Immunotherapy + Radiation in Resectable Soft Tissue Sarcoma

A single institution two cohort, open label, non-randomized study of neoadjuvant nivolumab
and ipilimumab with concurrent radiation followed by surgical resection.

Cohort A will comprise adult soft tissue sarcoma patents who consent to and receive
ipilimumab + nivolumab concurrently with standard of care radiation. Ipilimumab will be given
at a dose of 1 mg/kg every 6 weeks (total two doses) and nivolumab given as a flat dose of
240 mg every 2 weeks (total four doses).

Cohort B will comprise patients eligible for the trial who do not wish to receive
immunotherapy but consent to the same blood draws, surveys, and specimen analysis as Cohort
A. Cohort B will serve as a non-randomized but pragmatic and clinically relevant control
group.

Peripheral blood will be collected on day 1 pre-treatment, day 14, day 42, immediately prior
to surgery, and at 3 month follow up. Peripheral blood will be sent for multidimensional flow
analysis of changes in immune cell composition and markers of proliferation. Serum samples
will be obtained before starting treatment and after surgery. Samples from select subjects
whose resected tumors show significant response and whose tumors showed minimal response will
be sent to Serametrix for serum profiling to detect antibody response to a panel of
tumor-specific antigens.

Standard surgical resection will be done 2 to 4 weeks after completion of radiotherapy.
Accrual is expected to occur over 2 years. Follow up data will be collected for up to 3 years
post-treatment.

Inclusion Criteria:

- Diagnosed with biopsy-proven soft-tissue sarcoma with confirmatory pathology review at
University of Rochester Medical Center (URMC)

- 18 years or older.

- Able to provide informed consent.

- Resectable disease per surgical evaluation.

- Neoadjuvant/preoperative radiotherapy has been recommended

- Intermediate to high grade sarcoma on biopsy, tumor > 5 cm in size by imaging

- Willing to have blood draws for flow cytometry and Serametrix analysis.

- Willing to receive neoadjuvant radiation therapy and subsequent surgical resection.

- Patients with known human immunodeficiency virus (HIV) are eligible if the lymphocytes
> 350 CD4+ cells and no detectable viral load.

- Women of childbearing potential (defined as any woman, who 1) has not undergone tubal
ligation, a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 24 consecutive months or has had menses at any time in the
preceding 24 consecutive months):

- Must not be pregnant or nursing

- Must have a negative pregnancy test done within 7 days prior to registration as
well as within 72 hrs. prior to receiving first dose of study medication

- Women of childbearing potential must use at least two other accepted and
highly-effective methods of contraception and/or agree to abstain from sexual
intercourse for at least 5 months after the last dose of nivolumab and/or
ipilimumab.

- Should a woman become pregnant or suspect she is pregnant while she is
participating in this study, she should inform her treating physician
immediately.

- Sexually active males must use at least two other accepted and highly-effective
methods of contraception and/or agree to abstain from sexual intercourse for at least
7 months after the last dose of nivolumab and/or ipilimumab

- Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

Exclusion Criteria:

- Gastrointestinal stromal tumor, dermatofibrosarcoma protuberans, rhabdomyosarcoma,
Ewing's sarcoma, low-grade sarcomas, osteosarcoma subtypes

- History of radiation to the affected area

- Evidence of metastatic disease prior to treatment

- Any history of prior therapy with ipilimumab or nivolumab, or any agent targeting
PD-1, PD-L1 or CTLA-4.

- History of any the following:

- Active known or suspected autoimmune disease

- Active autoimmune colitis

- Autoimmune pan hypopituitarism

- Autoimmune adrenal insufficiency

- Known active hepatitis B or C

- Known active pulmonary disease with hypoxia defined as:

- Oxygen saturation < 85% on room air or

- Oxygen saturation < 88% despite supplemental oxygen

- No systemic treatment with either corticosteroids (> 10 mg daily prednisone
equivalents) or other immunosuppressive medications within 14 days of registration.

- Second active malignancy, not including localized basal cell skin cancer, squamous
cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the
breast; patients with a history of other malignancies are eligible if they have been
continuously disease-free for > 3 years prior to the time of registration.

- Absolute neutrophil count (ANC) <= 1,500/mm^3

- Platelet count <= 100,000/mm^3

- AST (Aspartate Aminotransferase) or ALT (Alanine Aminotransferase) => 2 x upper limit
of normal (ULN)

- Thyroid stimulating hormone (TSH) outside of normal limits; supplementation is
acceptable to achieve a TSH within normal limits; in patients with abnormal TSH if
free T4 is normal and patient is clinically euthyroid, patient is eligible.

- Life expectancy under 5 years.