Anti-Mesothelin Immunotoxin LMB-100 Followed by Pembrolizumab in Malignant Mesothelioma
Condition: Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: LMB-100; Pembrolizumab
Intervention description: Given intravenous (IV) at recommended phase 2 dose (RP2D) on days 1, 3 and 5 of two (2) 21 day cycles.; Given intravenous (IV) at approved dose on day 1 of each 21 day cycle, starting with cycle 3, for up to 2 years with the option of a second course for patients meeting criteria.
Intervention MeSH terms: Pembrolizumab; LMB-100
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Checkpoint Inhibitor; Immunotherapy

Summary:

      Background:

      Treatment outcomes for people with pleural or peritoneal mesothelioma are often poor. The
      drug LMB-100 can attack and kill cancer cells. The drug pembrolizumab helps the immune system
      fight cancer. Together, these drugs might help people with these cancers.

      Objective:

      To test if pembrolizumab given after LMB-100 shrinks tumors in people with pleural or
      peritoneal mesothelioma.

      Eligibility:

      People ages 18 and older with pleural or peritoneal mesothelioma that has not responded to
      platinum-based therapy

      Design:

      Participants will be screened with:

      Tumor sample. Participants will have a biopsy if one is needed.

      Medical history

      Physical exam

      Blood, heart, and urine tests

      X-rays and scans: Participants will lie on a table. A machine will take pictures of the body.

      Participants will receive LMB-100 by intravenous (IV) on days 1, 3, and 5 of two 21-day
      cycles. They will be observed for up to 2 hours after each infusion. They will receive drugs
      like Benadryl, Tylenol, and Zantac to help with side effects.

      Starting with the 3rd cycle, participants will receive pembrolizumab by IV on day 1 of each
      21-day cycle for up to 2 years.

      Participants will have blood and urine tests, heart tests, and chest x-rays at least once per
      cycle. They will have scans every 6 weeks.

      Participants may opt to provide tumor biopsies before starting the first cycle, after 2
      cycles of LMB-100, and after 2 cycles of pembrolizumab.

      Participants will a follow-up visit 4-6 weeks after their last drug dose of the study drug.
      This includes blood and heart tests and scans. They may then have scans every 6 weeks.

      Participants will be contacted once a year for follow-up.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Participants are eligible to be included in the study only if all of the following criteria
        apply.

          -  Male and female participants who are at least 18 years of age on the day of signing
             the informed consent will be enrolled in the study.

          -  Subjects must have histologically confirmed diagnosis of:

          -  Cohort 1: Histologically confirmed epithelial or biphasic pleural mesothelioma (with
             <50% sarcomatoid component) not amenable to potentially curative surgical resection.
             The diagnosis will be confirmed by the Laboratory of Pathology, Center for Cancer
             Research (CCR), National Cancer Institute (NCI). OR

          -  Cohort 2: Histologically confirmed epithelial or biphasic peritoneal mesothelioma
             (with <50% sarcomatoid component) not amenable to potentially curative surgical
             resection. The diagnosis will be confirmed by the Laboratory of Pathology, CCR, NCI.

          -  Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
             tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
             archived tissue.

        Note: If submitting unstained cut slides, newly cut slides should be submitted to the
        testing laboratory within 14 days from the date slides are cut.

          -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
             1.1. Lesions in a previously irradiated area are considered measurable if progression
             has been demonstrated in such lesions.

          -  Subjects must have at least one prior chemotherapy regimen that includes pemetrexed
             and cisplatin or carboplatin.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Evaluation of
             ECOG is to be performed within 7 days prior to start of study therapy.

          -  Have adequate organ and marrow function as defined below:

               -  Hematological- hemoglobin: >= 9 g/dL or >= 5.6 mmol/L(a)

               -  Hematological- absolute neutrophil count: >= 1,500/mcL

               -  Hematological- platelets: >= 100,000/mcL

               -  Hepatic- total bilirubin: less than or equal to 2.5 X institutional upper limit
                  of normal (ULN) OR direct bilirubin less than or equal to ULN for participants
                  with total bilirubin levels >1.5 X ULN

               -  Hepatic- aspartate aminotransferase (AST) and alanine aminotransferase (ALT):
                  less than or equal to 2.5 X institutional ULN (less than or equal to 5 X ULN for
                  participants with liver metastases)

               -  Renal-Creatinine less than or equal to 1.5 x ULN OR >= 50 mL/min for participant
                  with creatinine levels > 1.5 X institutional ULN. Measured or calculated(b)
                  creatinine clearance (Glomerular filtration rate (GFR) can also be used in place
                  of creatinine or creatinine clearance (CrCl)

               -  Coagulation-International normalized ratio (INR) OR prothrombin time (PT)/
                  Activated partial thromboplastin time (aPTT): less than or equal to 1.5 x ULN
                  unless participant is receiving anticoagulant therapy as long as PT or aPTT is
                  within therapeutic range of intended use of anticoagulants

               -  ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);

               -  AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);

               -  GFR=glomerular filtration rate; ULN=upper limit of normal.

               -  a. Criteria must be met without erythropoietin dependency and without packed red
                  blood cell (pRBC) transfusion within last 2 weeks.

               -  b. Creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR)
                  should be calculated per institutional standard.

          -  Must have left ventricular ejection fraction >50%.

          -  Must recovered from all adverse events (AEs) due to previous therapies to less than or
             equal to Grade 1 or baseline. Participants with less than or equal to Grade 2
             neuropathy may be eligible. If participant received major surgery, they must have
             recovered adequately from the toxicity and/or complications from the intervention
             prior to starting study treatment.

          -  Must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (less than or equal to 2 weeks of radiotherapy) to
             non-central nervous system (CNS) disease.

          -  If participant received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting study treatment.

          -  The effects of LMB-100 on the developing human fetus are unknown. For this reason and
             because anti-programmed cell death protein 1 (PD-1) antibodies such as pembrolizumab
             are assumed to be teratogenic:

          -  A male participant must agree to use contraception during the treatment period and for
             at least 180 days after the last dose of study treatment and refrain from donating
             sperm

          -  A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies:

               -  Not a woman of childbearing potential (WOCBP) OR

               -  A WOCBP who agrees to follow the contraceptive guidance in Appendix B during the
                  treatment period and for at least 180 days after the last dose of study
                  treatment.

          -  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.

          -  The participant provides written informed consent for the trial.

        EXCLUSION CRITERIA:

        - Is currently participating in or has participated in a study of an investigational agent
        or has used an investigational device within 4 weeks prior to the first dose of study
        treatment.

        Note: Participants who have entered the follow-up phase of an investigational study may
        participate as long as it has been 4 weeks after the last dose of the previous
        investigational agent.

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment.

          -  Has severe hypersensitivity (>= Grade 3) to pembrolizumab, LMB-100 and/or any of their
             excipients.

          -  Subjects who have received prior therapy with LMB-100, an anti-PD-1, anti-PD-L1, or
             anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another
             stimulatory or co-inhibitory T-cell receptor (e.g., Cytotoxic T-lymphocyte antigen 4
             (CTLA-4), OX-40, tumor necrosis factor receptor superfamily member 9 (CD137).

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to start of study therapy.

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.

          -  Has had a prior pneumonectomy

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist(R)) are live attenuated vaccines and are not allowed.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to start of study therapy.

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Has a history of (non-infectious) pneumonitis/interstitial lung disease (ILD) that
             required steroids or has current pneumonitis/ILD

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of
             study therapy (see Appendix B). If the urine test is positive or cannot be confirmed
             as negative, a serum pregnancy test will be required. Note: in the event that 72 hours
             have elapsed between the screening pregnancy test and the first dose of study
             treatment, another pregnancy test (urine or serum) must be performed and must be
             negative in order for subject to start receiving study medication.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 180 days
             after the last dose of trial treatment. Pregnant women are excluded from this study
             because LMB-100 + pembrolizumab are agents with the potential for 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 +
             pembrolizumab, breastfeeding should be discontinued if the mother is treated with
             LMB-100 + pembrolizumab. These potential risks may also apply to other agents used in
             this study.

          -  Has a known history of Human Immunodeficiency Virus. 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. (Note: No HIV testing
             is required)

          -  Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV ribonucleic acid (RNA)
             [qualitative] is detected) infection. or active hepatitis B virus (HBV) or HCV
             infection. (Note: No testing for Hepatitis B and Hepatitis C is required.)

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 2 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded.

          -  Has an active infection requiring systemic therapy.