SAINT:Trabectedin, Ipilimumab and Nivolumab as First Line Treatment for Advanced Soft Tissue Sarcoma

I. Dose Escalation Phase 1 of Study: The study will employ the standard "Cohort of Three"
design (Storer, 1989). Three patients are treated at each dose level with expansion to six
patients per cohort if DLT is observed in one of the three initially-enrolled patients at
each dose level. If no DLT occurs after 2 doses, escalation to the next dose level will be
permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, where
not more than one patient experienced DLT, with the next higher dose level having at least
two patients who experienced DLT. Patients in the dose escalation study may continue
treatment at their designated dose levels until disease progression or unacceptable toxicity
occurs or up to 9 six-week cycles (one year) of therapy (up 18 TRABECTEDIN doses). No
intra-patient dose escalation will take place.

Dose of IPILIMUMAB: 1 mg/kg IV over 30 min. q 12 weeks, beginning 2 weeks after first dose of
TRABECTEDIN, until disease progression or unacceptable toxicity, up to 5 doses

Dose of NIVOLUMAB: 3 mg/kg over 30 min. q 2 weeks, beginning 2 weeks after first dose of
TRABECTEDIN, until disease progression or unacceptable toxicity, up to 26 doses

Dose of TRABECTEDIN: Escalating doses of TRABECTEDIN IV as continuous intravenous infusion
(CIV) over 24 hrs) q 3 weeks:

Dose Level I: 1 mg/m2 (n = 3-6); Dose Level II: 1.2 mg/m2 (n=3-6); Dose Level III: 1.5 mg.m2
(n=3-6)

II. Expansion Phase 2 of Study: Following dose escalation, an additional 22-28 previously
untreated patients will receive TRABECTEDIN at the MTD and defined doses of IPILIMUMAB and
NIVOLUMAB to assess overall safety and potential efficacy in a greater number of patients.
Patients in the expansion phase of the study may continue treatment until significant disease
progression (see criteria for discontinuation of therapy) or unacceptable toxicity occurs up
to 9 six-week cycles (one year) of therapy.

Surgical Resection: After one or more treatment cycles, the principal investigator may
recommend surgical debulking, complete surgical removal or a biopsy. If residual disease is
present either by histopathological examination or by CT scan/MRI, repeat treatment cycles
may be given 4 weeks after surgery, if the surgical incision has healed, and if the patient
has < grade I toxicity.

Resected or biopsied tumors will be analyzed for the effects of this triple therapy on
response, and immune cell trafficking in the tumor microenvironment. Fresh and paraffin
embedded tissue blocks will be analyzed by FACS for PD-L1 and other biomarkers, including
Tregs, CD8+, CD4+ cells etc. Immunohistochemistry for cyclin G1, cyclin D1 and Ki67 will be
conducted to determine the tumor's proliferative state. Histopathologic examination for tumor
necrosis and mitotic index will also be determined.

Inclusion Criteria:

- Individuals must meet all of the inclusion criteria in order to be eligible to
participate in the study, as follows:

- Male or Female ≥ 18 years of age

- Pathologically confirmed diagnosis of locally advanced unresectable or metastatic
soft tissue sarcoma

- For the Phase 1 Part of Study, only previously treated patients will be enrolled.
For the Phase 2 Part of Study, previously untreated patients will be enrolled.

- Ability to understand the purposes and risks of the study and has signed and
dated a written informed consent form approved by the investigator's IRB/Ethics
Committee

- Willingness to comply with all study procedures and availability for the duration
of the study.

- Measurable disease by RECIST v1.1

- ECOG performance status ≤1

- Life expectancy of at least 3 months

- Acceptable liver function: Bilirubin ≤ 1.5 times upper limit of normal (ULN;
except subjects with Gilbert Syndrome who must have a total bilirubin level ≤ 3.0
ULN);AST (SGOT), ALT (SGPT) and alkaline phosphatase ≤ 3 x ULN (≤ 5 x ULN if
liver metastases)

- Acceptable renal function: Creatinine ≤1.5 times ULN or ≥ 60 mL/min (using the
Cockcroft Gault formula)

- Acceptable hematologic status (without hematologic support): WBC ≥2000/µL; ANC ≥
1500 cells/μL; Platelet count ≥ 100,000/μL; Hemoglobin ≥ 9.0 g/dL; Normal PT,
PTT, INR

- All women of childbearing potential must have a negative pregnancy test and all
subjects must agree to use highly effective means of contraception (surgical
sterilization or the use of barrier contraception with either a condom or
diaphragm in conjunction with spermicidal gel or an IUD) with their partner from
entry into the study through 5 months for women and 7 months for men after the
last dose.

Exclusion Criteria:

- All individuals meeting any of the exclusion criteria at baseline will be excluded
from study participation, as follows:

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody,
or any other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathways

- Subjects with untreated CNS metastases. Subjects are eligible if CNS metastases
have been adequately treated and have neurologically returned to baseline (except
for residual signs or symptoms related to the CNS treatment) for at least 2 weeks
prior to treatment initiation. In addition, subjects must be either off
corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or
equivalent) for at least 2 weeks prior to treatment initiation.

- Subjects with carcinomatous meningitis

- Anticancer treatment with radiation therapy, chemotherapy, targeted therapy or
other antitumor treatment within 2 weeks prior to study entry

- Subjects who participated in an investigational drug or device study within 14
days prior to study entry

- Females who are pregnant or breast-feeding

- Unwillingness or inability to comply with the study protocol for any reason

- Concurrent or prior immunotherapy with anti-CTLA4 or anti-PD-1 inhibitors

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

- Autoimmune disease including rheumatoid arthritis, systemic progressive sclerosis
(scleroderma), systemic lupus erythematosus, autoimmune vasculitis and motor
neuropathy considered to be of autoimmune origin (e.g. Guillain-Barre Syndrome)

- Systemic immunosuppression, including HIV positive status with or without AIDS

- Skin rash (psoriasis, eczema) affecting ≥ 25% body surface area

- Inflammatory bowel disease (Crohn's or ulcerative colitis)

- Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment

- Recent history of acute diverticulitis, intraabdominal abscess or
gastrointestinal obstruction within 6 months of trial enrollment, which are known
risk factors for bowel perforation

- Patients with congestive heart failure or recent cardiac event

- Evidence of severe or uncontrolled systemic disease or any other concurrent
condition, including psychiatric, which in the principal investigator's opinion
makes it undesirable for the patient to participate in the trial or which would
jeopardize compliance with the trial

- Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

- Inadequate hematologic, renal or hepatic function defined by any of the following
screening laboratory values: WBC ≤2000/µL; Neutrophils ≤1500/µL; Platelets ≤
100,000/µL; hemoglobin ≤9.0 g/dL; Serum creatinine ≥1.5 x ULN or creatinine
clearance ≤ 60 mL/min (using the Cockcroft Gault formula); AST/ALT ≥3 x ULN (≥ 5
x ULN if liver metastases); Total Bilirubin ≥1.5 x ULN (except subjects with
Gilbert Syndrome who must have a total bilirubin level ≥ 3.0 ULN)

- Current, active or previous history of heavy alcohol abuse

- Pituitary endocrinopathy

- Adrenal insufficiency or excess