Anti-Mesothelin Immunotoxin LMB-100 Followed by Pembrolizumab in Malignant Mesothelioma

Background:

- LMB-100, and a closely related immunotoxin, SS1P, also targeting mesothelin, have been
studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.

- LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor
models including mesothelioma PDX models

- PD-1 (encoded by the gene Pdcd1) 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

- The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress
immune control. The normal function of PD-1, expressed on the cell surface of activated
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune
responses, including autoimmune reactions.

- In immune-competent mice bearing human mesothelin expressing tumors local administration
of LMB-100 with CTLA-4 blockade eradicates murine tumors by promoting anti-cancer
immunity.

- LMB-100 treatment increase CD8+ T cell infiltration in murine lung adenocarcinoma tumors
that express human mesothelin.

- Combination treatment with LMB-100 plus anti-PD1 results in greater anti-tumor efficacy
in murine lung cancer model

- Pembrolizumab is an anti PD-1 antibody that has demonstrated responses of long duration
in clinical trials and has generally been well-tolerated

- It is hypothesized that the anti-mesothelin immunotoxin LMB-100 followed by
pembrolizumab will result in greater anti-tumor efficacy in patients with mesothelioma.

Objectives:

- To determine the objective response rate of sequential therapy with LMB-100 followed by
pembrolizumab in subjects with pleural and peritoneal mesothelioma.

Eligibility:

- Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma (with
<50% sarcomatoid component) not amenable to potentially curative surgical resection.

- Subjects must have at least one prior chemotherapy regimen that includes pemetrexed and
cisplatin or carboplatin.

- Age greater than or equal to 18 years.

- ECOG performance status of 0 or 1.

- Adequate organ and bone marrow function

- Prior PD1/PD-L1 inhibitor treatment is prohibited

- Chemotherapy within 4 weeks or radiotherapy within 2 weeks prior to start of study
therapy is prohibited.

- Subjects with active CNS metastasis are excluded

- Subjects with active autoimmune disease for which they had received systemic treatment
during the previous 2 years receiving systemic glucocorticoids (excluding daily
glucocorticoid-replacement therapy for conditions such as adrenal or pituitary
insufficiency) are excluded

- Subjects with active interstitial lung disease, or a history of pneumonitis for which
they had received glucocorticoids are excluded

Design:

- This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab
in subjects with advanced pleural or peritoneal mesothelioma who have progressed on
standard therapies.

- Subjects will receive LMB-100 at the single agent MTD on days 1, 3 and 5 of a 21-day
cycle for 2 cycles and pembrolizumab 200 mg on day1 of each subsequent 21-day cycle
until disease progression (on or after pembrolizumab) or intolerable toxicity for a
maximum of 2 years (unless second course initiated).

- Tumor biopsies will be performed at baseline, at the end of cycle 2 and at the end of
cycle 4 to evaluate changes in the tumor immune microenvironment following treatment
with LMB-100 and pembrolizumab.

- Up to 35 evaluable subjects will be enrolled

- 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, CCR, 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 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 ULN OR direct
bilirubin less than or equal to ULN for participants with total bilirubin levels
>1.5 X ULN

- Hepatic- AST and 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 (GFR can also be used in place of creatinine or 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 eGFR should be calculated per institutional
standard.

- 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 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-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory
T-cell receptor (e.g., CTLA-4, OX-40, CD137).

- 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 less than
or equal to Grade 1 or baseline. Participants with less than or equal to 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 1-week washout is permitted
for palliative radiation (less than or equal to 2 weeks of radiotherapy) to non-CNS
disease.

- Has had a prior pneumonectomy

- Has recovered from all 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.

- 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 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.