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

NCT04034238

Description:

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.

Related Conditions:
  • Epithelioid Mesothelioma
  • Extrahepatic Cholangiocarcinoma
  • Malignant Solid Tumor
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors
  • Official Title: A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 190128
  • SECONDARY ID: 19-C-0128
  • NCT ID: NCT04034238

Conditions

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

Interventions

DrugSynonymsArms
LMB-1001. Dose escalation
Tofacitinib1. Dose escalation

Purpose

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.

Detailed Description

      Background:

        -  Pancreatic cancer is the fourth most common cause of cancer death in the United States,
           claiming more than 40,000 lives each year.

        -  Incidence nearly equals mortality with just 6% of participants living five years beyond
           their diagnosis. Most patients are diagnosed at an advanced stage, but even patients
           with early stage disease have a long-term survival of less than 20%.

        -  Cholangiocarcinoma is a rare disease and just 3,000 patients are diagnosed with the
           extrahepatic form yearly. The median overall survival of patients with advanced disease
           receiving standard of care treatment is less than 1 year.

        -  Expression of mesothelin (MSLN) in pancreatic ductal adenocarcinoma (PDA) has been
           examined in several published studies and ranges from 86 to 100%. Similar incidence of
           expression has been observed in extrahepatic cholangiocarcinoma.

        -  In addition to pancreatobiliary tumors, many other solid tumor types also express MSLN
           such as mesothelioma, colorectal, lung adenocarcinomas, epithelial ovarian, gastric and
           triple negative breast cancers, as well as some tumors of squamous cell origin.

        -  LMB-100 and a closely related immunotoxin also targeting MSLN have been studied in
           previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.

        -  Results from these studies showed that almost all patients formed anti-drug-antibodies
           (ADAs) that neutralized subsequent injection of the product making it ineffective.

        -  Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the
           treatment of rheumatoid arthritis and ulcerative colitis.

        -  Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs
           against an immunotoxin closely related to LMB-100

        -  Co-administration of tofacitinib with immunotoxin increased immunotoxin serum half- life
           in mice and enhanced anti-tumor efficacy

        -  This clinical trial will investigate whether co-administration of tofacitinib with LMB-
           100 can prevent or delay the formation of ADAs and thus allow patients to receive
           additional effective cycles of LMB-100.

      Objectives:

        -  The primary objective of the dose escalation phase of this study is to assess the safety
           and tolerability of LMB-100 given in combination with tofacitinib to patients with
           pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma and other mesothelin-
           positive solid tumors

        -  The primary objective of the expansion phase of this study is to determine whether co-
           administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs through
           cycle 2 of treatment (as measured by LMB-100 serum drug levels) in patients with
           pancreatobiliary cancers.

      Eligibility:

        -  Age >= 18 years

        -  Histologically confirmed solid tumor malignancy for which no curative therapy exists

        -  Participants must have received at least one prior chemotherapy regimen for their
           disease OR be ineligible to receive chemotherapy for their disease

      Design:

        -  This is a Phase I study which will accrue up to 45 subjects total, accounting for screen
           failure.

        -  Participants will be co-treated for 3 cycles with tofacitinib given orally for the first
           10 days of each 21 day cycle, and LMB-100 given on days 4, 6 and 8.

        -  A 3+3 dose escalation schema will be used. Two dose levels are planned. One minus dose
           level could be utilized if dose de-escalation is necessary.

        -  Following identification of an optimal dose and schedule, an expansion phase of 15
           participants will be initiated at the optimal dose for patients with pancreatic
           adenocarcinoma and extrahepatic cholangiocarcinoma. At least 8 participants in the
           expansion phase must have pancreatic adenocarcinoma.
    

Trial Arms

NameTypeDescriptionInterventions
1. Dose escalationExperimentalLMB-100 at escalating doses plus tofacitinib
  • LMB-100
  • Tofacitinib
2. Dose expansionExperimentalLMB-100 at optimal dose plus tofacitinib
  • LMB-100
  • Tofacitinib

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  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 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 RECIST 1.1. or by
             following 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 chemotherapy 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.

          -  Patients with dMMR/MSI-H disease must have received at least one prior anti-PD1
             therapy, be ineligible to receive this treatment due to concurrent medical conditions,
             or have refused this therapy.

          -  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, 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 * 103 cells/micro liters,
             platelet count of >= 85,000/micro liters, hemoglobin (Bullet) 9 g/dL

          -  Serum albumin >= 2.5 mg/dL without intravenous supplementation

          -  Adequate liver function: Bilirubin <2.5 x ULN for all, AST and 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.

          -  The effects of LMB-100 alone or in combination with tofacitinib on the developing
             human fetus are unknown. For this reason, women of child-bearing potential and men
             must agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry until 3 months the last dose of study therapy. Should
             a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately.

          -  Ability of participant to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          -  Known or clinically suspected 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.

          -  Prior diagnosis of hematologic malignancy

          -  Active or uncontrolled infections (including tuberculosis, HIV, HBV, or 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 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 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 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.

          -  Patients who have previously received LMB-100 (and therefore have high-levels of
             preexisting ADA s to drug)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of LMB-100 with tofacitinib
Time Frame:Day 3 of each cycle after LMB-100 plus tofacitinib is administered
Safety Issue:
Description:The MTD and the desirable dose and schedule of LMB-100 when given in combination with tofacitinib

Secondary Outcome Measures

Measure:Formation of anti LMB-100 antibodies
Time Frame:at day 3 of each cycle and at time of progression
Safety Issue:
Description:Determine if tofacitinib delays formation of neutralizing anti-LMB-100 ADA in Cohort 1
Measure:safety and tolerability of the combination in patients with pancreatobiliary cancer
Time Frame:Day 3 of each cycle after LMB-100 plus tofactiinib is administered
Safety Issue:
Description:Safety and tolerability of LMB-100 when given in combination with tofacitinib in Cohort 2
Measure:LMB-100 PK assessment
Time Frame:at day 4 and 8 of each cycle
Safety Issue:
Description:Determine if tofacitinib affects LMB-100 PK in Cohort 1 and 2
Measure:Formation of anti LMB-100 antibodies
Time Frame:at day 3 of each cycle and at time of progression
Safety Issue:
Description:Determine the percentage of patients with delayed formation of neutralizing anti-LMB-100 ADAs through cycle 3 of treatment in both Cohorts

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Advanced Cancer
  • Immunotoxin
  • Antibody Based Therapeutics
  • Mesothelin

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