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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

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ClinicalTrials.gov Identifier: NCT04034238
Recruitment Status : Recruiting
First Posted : July 26, 2019
Last Update Posted : September 19, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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.


Condition or disease Intervention/treatment Phase
Neoplasms With Mesothelin Expression Epithelioid Mesothelioma Cholangiocarcinoma, Extrahepatic Adenocarcinoma, Pancreatic Drug: LMB-100 Drug: Tofacitinib Device: Mesothelin Expression Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 29, 2019
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : July 1, 2023


Arm Intervention/treatment
Experimental: 1. Dose escalation
LMB-100 at escalating doses plus tofacitinib
Drug: LMB-100
Arms 1 and 2: Administered 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.

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

Device: Mesothelin Expression
Test for mesothelin expression in tumor tissues for study eligibility

Experimental: 2. Dose expansion
LMB-100 at optimal dose plus tofacitinib
Drug: LMB-100
Arms 1 and 2: Administered 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.

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




Primary Outcome Measures :
  1. Safety and tolerability of LMB-100 with tofacitinib [ Time Frame: Day 3 of each cycle after LMB-100 plus tofacitinib is administered ]
    The MTD and the desirable dose and schedule of LMB-100 when given in combination with tofacitinib

  2. Timing of anti-LMB-100 anti- drug antibody development [ Time Frame: at day 3 of each cycle and at time of progression ]
    Time of development of anti- drug antibodies through cycle 2 of LMB-100 treatment.


Secondary Outcome Measures :
  1. Formation of anti LMB-100 antibodies [ Time Frame: at day 3 of each cycle and at time of progression ]
    Determine if tofacitinib delays formation of neutralizing anti-LMB-100 ADA in Cohort 1

  2. 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 and tolerability of LMB-100 when given in combination with tofacitinib in Cohort 2

  3. LMB-100 PK assessment [ Time Frame: at day 4 and 8 of each cycle ]
    Determine if tofacitinib affects LMB-100 PK in Cohort 1 and 2

  4. Formation of anti LMB-100 antibodies [ Time Frame: at day 3 of each cycle and at time of progression ]
    Determine the percentage of patients with delayed formation of neutralizing anti-LMB-100 ADAs through cycle 3 of treatment in both Cohorts



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04034238


Contacts
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Contact: NCI Medical Oncology Referral Office (240) 760-6050 ncimo_referrals@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: NCI Medical Oncology Referral Office    240-760-6050    ncimo_referrals@mail.nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Christine C Alewine, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04034238     History of Changes
Other Study ID Numbers: 190128
19-C-0128
First Posted: July 26, 2019    Key Record Dates
Last Update Posted: September 19, 2019
Last Verified: September 9, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Advanced Cancer
Immunotoxin
Antibody Based Therapeutics
Mesothelin
Additional relevant MeSH terms:
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Adenocarcinoma
Mesothelioma
Cholangiocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenoma
Neoplasms, Mesothelial
Tofacitinib
Immunotoxins
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs