Pembrolizumab in Treating Patients With Malignant Mesothelioma

PRIMARY OBJECTIVES:

I. To determine the objective response rate of patients with malignant mesothelioma treated
with pembrolizumab in A) an unselected patient population, as well as B) in a programmed cell
death ligand 1 (PD-L1) positive population (should the trial proceed to Part B, and PD-L1
expression correlate with improved efficacy).

II. To determine the optimal threshold for PD-L1 expression using the 22C3 antibody based
immunohistochemistry (IHC) assay in correlation to tumor response.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival of patients with malignant mesothelioma in A)
an unselected patient population and B) a PD-L1 positive population when treated with
pembrolizumab.

II. To determine the overall survival of patients with malignant mesothelioma in A) an
unselected patient population and B) a PD-L1 positive population when treated with
pembrolizumab.

III. To determine the disease control rate (complete response [CR] + partial response [PR] +
stable disease [SD]) of patients with malignant mesothelioma who are treated with
pembrolizumab in A) an unselected patient population and B) a PD-L1 positive population.

IV. To determine toxicity in patients with malignant mesothelioma who are treated with
pembrolizumab.

V. To determine percentage of patients with mesothelioma who have PD-L1 tumor expression, and
the distribution of PD-L1 expression (percent positivity of tumor cells/stroma staining).

TERTIARY OBJECTIVES:

I. To characterize the T-cell inflamed phenotype in mesothelioma patients via presence of
cluster of differentiation (CD)8 tumor infiltrating lymphocytes (TILs) and/or use of a gene
expression signature (Nanostring).

II. To evaluate other immune escape mechanisms including indoleamine-pyrrole 2,3-dioxygenase
(IDO) expression, regulatory T cells (Tregs) (forkhead box P3 [FOXP3] expression),
myeloid-derived suppressor cells (MDSCs) and other checkpoints by immunohistochemistry (or
other methods e.g. flow cytometry).

III. To determine PD-L1 expression by mass spectrometry and correlate with tumor response,
PD-L1 expression by IHC, and the T-cell inflamed phenotype.

IV. To determine the immune cell populations present in fresh tumor (when available), via
tumor digests and mass spectrometry-based flow cytometric analysis (e.g. using CyTOF) in a
multiplex fashion in patients with fresh tumor tissue.

V. To characterize the T-cell receptor repertoire of TILs compared to circulating T-cells in
mesothelioma patients with available fresh frozen tissue (spectrotyping, T-cell repertoire
sequencing [e.g. using the Adaptive platform]).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for up to 24 months in the absence of disease progression or unacceptable
toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if
they progress after stopping pembrolizumab.

After completion of study treatment, patients are followed up for 30 days (up to 90 days for
serious adverse events), every 8 weeks until patient experiences confirmed disease
progression or starts a new anti-cancer therapy, and then every 12 weeks for 3 years.

Inclusion Criteria:

- Histologically or cytologically confirmed pleural or peritoneal malignant
mesothelioma, epithelial, sarcomatoid, or biphasic subtypes

- Disease progression on or after pemetrexed and cis- or carboplatin

- ONLY FOR PART B - PD-L1 selection should a PD-L1 expression threshold have been
defined in Part A and potentially additional mesothelioma trial data; there will be no
PD-L1/biomarker selection for Part A

- No more than 2 prior lines of cytotoxic therapy, which should have included pemetrexed
and a platinum

- Enrollment of treatment naïve patients who refuse standard chemotherapy or are
intolerant may be permissible if reviewed and deemed clinically appropriate by the
principal investigator (PI)

- Be willing and able to provide written informed consent for the trial

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 for peritoneal mesothelioma, and modified RECIST for pleural mesothelioma

- Have provided tissue from an archival tissue sample or newly obtained core or
excisional biopsy of a tumor lesion; while 20 unstained slides or a tumor block are
preferred, at least 14 unstained slides are requested for analysis; PI approval for a
lower number of slides is acceptable

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 50 mL/min for subject with creatinine
levels > 1.5 X institutional ULN; creatinine clearance should be calculated per
institutional standard

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants

- Female subjects of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication; if
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required

- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year

- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 2 weeks (4 weeks for monoclonal
antibodies) of the first dose of treatment

- Side effects from prior treatment have not resolved to =< grade 1 (or baseline due to
previously administered agent/pre-existing conditions)

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

- Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not
recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to a previously administered agent

- Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

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

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, in situ cervical cancer, or other indolent cancers which either have undergone
curative-intent therapy or inactive (i.e. not expected to limit life expectancy or
interfere with therapy)

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment

- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents; subjects with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule; subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; subjects with hypothyroidism stable on hormone replacement or
Sjorgen's syndrome will not be excluded from the study

- Has evidence of interstitial lung disease or active, non-infectious pneumonitis

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, 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

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways)

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Has received a live vaccine within 30 days prior to the first dose of trial treatment