Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma
Condition: Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: LMB-100; ipilimumab; Diphenhydramine; Famotidine; Acetaminophen; Dexamethasone; Biopsy; FDG-PET; CT CAP; MRI; ECG; Echocardiogram
Intervention description: LMB-100 administered into lesion on days 1 and 4 during cycle 1.; Administered intravenously once per cycle up to three 21-day cycles. Administration will occur during cycles 2,3,4.; Infusion related reactions precaution: All participants will be premedicated with 25-50 mg Diphenhydramine by mouth (PO) or intravenous (IV) (or alternative antihistamine at adequate dose) 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration.; Infusion related reactions precaution: All participants will be premedicated with 20 mg Famotidine by mouth (PO) or intravenous (IV) (or alternative histamine H2- receptor antagonists (H2) blocker at adequate dose) 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration.; Infusion related reactions precaution: All participants will be premedicated with 650 mg Acetaminophen by mouth (PO) or intravenous (IV) 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration.; Additional infusion precaution at infusions of LMB-100 after Cycle 1 Day 1 (as appropriate): Dexamethasone 20 mg by mouth (PO), 6-12 hours prior to LMB-100 administration OR 10mg, intravenous (IV), 30-60 minutes prior to LMB-100 administration OR equivalent dose of another corticosteroid as clinically indicated.; As feasible at screening, Cycle 1 Day 1 and 5, Cycle 2, 3, & 4 Day 1, and Cycle 4 Day 21 (±7 days).; At screening, at the end of cycles 2 & 4 ± 7 days, Follow-Up Visit (4-6 weeks after end of treatment), and Long-Term Follow-Up (every 6-12 weeks).; At screening, at the end of cycles 2 & 4 ± 7 days, Follow-Up Visit (4-6 weeks after end of treatment), and Long-Term Follow-Up (every 6-12 weeks).; At screening, at the end of cycles 2 & 4 ± 7 days, Follow-Up Visit (4-6 weeks after end of treatment), and Long-Term Follow-Up (every 6-12 weeks).; At screening, Cycle 1 Day 1, Cycles 2, 3, & 4 Day 1 and Follow-Up Visit (4-6 weeks after end of treatment).; At screening.
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Dexamethasone; Ipilimumab; Famotidine; LMB-100
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: Immunotherapy; Checkpoint Inhibitor; anti CTLA-4

Summary:

      Background:

      Mesothelioma is a type of cancer. It originates in cells that line human body cavities. Most
      people have advanced disease when they are diagnosed. Researchers want to see if a
      combination of drugs can help.

      Objective:

      To find a safe dose of LMB-100 in combination with ipilimumab when LMB-100 is injected into
      tumors.

      Eligibility:

      Adults ages 18 and older with malignant pleural or peritoneal mesothelioma, that cannot be
      cured with surgery and has not responded to standard first-line treatments for mesothelioma.

      Design:

      Participants will be screened with:

        -  Tumor biopsy or effusion, if needed

        -  Medical history

        -  Physical exam

        -  Blood and urine tests

        -  Imaging scans

        -  Heart and lung function tests

        -  Pregnancy test, if needed

      Some screening tests will be repeated during the study.

      Participants will get LMB-100 on Days 1 and 4 for up to 2 cycles. Each cycle lasts 21 days.
      They will stay in the hospital for about 8 days each time they get LMB-100. It will be
      injected into their tumor with needles.

      Participants will get ipilimumab through a tube that is put in a vein. It will be given on
      Day 2 of the first 2 cycles and Day 1 of the next 2 cycles.

      Participants will be assessed for how well they do daily activities. They will give blood and
      tissue samples for research.

      Participants will have a safety visit 4 to 6 weeks after the last dose of the study drugs.
      Then they will have scans every 6 weeks until their disease gets worse. If their tumor gets
      bigger, they will have phone, video, or email follow-ups every 12 weeks.

      Participants will be on this study for life....
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Histologically confirmed malignant pleural or peritoneal mesothelioma 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).

               2. Tumor must have epithelioid histology determined by the Laboratory of Pathology
                  at the NCI. If the patient has biphasic histology, the epithelioid component must
                  be >50%

               3. Have provided archival tumor tissue sample or able to provide 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.

               4. Have disease locally, accessible disease to suitable for intra-tumoral injection
                  of LMB- 100.

               5. 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.

               6. Subjects must have received prior immune checkpoint therapy with anti-Programmed
                  cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors alone or
                  in combination with anti-CTLA4 blocking antibodies, as well as platinum-based
                  chemotherapy.

               7. Age >= 18 years.

               8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
                  Evaluation of ECOG is to be performed within 28 days prior to initiation of study
                  therapy.

               9. Have adequate organ and marrow function as defined below:

                  System and Laboratory Value

                  Hematological -

                  hemoglobin >= 9 g/dL(a)

                  absolute neutrophil count >= 1,500/mcL

                  platelets >= 100,000/mcL

                  Hepatic

                  total bilirubin <= 2.5 X institutional upper limit of normal (ULN) OR direct
                  bilirubin <=ULN for participants with total bilirubin levels >1.5 X ULN

                  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 X
                  institutional ULN (<= 5 X ULN for participants with liver metastases)

                  Renal

                  Creatinine <=1.5 x ULN OR Measured or calculated(b) creatinine clearance
                  (glomerular filtration rate (GFR) can also be used in place of creatinine or
                  CrCl) >= 50 mL/min for participant with creatinine levels; > 1.5 X institutional
                  ULN

                  Coagulation

                  International normalized ratio (INR) OR prothrombin time (PT); Activated partial
                  thromboplastin time (aPTT): <=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.

                    1. Criteria must be met without erythropoietin dependency and without packed
                       red blood cell (pRBC) transfusion within last 2 weeks.

                    2. Creatinine clearance (CrCl) should be calculated per institutional standard.

              10. Must have left ventricular ejection fraction >50%.

              11. The effects of LMB-100 on the developing human fetus are unknown. For this reason
                  and because ipilimumab is a Category C agent, women of child-bearing potential
                  and men must agree to use adequate contraception (hormonal or barrier method of
                  birth control; abstinence) while on study therapy and for four months after 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.

              12. Ability of subject to understand and the willingness to sign a written informed
                  consent document.

        EXCLUSION CRITERIA:

          1. Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 3 weeks prior to initiation of
             study therapy.

             Note: Participants who have entered the follow-up phase of an investigational study
             may participate as long as it has been 3 weeks after the last dose of the previous
             investigational agent. Patients with active devices will be excluded from the study.

          2. 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
             initiation of study therapy.

          3. Has active systemic issues as bleeding diathesis or active infections

          4. Presence of a clinically significant pericardial effusion

          5. Has severe hypersensitivity (>=Grade 3) anti-CTLA4 therapies and/or any of their
             excipients.

          6. Has received prior radiotherapy to the site of local administration

          7. Subjects who have received LMB-100 previously

          8. Has received prior systemic anti-cancer therapy including investigational agents
             within 3 weeks prior to initiation of study therapy. Patients who have received prior
             anti-PD-1/PD- L1 or CTLA4 antibodies are eligible. Any toxicity related to these
             agents must have resolved to grade 1 and they must not be on systemic
             immunosuppressive therapies (physiologic dose of steroids are permitted).

          9. Has received prior radiotherapy to site other than target lesion within 2 weeks prior
             to initiation of study therapy. Participants 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 (<=2 weeks of
             radiotherapy) to non-CNS disease.

         10. Has not recovered from all adverse events (AEs) due to previous therapies to <=Grade 1
             or baseline. Participants with <=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 initiation of study therapy.

         11. Has received a live vaccine within 30 days prior to initiation of study therapy.
             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.

         12. Is receiving therapeutic anti-coagulation. Patients receiving prophylactic
             anticoagulation may be eligible if in the opinion of the study team, anti-coagulation
             may be stopped during the time of LMB-100 administration and tumor biopsies.

         13. 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 initiation of study therapy.

         14. 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.

         15. Has a QT corrected for heart rate by Fridericia's cube root formula (QTcF) interval
             >480 milliseconds.

         16. Has a history of (non-infectious) pneumonitis/interstitial lung disease (ILD) that
             required steroids or has current pneumonitis/ILD

         17. 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.

         18. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         19. A woman of childbearing potential who has a positive pregnancy test within 72 hours
             prior to initiation of study therapy. If the using a urine test and test 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.

         20. Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 4 months
             after the last dose of trial treatment. Pregnant women are excluded from this study
             because LMB-100 + ipilimumab 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 +
             ipilimumab, breastfeeding should be discontinued if the mother is treated with LMB-100
             + ipilimumab. These potential risks may also apply to other agents used in this study.

         21. 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.

         22. Positive for Hepatitis B or C (defined as Hepatitis B surface antigen reactive) or
             known active Hepatitis C virus (defined as HCV ribonucleic acid (RNA) detected)
             infection. or active hepatitis B virus (HBV) or HCV infection.

         23. 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.

         24. Has an active infection requiring systemic therapy.