Study of Neoadjuvant Checkpoint Blockade in Patients With Surgically Resectable Undifferentiated Pleomorphic Sarcoma and Dedifferentiated Liposarcoma

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the flip of a coin) to 1 of 2 study groups depending on the location of your tumor. This
is done because no one knows if one study group is better, the same, or worse than the other
group. You will have an equal chance (50/50) of being assigned to either of the groups:

Retroperitoneal sarcoma:

- If you are in Group A, you will receive nivolumab.

- If you are in Group B, you will receive nivolumab and ipilimumab in combination 1 time,
and then you will only receive nivolumab.

Extremity/Trunk sarcoma:

- If you are in Group C, you will receive nivolumab along with your standard of care
radiation therapy.

- If you are in Group D, you will receive nivolumab and ipilimumab in combination 1 time,
then you will receive nivolumab along with your standard of care radiation therapy.

You will sign a separate consent form that describes radiation therapy and its risks.

You and the study staff will know to which group you have been assigned.

Study Drug Administration:

If you are in Group A, you will receive nivolumab by vein over about 1 hour on Days 1, 15,
and 29.

If you are in Group B, you will receive nivolumab by vein over about 1 hour and ipilimumab by
vein over about 90 minutes on Day 1. Then, you will receive nivolumab by vein over about 1
hour on Days 15 and 29.

If you are in Group C, you will receive nivolumab by vein over about 1 hour on Days 1, 15,
29, and 43. You will have radiation therapy 1 time each day, 5 days a week (Monday through
Friday) from Day 15 to Day 47.

If you are in Group D, you will receive nivolumab by vein over about 1 hour and ipilimumab by
vein over about 90 minutes on Day 1. Then, you will receive nivolumab by vein over about 1
hour on Days 15, 29, and 43. You will have radiation therapy 1 time each day, 5 days a week
(Monday through Friday) from Day 15 to Day 47.

If treatment needs to be delayed more than 2 weeks because of safety reasons, the next
dose(s) can be skipped and you can have any standard of care surgery as planned.

Length of Treatment:

You may continue receiving the study drug(s) until you receive your surgery. You will no
longer be able to take the study drug(s) if the disease gets worse, if intolerable side
effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Study Visits:

Groups A and B Before Standard of Care Surgery:

On Days 1, 15, and 29:

- You will have a physical exam.

- Blood (about 3 ½ tablespoons) will be drawn for routine tests.

- On Day 1 only, if you can become pregnant, blood (about ½ teaspoon) or urine will be
collected for a pregnancy test.

- On Day 15 only, blood (about 3 tablespoons) will be drawn for biomarker and immune
system testing.

- On Day 15 only, you will have a tumor biopsy for biomarker testing.

On Day 43:

- You will have an EKG.

- You will have a physical exam.

- Blood (about 6 ½ tablespoons) will be drawn to check how well your blood clots and for
routine and immune system testing.

- You will have an MRI or CT scan to check the status of the disease.

- If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for
pregnancy test.

Groups C and D Before Standard of Care Surgery:

On Days 1, 15, 29, and 43:

- You will have a physical exam.

- Blood (about 3 ½ tablespoons) will be drawn for routine tests.

- On Day 1 only, if you can become pregnant, blood (about ½ teaspoon) or urine will be
collected for a pregnancy test.

- On Day 15 only, blood (about 3 tablespoons) will be drawn for biomarker and immune
system testing.

- On Day 15 only, you will have a tumor biopsy for biomarker testing.

On Day 71:

- You will have an EKG.

- You will have a physical exam.

- Blood (about 6 ½ tablespoons) will be drawn to check how well your blood clots and for
routine and immune system testing.

- You will have an MRI or CT scan to check the status of the disease.

- If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
pregnancy test.

Standard of Care Surgery:

If the doctor thinks the disease can still be removed through surgery, you will have standard
of care surgery within 2 weeks after Day 43 (Groups A and B) or within 2 weeks after Day 71
(Groups C and D). You will sign a separate surgery consent form that describes the procedure
and its risks. You will have a tumor biopsy at the time of surgery to collect tissue to test
for any remaining sarcoma cells and to check the status of the disease.

If the disease is no longer able to be treated with surgery, you will be taken off study.
Your doctor will discuss other treatment options with you.

Follow-Up Visits:

About 6 weeks after your surgery:

- You will have a physical exam.

- Blood (about 3 ½ tablespoons) will be drawn for routine, immune system, and biomarker
testing.

- You will have an MRI or CT scan to check the status of the disease.

About 18 weeks after surgery and then every 12 weeks for up to 102 weeks (about 2 years):

- You will have a physical exam.

- Blood (about 6 tablespoons) will be drawn for routine and immune system testing. At 54
weeks after your surgery, this blood will also be used for biomarker testing.

- You will have an MRI or CT scan to check the status of the disease.

Long-Term Follow-Up:

A member of the study staff will contact you every 3 months for up to 2 years after surgery
to ask how you are doing, how the disease may be responding to any therapy you may be taking
part in, and about any anti-cancer therapy you receive.

If you need to stop taking part in this study early, the study staff will contact you to see
how you are doing every 3 months until you start a new treatment for sarcoma.

This follow-up contact may be done at regularly scheduled visits, if you continue treatment
at MD Anderson. If not, you will be contacted by phone, email, or letter. If you are
contacted by phone, each call should last about 5 minutes.

Inclusion Criteria:

1. Adult subjects (>18 years) with treatment naïve primary or locally recurrent DDLPS of
the retroperitoneum or UPS of the trunk or extremity will be eligible for inclusion in
this study only if all of the following criteria apply:

2. Patients must be capable of giving written informed consent, which includes compliance
with the requirements and restrictions listed in the consent form.

3. Patients must have disease determined to be surgically resectable and candidates for
upfront surgery as agreed upon by a multidisciplinary consensus (Surgical Oncology,
Medical Oncology, Radiation Oncology) after presentation at sarcoma multidisciplinary
conference. Resectable tumors are defined as having no significant vascular, neural or
bony involvement. Only cases where a complete surgical resection can safely be
achieved are defined as resectable.

4. Patients will be evaluated by the anesthesia team prior to surgery

5. Patient must have recent imaging (CT or MRI, as appropriate) within 4 weeks of trial
enrollment, demonstrating measurable disease as defined by RECIST 1.1

6. Patients must have at least one tumor amenable to serial biopsy in clinic or be
willing to undergo serial biopsies through image-guided procedures during the
neoadjuvant phase of the protocol. Patients must be willing to provide tumor samples
at the time points

7. Patients must be medically fit to undergo surgery as determined by the treating
medical and surgical oncology team and have ECOG performance status 0-2

8. Patients must have life expectancy > 6 months.

9. Patients must be immunotherapy-naïve. Those who have previously been treated with
conventional chemotherapy for a prior history of sarcoma in the adjuvant setting may
be included.

10. Patients must have organ and marrow function as defined below: White blood cell count
> 3K/uL, Absolute neutrophil count (ANC) > 1 K/uL, Hemoglobin > 9 g/dL, Platelets >
100 K/mm3, Serum creatinine 50 mL/min, Aspartic
transaminase (AST) ≤ 1.5 x upper limit of normal (ULN), Alanine transaminase (ALT) 1.5 x ULN, Bilirubin ≤ 1.5 x ULN

11. Women are eligible to participate if: Non-childbearing potential defined as
pre-menopausal females with a documented tubal ligation or hysterectomy; or
postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a
blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and
estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement
therapy (HRT) and whose menopausal status is in doubt will be required to use one of
the contraception methods if they wish to continue their HRT during the study.
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status
prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse
between the cessation of therapy and the blood draw; this interval depends on the type
and dosage of HRT. Following confirmation of their post-menopausal status, they can
resume use of HRT during the study without use of a contraceptive method.

12. Childbearing potential and agrees to use method(s) of contraception. For a teratogenic
study drug and/or when there is insufficient information to assess teratogenicity
(preclinical studies have not been done), a highly effective method(s) of
contraception (failure rate of less than 1% per year) is required. The individual
methods of contraception and duration should be determined in consultation with the
investigator. Women of childbearing potential (WOCBP) must follow instructions for
birth control when the half-life of the investigational drug is greater than 24 hours,
contraception should be continued for a period of 30 days plus the time required for
the investigational drug to undergo five half-lives. WOCBP should use an adequate
method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab
to undergo five half-lives) after the last dose of investigational drug.

13. CONTINUATION OF #10: WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of
investigational product.

14. Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. The investigator shall review contraception
methods and the time period that contraception must be followed. Men who are sexually
active with WOCBP must follow instructions for birth control when the half-life of the
investigational drug is greater than 24 hours, contraception should be continued for a
period of 90 days plus the time required for the investigational drug to undergo five
half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days,
respectively. Therefore, men who are sexually active with WOCBP must continue
contraception for 7 months (90 days plus the time required for nivolumab to undergo
five half-lives) after the last dose of investigational drug.

15. Women who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile) and azoospermic men do not require contraception.

16. Women must not be breastfeeding

17. Other terms for undifferentiated pleomorphic sarcoma (UPS) may include, but are not
limited to: pleomorphic undifferentiated sarcoma, unclassified spindle cell sarcoma,
spindle cell sarcoma not otherwise specified, pleomorphic spindle cell sarcoma,
pleomorphic fibroblastic sarcoma, undifferentiated high-grade pleomorphic sarcoma,
pleomorphic sarcoma with prominent inflammation, pleomorphic sarcoma with giant cells,
malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory
subtypes), fibrosarcoma, and myxofibrosarcoma (at least intermediate grade; located
deep to the fascia in muscle)

Exclusion Criteria:

1. Disease that is considered surgically unresectable, including, but not limited to
significant vascular, neural, or bone involvement, and in cases where a complete
surgical resection cannot be safely performed.

2. Prior intraabdominal surgery within 4 weeks of trial enrollment.

3. Prior chemotherapy or targeted small molecule therapy of the current sarcoma. In
patients with locally recurrent disease, previous systemic chemotherapy of the primary
tumor is allowed, as long as treatment was completed prior to study enrollment and
patient has recovered (i.e., < Grade 1 or at baseline) from any adverse events due to
previously administered agents.

4. Prior radiation therapy for sarcoma in the same area

5. Active concurrent second malignancy

6. Prior or concurrent immunotherapy, including treatment with an anti-PD-1, anti-PD-L1,
anti-PD-L2, or anti-CTLA-4 antibody; tumor vaccines; interferon, or interleukins.

7. Prior malignancy active within the previous 2 years except for patient's prior
diagnosis of sarcoma and locally curable cancers that have been apparently cured, such
as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in
situ of the prostate, cervix, or breast with local control measures (surgery,
radiation).

8. Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks
of trial enrollment

9. Pregnant or lactating female

10. Unwillingness or inability to follow the procedures required in the protocol

11. Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at
therapeutic levels

12. Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results.

13. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.

14. Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease. Brief dosing for contrast allergy prophylaxis is allowed.

15. Any positive test result for hepatitis B or C virus indicating acute or chronic
infection

16. Known history of testing positive for human immunodeficiency virus or known acquired
immunodeficiency syndrome

17. History of severe hypersensitivity reaction to any monoclonal antibody

18. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (infection disease) illness

19. Prisoners or subjects who are involuntarily incarcerated