LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Background:

 Over 230,000 new lung cancer cases are diagnosed every year in the U.S. About 80% of lung
 cancers are NSCLC. Most people have a more advanced stage of the disease that doesn t respond
 well to standard treatment. Researchers want to see if a combination of drugs may be able to
 help.

 Objective:

 To find out if LMB-100 followed by pembrolizumab can help tumors to shrink in people with
 NSCLC.

 Eligibility:

 People ages 18 and older with NSCLC that has not responded to standard therapies

 Design:

 Participants will be screened with:

 -  Medical history

 -  Physical exam

 -  Tumor sample. If one is not available, they will have a biopsy.

 -  Assessments of ability to perform normal activities

 -  Lung function tests

 -  Blood, heart, and urine tests

 -  CT and PET scans: They will like in a machine that takes pictures of the body.

 Participants will take LMB-100 in 21-day cycles for up to 2 cycles. They will take the drug
 by injection into an arm vein on days 1, 3, and 5 of each cycle. They will stay in the
 hospital 7-10 days each cycle. Then they will get pembrolizumab by injection into an arm vein
 every 3 weeks for up to 2 years. They may be able to take pembrolizumab an additional year if
 their cancer gets worse.

 Participants will have repeats of the screening tests throughout the study.

 About 30 days and 90 days after they stop treatment, participants will have follow-up visits.
 Then they will have visits every 6-12 weeks. They will be followed for the rest of their life
 through phone calls and emails.
Background:

 -  Mesothelin is expressed in approximately half of all lung adenocarcinomas.

 -  LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor
 models including non-small cell lung cancer (NSCLC).- Programmed death ligand 1 (PD-1)
 is an Ig superfamily member related to CD28 and CTLA-4 that has been shown to negatively
 regulate antigen receptor signaling upon engagement of its ligands.

 -  Pembrolizumab, an IgG4 monoclonal antagonist antibody to PD-1, is FDA approved in the
 frontline for advanced non-squamous NSCLC as a single agent with high PD-L1 expression
 [tumor proportion score (TPS) >=50%] or in combination with platinum-based doublet
 chemotherapy (PD-L1 unselected). It also approved in the second-line for high PDL1
 expressing tumors (TPS >=1%).

 -  Combination treatment with LMB-100 plus pembrolizumab results in greater anti-tumor
 efficacy in murine lung cancer model.

 Objectives:

 -To determine the objective response rate of LMB-100 followed by pembrolizumab in the
 treatment of subjects with mesothelin-expressing non-squamous non-small cell lung cancer
 (NSCLC) previously treated with immune checkpoint inhibitors.

 Eligibility:

 -  Histologically confirmed locally advanced or metastatic non-squamous, non-small cell
 lung cancer lacking an EGFR sensitizing mutation, ALK or ROS1 gene rearrangement and not
 amenable to potentially curative surgical resection or chemoradiation.

 -  Tumor mesothelin expression of at least 25% of tumor cells as determined by the
 Laboratory of Pathology at the NCI.

 -  Subjects must have at least progressed after one prior platinum-based doublet
 chemotherapy AND standard immune checkpoint inhibitor (ICI) with either frontline
 single-agent pembrolizumab, or in combination with platinum-based doublet chemotherapy,
 or second-line single-agent nivolumab, pembrolizumab, or atezolizumab.

 -  Age >= 18 years.

 Design:

 -  This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab
 in subjects with mesothelin expressing NSCLC who have progressed on standard therapies

 -  Subjects will receive LMB-100 at the single agent MTD (140mg/kg) on days 1, 3 and 5 of a
 21-day cycle for up to 2 cycles and pembrolizumab 200 mg on day 1 of cycle 3 of a 21-
 day cycle (or cycle 2 if disease progression is observed after 1 cycle) onwards until
 disease progression (on or after pembrolizumab) or intolerable toxicity for a maximum of
 2 years (unless second course initiated).

 -  The total accrual ceiling for the screening will be set at 100 total patients in order
 to treat 23 subjects.
-  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 non-squamous non-small cell
 lung cancer not amenable to potentially curative treatments (surgical resection,
 definitive radiation therapy or a combined modality approach) or targeted agents to
 actionable EGFR mutations or ALK or ROS1 gene rearrangement and excluding
 neuroendocrine tumors. Activating KRAS mutations are allowed. The diagnosis must be
 confirmed by the Laboratory of Pathology, CCR, NCI. Mutation confirmation may be done
 by referring institutions or by one of the assays in the Protocol.

 -  Have provided archival tumor tissue sample or newly obtained fresh 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.

 -  Histologically confirmed 25% of tumor cells expressing mesothelin as determined by NCI
 Laboratory of Pathology. Determination can be made using archival tumor tissue or
 fresh biopsy.

 -  Have measurable disease based on RECIST 1.1. Lesions in a previously irradiated area
 are considered measurable if progression has been demonstrated in such lesions.

 -  Subjects must have received prior standard of care treatments for locally advanced or
 metastatic NSCLC.

 -  Patients must be more than 3 weeks out of systemic treatments, such as chemotherapy.

 -  All acute toxic effects of any prior radiotherapy, chemotherapy, immunotherapy, or
 surgical procedure must have resolved to Grade less than or equal to 1, except
 alopecia (any grade) and Grade 2 peripheral neuropathy.

 -  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:

 -  Patients must have normal organ and marrow function as defined below:

 -  hemoglobin greater than or equal to 9g/dL or 5.6 mmol/L

 -  absolute neutrophil count greater than or equal to 1,500mcL

 -  platelets greater than or equal to 100,000/mcL

 -  total bilirubin less than or equal to 2.5 x the upper limit of normal range (UNL)
 OR direct bilirubin less than or equal to ULN for participants with total
 bilirubin levels of greater than 1.5 X ULN

 -  AST and ALT less than or equal to 2.5 x ULN OR less than or equal to 5 x ULN for
 subjects with metastatic disease to the liver

 -  creatinine greater than or equal to 1.5 x ULN OR creatinine clearance greater
 than or equal to 50 mL/min for participants with creatinine levels greater than
 1.5 X ULN

 -  International normalized ratio (INR) or prothrombin time (PT) or activated
 thromboplastin time (aPTT) greater 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

 -  Must have left ventricular ejection fraction >50%.

 -  The effects of LMB-100 on the developing human fetus are unknown. For this reason and
 because anti-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 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.

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

 -  Subjects with non-life-threatening immune-related endocrinopathies or AEs reduced
 to Grade 1 or 0 after withholding ICI or medical intervention are eligible as
 long as the AE resolved within 12 weeks of last dose and not requiring
 corticosteroids.

 EXCULSION 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.

 -  Subjects who have received prior therapy with LMB-100.

 Has received prior systemic anti-cancer therapy including investigational agents within 4
 weeks prior to start of study therapy.

 -  Note: Participants must have recovered from all AEs due to previous therapies to
 <=Grade 1 or baseline. Participants with <=Grade 2 neuropathy may be eligible.

 -  Note: If participant received major surgery, they must have recovered adequately from
 the toxicity and/or complications from the intervention prior to starting study
 treatment.

 -  Has received prior radiotherapy within 2 weeks of start of study treatment.
 Participants must have recovered from all radiation-related toxicities, not
 require corticosteroids, and not have had radiation pneumonitis. A 2-week washout
 is permitted for palliative radiation (<=2 weeks of radiotherapy) to non-CNS
 disease.

 -  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 Gu(SqrRoot)(Copyright)rin (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. 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). 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 RNA
 [qualitative] is detected) infection. or active 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.

 -  Participants with contra-indication and/or history of severe hypersensitivity
 reactions to any components related to LMB-100 or pembrolizumab (or any other
 immune checkpoint inhibitor such as PD1, PDL-1 and CTLA4).

 -  Active or uncontrolled infections.

 -  Subjects who experienced severe or life-threatening immune-related AEs with prior
 immune checkpoint therapy requiring medical intervention (steroid or
 immunosuppressant drugs) and permanent discontinuation of therapy, will be
 excluded. These include, but not limited to colitis, autoimmune hepatitis,
 hypophysitis, hyperthyroidism, nephritis, myocarditis, GBS, encephalitis.

 -  Subjects with a history of pneumonitis that required steroids will be excluded.

 -  Recruitment Strategies

 Information about the study will be posted on sites such as clinicaltrials.gov and the CCR
 recruitment website. Subjects will also be drawn from patients seen at the thoracic clinic
 at the NIH Clinical Center as well as from referrals from outside providers. Social media
 platforms managed by NIH/NCI may also be used to publicize the study. There is no plan to
 advertise this study at this time.