Pembrolizumab and Radiation Therapy in Treating Patients With Intermediate or High-Grade Soft Tissue Sarcoma

PRIMARY OBJECTIVES:

I. To determine the rate of complete histopathologic necrosis following the combination of
pembrolizumab and neoadjuvant radiation.

SECONDARY OBJECTIVES:

I. To determine response based on Response Evaluation Criteria in Solid Tumors (RECIST)
criteria following the combination of radiation and pembrolizumab.

II. To confirm the tolerability and safety of the combination of neoadjuvant pembrolizumab
and radiation in a population with localized soft tissue sarcoma (STS) based on Common
Terminology Criteria for Adverse Events (CTCAE) version (v)4.03.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat
every 3 weeks for 3 months in the absence of disease progression or unacceptable toxicity.
Patients also undergo radiation therapy daily for 5-6 weeks.

After completion of study treatment, patients are followed up at 30 days and then every 12
weeks for up to 5 years.

Inclusion Criteria:

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

- Have measurable disease based on RECIST 1.1

- Has newly diagnosed disease (no prior chemotherapy or radiation for this sarcoma - may
have received for a different, older cancer) or localized recurrent or oligometastatic
lesions that are candidates for radiation; oligometastatic disease will be defined as
3 or fewer detectable lesions with plans to radiate all detectable disease with
conventionally fractionated radiation prior to resection

- Have an intermediate- or high-grade soft tissue sarcoma according to French Federation
of Cancer Centers (FNCLCC) criteria

- The tumor must be at least 3 cm in maximum dimension; smaller tumors are also allowed
if radiation has been determined by their treating physicians to be appropriate as
part of their standard of care; these cases must be approved by the principal
investigator (PI) prior to enrollment

- Plans to undergo neo-adjuvant radiation and surgery with curative intent

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion; if a freshly procured research specimen has already been made available
to the Pollack Lab prior to consent as part of another sample collection research
protocol, may be omitted with approval of the primary investigator so long as the
patient has not received anti-cancer therapy or immunosuppressive therapy since the
biopsy sample was collected

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale or > 70% on the Karnofsky scale

- Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 28 days of treatment
initiation)

- Platelets >= 100,000/mcL (performed within 28 days of treatment initiation)

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 28 days of treatment
initiation)

- 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]) >= 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN (performed within 28 days of treatment initiation)

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (performed within 28 days of treatment initiation)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN (performed within 28 days of treatment initiation)

- Albumin >= 2.5 mg/dL (performed within 28 days of treatment initiation)

- 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 (performed
within 28 days of treatment initiation)

- 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 (performed within 28 days of treatment initiation)

- 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

- All individuals must be willing to use an adequate method of contraception, for the
course of the study through 120 days after the last dose of study medication; Note:
Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject

- Male subjects of childbearing potential must 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; Note: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject

Exclusion Criteria:

- Prior radiation to affected area

- Has one of the following sarcoma subtypes where neoadjuvant chemotherapy is
established as practice at our institution: extra-skeletal Ewing's sarcoma, embryonal
rhabdomyosarcoma, alveolar rhabdomyosarcoma (pleomorphic rhabdomyosarcoma is allowed,
bone sarcomas including osteosarcoma, Ewings sarcoma and chondrosarcoma are not
allowed)

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment

- 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 a known history of active TB (Bacillus tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients

- Has had a prior, anti-cancer monoclonal antibody (mAb) 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 28 days 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 with principal investigator (PI) approval

- 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 or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has current or a history of any distant metastatic disease (including brain); an
isolated or oligo-metastatic regional recurrence may be allowed if all other criteria
are met, curative attempt is being pursued and if PI approval is granted

- 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Has an active infection requiring systemic therapy

- Has known psychiatric or substance abuse disorders that would interfere with adherence
to 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-CTLA4 or anti-PD-L2
agent

- Has a known history of human immunodeficiency virus (HIV) infection

- 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 of planned start of study therapy; Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not permitted