid Mesothelioma; Cholangiocarcinoma, Extrahepatic; Adenocarcinoma, Pancreatic

Keywords

Advanced Cancer; Immunotoxin; Antibody Based Therapeutics; Mesothelin

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib

  MTD is defined as the maximum dose at which less than 33% of participants experience a dose-limiting toxicity (defined as any events occurring within the first cycle of treatment (21 days) such as any death not clearly due to the underlying disease or extraneous causes).

  First cycle of treatment (21 days)

• Percentage of Participants With Pancreatobiliary Cancer and LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 Who Received LMB-100 at Maximum Tolerated Dose

  This measure assessed how many participants have LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 2 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.

  Plasma LMB-100 levels during Cycle 2 treatment (each cycle = 21 days)

• Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group

  Grade 1-5 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 observed in participants with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. Grade 5 is death related to adverse events.

  Throughout study treatment until 30 days post-completion, approximately 13 weeks

Secondary Outcomes (6)

• Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation

  Plasma LMB-100 levels during Cycle 2 of treatment (each cycle = 21 days)

• Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100

  Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)

• Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs)

  Plasma LMB-100 levels during Cycle 3 treatment (each cycle = 21 days)

• Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100

  Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)

• Plasma Half-Life (T1/2) of LMB-100

  Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)

Other Outcomes (2)

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

  Throughout study treatment until 30 days post-completion, approximately 13 weeks.

• Number of Participants With a Dose-Limiting Toxicity (DLT)

  First cycle (21 days)

Study Arms (2)

1. Dose escalation

EXPERIMENTAL

LMB-100 at escalating doses plus tofacitinib

Drug: LMB-100; Drug: Tofacitinib; Device: Mesothelin Expression

2. Dose expansion

EXPERIMENTAL

LMB-100 at optimal dose plus tofacitinib

Drug: LMB-100; Drug: Tofacitinib

Interventions

LMB-100 DRUG

Arms 1 and 2: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

1. Dose escalation; 2. Dose expansion

Tofacitinib DRUG

Arms 1 and 2: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Also known as: Xeljanz

1. Dose escalation; 2. Dose expansion

Mesothelin Expression DEVICE

Test for mesothelin expression in tumor tissues for study eligibility

1. Dose escalation

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically confirmed solid tumor malignancy for which no curative therapy exists.
• Pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma or epithelioid subtype of mesothelioma, as determined by National Cancer Institute (NCI) Laboratory of Pathology, OR for all other tumor types, at least 20% of tumor cells must express mesothelin. Determination can be made using archival tumor tissue or fresh biopsy if archival tumor tissue is not available.
• All patients must have evaluable disease (i.e., measurable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. or by following carbohydrate antigen 19-9 (CA19-9) tumor marker). Patients in the expansion cohort must have measurable disease, per RECIST 1.1. evaluation of measurable disease.
• Patients must have received at least one prior standard systemic treatment regimen for advanced disease OR be ineligible to receive available standards due to co-morbidities, prior toxicity, lack of standard options for tumor type, or having received all standards available for prior treatment of early-stage disease OR have refused first-line standard systemic treatment but have received prior anti-cancer treatments.
• Patients with deficient Mismatch Repair (dMMR)/high levels of MicroSatellite Instability (MSI-H) disease must have received at least one prior anti-programmed cell death 1 (PD1) therapy, be ineligible to receive this treatment due to concurrent medical conditions or have refused this therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
• Age \>=18 years. Because no dosing or adverse event data are currently available on the use of LMB-100 alone or in combination with tofacitinib in persons with \<18 years of age, children are excluded from this study.
• Patients must be more than 14 days removed from most recent minor surgical procedure (such as biliary stenting), 28 days from most recent major surgical procedure and 14 days from radiation therapy, systemic treatments (such as chemotherapy), or experimental drug treatment. All acute toxicities from prior treatment must have resolved to grade 1 or less except alopecia, anemia, peripheral neuropathy, or endocrinopathies corrected by replacement therapy.
• Adequate hematological function: neutrophil count of \>= 1.5 x 10\^3 cells/micro liters, platelet count of \>= 85,000/micro liters, hemoglobin greater than or equal to 9 g/dL
• Serum albumin \>= 2.5 mg/dL without intravenous supplementation
• Adequate liver function: Bilirubin \<2.5 x upper limit of normal (ULN) for all, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN except for patients with significant tumor burden in their liver where AST and ALT \< 5x ULN is acceptable in the absence of other etiologies for transaminitis
• Adequate renal function: creatinine clearance \[Estimating glomerular filtration rate (EGFR) method or measured\] \>= 50 mL/min. Measured clearance will be used if both numbers are available.
• Must have left ventricular ejection fraction \>= 50%
• Must have an ambulatory oxygen saturation of \> 88% on room air
• The expansion phase patients must meet all eligibility criteria above AND must have diagnosis of pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma with pathology confirmed to be consistent with one of these diagnoses by NCI Laboratory of Pathology.

You may not qualify if:

• Known or clinically suspected central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases as CNS penetration of LMB-100 is expected to be poor. CNS metastases are permitted if 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 that related to the 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).
• Any known diagnoses, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition (other than mesothelin \[+\] cancer diagnosis) that would contraindicate the use of an investigational drug, interfere with tumor measurement or lead to a life expectancy of less than 6 months as judged by the investigator.
• Contraindication to receiving prophylactic doses of low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC) such as current active bleeding (except for grade 1 hematuria or epistaxis), recent history of significant bleeding without subsequent effective medical or surgical intervention, known history of gastric varices, uncontrolled malignant hypertension, history of coagulopathy that confers increased risk of bleeding. Patients on concurrent treatment with anti-platelet agents such as aspirin or clopidogrel are eligible if deemed to have acceptable risk of bleeding in consultation with Hematologist. Patients already receiving prophylactic or therapeutic doses of anticoagulant (heparin-based, or DOAC) for at least 4 weeks with no indication of significant bleeding while on therapy are considered NOT to have a contraindication to this therapy.
• Inability to administer or unwillingness to comply with recommended venous thromboembolism (VTE) prophylaxis for the duration of study treatment.
• Prior diagnosis of hematologic malignancy
• Active or uncontrolled infections (including tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) or reasonable clinical suspicion of an active infection (such as cholangitis) as tofacitinib suppresses lymphocyte signaling and will impair host response to infection
• Latent tuberculosis (TB) infection as identified by interferon-gamma release assay (IGRA). If IGRA is indeterminate, tuberculin skin test (TST) may be used to determine status.
• Live attenuated vaccinations within 14 days prior to treatment.
• Use of a strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 14 days prior to enrollment or similarly updated source for a list of such agents)
• Inability to take or digest oral medication.
• Dementia or altered mental status that would prohibit informed consent.
• Pregnant women are excluded from this study because the effects of LMB-100 and/or tofacitinib on the developing fetus are unknown and may have the potential to cause teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LMB-100 and/or tofacitinib, breastfeeding should be discontinued if the mother is treated with either of these agents.
• Baseline corrected QT interval by Fredericia (QTcF) interval of \> 470 ms, participants with baseline resting bradycardia \< 45 beats per minute, or baseline resting tachycardia \>100 beats per minute.
• Participants with contra-indication and/or history of severe hypersensitivity reactions to any components related to LMB-100 and tofacitinib.

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)

• Skorupan N, Peer CJ, Zhang X, Choo-Wosoba H, Ahmad MI, Lee MJ, Rastogi S, Sato N, Yu Y, Pegna GJ, Steinberg SM, Kalsi SS, Cao L, Figg WD, Trepel JB, Pastan I, FitzGerald D, Alewine C. Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers. Front Oncol. 2024 Apr 19;14:1386190. doi: 10.3389/fonc.2024.1386190. eCollection 2024.

  PMID: 38706610 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Cholangiocarcinoma; Adenocarcinoma

Interventions

LMB-100; tofacitinib

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Results Point of Contact

• Title: Dr. Christine C. Alewine
• Organization: National cancer Institute

christine.alewine@nih.gov

240-760-6146

Study Officials

• Christine C Alewine, 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: Principla Investigator

Study Record Dates

• First Submitted: July 25, 2019
• First Posted: July 26, 2019
• Study Start: August 29, 2019
• Primary Completion: December 1, 2020
• Study Completion: November 19, 2021
• Last Updated: August 1, 2023
• Results First Posted: February 8, 2022

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)