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

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ClinicalTrials.gov Identifier: NCT02798536
Recruitment Status : Recruiting
First Posted : June 14, 2016
Last Update Posted : April 25, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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

CT or MRI scans

FDG-PET scans

Participants will get LMB-100 on days 1, 3, and 5 of each 21-day cycle. It will be given through an 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.


Condition or disease Intervention/treatment Phase
Mesothelioma Drug: LMB-100 Drug: nab-paclitaxel Phase 1

Detailed Description:

Background:

  • Although mesothelioma patients with a limited tumor burden may benefit from surgical resection, most patients have advanced disease at diagnosis and are not candidates for cytoreductive surgery.
  • For mesothelioma patients who are not eligible for curative surgery, the median survival with supportive care alone is 6 months whereas with the current standard treatment, a combination of cisplatin and pemetrexed, the median survival is 12 months.
  • Mesothelin, a tumor differentiation antigen, is expressed in over 95% of epitheloid mesothelioma. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal human tissue and its high expression in several tumors including mesothelioma.
  • LMB-100 is a novel recombinant anti-mesothelin immunotoxin developed for the treatment of patients with solid tumors that express mesothelin. Mesothelin is targeted by linking a humanized fragment of the anti-mesothelin Fab to a de-immunized Pseudomonas exotoxin (PE).
  • The clinical use of first generation immunotoxins such as SS1P was hampered mainly by their high immunogenicity. LMB-100 is a next generation PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity. LMB-100 has shown broad activity against different mesothelinexpressing cancer cell lines and tumor xenograft models.

Objectives: Phase 1

To identify the recommended phase 2 dose (RP2D) of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma and evaluate potential efficacy of the identified PP2D.

-Phase 2

To determine the efficacy of LMB-100 with respect to objective response rate in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

Eligibility:

  • Age greater than or equal to 18 years
  • Histologically confirmed advanced pleural or peritoneal mesothelioma
  • Subjects must have had at least 1 prior chemotherapy regimen with last dose of previous therapy occurring at 3 weeks before the start of study treatment
  • Adequate organ function
  • Participants with CNS metastases or prior pneumonectomy are excluded

Design:

  • This is a Phase I, open-label study to evaluate the safety, pharmacokinetics, and activity of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.
  • LMB-100 will be administered intravenously on days 1, 3 and 5 of each 21 day cycle for up to 4 cycles
  • Tumor response will be assessed after every 2 cycles
  • Optional tumor biopsies may be collected at baseline and after 2 cycles of therapy
  • The accrual ceiling will be set at 30

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of the Mesothelin-Targeted Immunotoxin LMB-100 With or Without Nab-Paclitaxel (Abraxane) in Patients With Malignant Mesothelioma
Study Start Date : June 10, 2016
Estimated Primary Completion Date : August 6, 2019
Estimated Study Completion Date : August 5, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Mesothelioma
Drug Information available for: Paclitaxel

Arm Intervention/treatment
Experimental: B2/LMB-100+ nab- paclitaxel dose expansion
Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects
Drug: LMB-100
Administered 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)

Drug: nab-paclitaxel
Arms B1 and B2 only. Administered IV on days 1 and 8 of each 21 day cycle for up to 6 cycles

Experimental: B1/LMB-100+ nab- paclitaxel dose escalation
De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects
Drug: LMB-100
Administered 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)

Drug: nab-paclitaxel
Arms B1 and B2 only. Administered IV on days 1 and 8 of each 21 day cycle for up to 6 cycles

Experimental: A1/LMB-100 dose escalation (closed)
De-escalating doses of LMB-100 in up to 18 subjects
Drug: LMB-100
Administered 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)

Experimental: A2/LMB-100 dose expansion (closed)
Fixed dose of LMB-100 as determined in Arm A1 in up to 16 subjects
Drug: LMB-100
Administered 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)




Primary Outcome Measures :
  1. maximum tolerated dose of LMB100 +nab-paclitaxel [ Time Frame: 3 weeks after initial dose ]
    highest administered dose of LMB-100 + nab-paclitaxel at which no more than 1 of 6 subjects experiences a dose limiting toxicity

  2. maximum tolerated dose of LMB-100 [ Time Frame: 3 weeks after initial dose ]
    highest administered dose of LMB-100 at which no more than 1 of 6 subjects experiences a dose limiting toxicity


Secondary Outcome Measures :
  1. proportion of patients at MTD with paartial or complete response per RECIST [ Time Frame: end of treatment ]
  2. average time from treatment initiaition to disease progression or death [ Time Frame: progression ]
  3. average time from start of treatment to death [ Time Frame: death ]
  4. pharmacokenetic characteristics [ Time Frame: end of treatment ]
  5. number of cycles LMB-100 can be given before ADAs develop [ Time Frame: end of treatment ]
  6. listing and frequency of treatment related adverse events [ Time Frame: 30 days after treatment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA (All Cohorts):
  • 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, CCR, 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 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.
  • ECOG performance status (PS) 0 or1
  • Adequate hematological function: neutrophil count of more than of equal to 1.5 (SqrRoot) 10^9 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: AST and 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 metastsis.
  • Bilirubin less than or equal to 1.5 mg/dL (excluding Gilbert s Syndrome, see below).
  • Patients with Gilbert s syndrome will be eligible for the study. The diagnosis of Gilbert's syndrome is suspected in people who have persistent, slightly elevated levels of unconjugated bilirubin without any other apparent cause. A diagnosis of Gilbert s syndrome will be based on the exclusion of other diseases based on the following criteria:

    • Unconjugated hyperbilirubinemia noted on several occasions
    • No evidence of hemolysis (normal hemoglobin, reticulocyte count, and LDH)
    • Normal liver function tests
    • Absence of other diseases associated with unconjugated hyperbilirubinemia
  • Adequate renal function: creatinine less than 1.5 mg/dL OR creatinine clearance (by Cockcroft Gault formula) greater than or equal to 50 mL/min.
  • Must have serum albumin > 2.5 mg/dL without intravenous supplementation
  • Must have left ventricular ejection fraction > 50%
  • Must have an ambulatory oxygen saturation of > 90% on room air
  • Women of child-bearing potential (defined as a sexually mature woman who (1) has not undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must:

    • Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis), or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study therapy (including dose interruptions), while on study medication and for 3 months after the last dose of study therapy; and
    • Have a negative serum pregnancy test ( <= -hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact.
  • Men must agree to practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 6 months following discontinuation of study therapy, even if he has undergone a successful vasectomy.
  • Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA (All Cohorts):

-Known or clinically suspected 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.
  • HIV or active HBV or 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.

EXCLUSION CRITERIA (Cohort B only)

  • 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.

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): NCT02798536


Contacts
Contact: Maria Agra (301) 594-1106 mariagracia.agra@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Raffit Hassan, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02798536     History of Changes
Other Study ID Numbers: 160127
16-C-0127
First Posted: June 14, 2016    Key Record Dates
Last Update Posted: April 25, 2018
Last Verified: April 3, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immunotoxin
Mesothelin
Targeted Therapy

Additional relevant MeSH terms:
Mesothelioma
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Mesothelial
Paclitaxel
Albumin-Bound Paclitaxel
Immunotoxins
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs