Axitinib and Pembrolizumab in Subjects With Advanced Alveolar Soft Part Sarcoma and Other Soft Tissue Sarcomas

The study will be a single-institution, open-label, single-arm phase II study. Since the
primary endpoint is survival outcome, progression-free survival (PFS) sample size calculation
is based on a single-arm survival design. The investigators will employ early stopping rules
for lack of efficacy, based on previously reported historical controls (19% PFS at 3 months)
and a large database suggesting that a progression-free rate at 3 months of > 40% correlates
with an active drug in the second-line setting for patients with advanced sarcoma.

Patients will be treated with twice daily dosing of axitinib alone for the first 7 days,
followed by concurrent axitinib administered twice daily at 5 mg orally (PO), plus
intravenous administration of pembrolizumab every 21 days. Patients will be assessed every
three weeks for toxicity. After the first five patients are enrolled, the investigators will
assess safety of the combination. If 2 or fewer patients exhibit dose-limiting toxicity
(DLT), the investigators will then proceed with intrapatient titration of axitinib dosing at
each cycle based on the presence or absence of predefined toxicities.

Correlative studies characterizing T-cells in tumor tissue and in peripheral blood will be
performed at three timepoints: 1. pre-treatment, 2. on-treatment on cycle 3 day 1, and 3.
off-study. Additional exploratory imaging investigations, and assessment of circulating tumor
cells are included for all patients.

Trial therapy will last until withdrawal of consent, disease progression and/or unacceptable
toxicity, whichever occurs first.

Inclusion Criteria:

1. Patients must have histologically confirmed sarcoma with pathology review required for
any outside samples.

2. The following histologies may be enrolled without prior treatment:

- alveolar soft part sarcoma,

- clear cell sarcoma,

- epithelioid hemangioendothelioma, and

- chordoma.

3. The following histologies may be enrolled ONLY if refractory to anthracycline-based
chemotherapy or if the patient refuses to undergo standard of care treatment:

- synovial sarcoma,

- rhabdomyosarcoma,

- malignant peripheral nerve sheath tumors,

- dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,

- leiomyosarcoma,

- malignant phylloides tumor,

- high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH),

- angiosarcoma,

- spindle cell sarcoma, not otherwise specified (NOS)

- malignant myoepithelioma.

4. The following histologies may be enrolled ONLY if refractory to at least one line of
chemotherapy or if the patient refuses to undergo standard of care treatment:

- solitary fibrous tumor/hemangiopericytoma.

5. The following histologies may be enrolled ONLY if refractory to at least first-line
targeted therapy or if the patient refuses to undergo standard of care treatment:

- gastrointestinal stromal tumors,

- extraskeletal myxoid chondrosarcoma,

- PEComa.

6. Primary tumors of bone including Ewing's sarcoma, osteosarcoma, and dedifferentiated
chondrosarcoma may only be enrolled if there are measurable target lesions occurring
in soft tissue and they are refractory to standard of care anthracycline-based
chemotherapy.

7. Any other histology or standard of care therapy not specifically addressed will be
reviewed by the principal investigator and pathologist for final determination of
eligibility.

8. Measurable disease as defined by RECIST v1.1 (provided in Section 14.0).

9. Radiographic progression as defined by RECIST v1.1, based on comparison between two
radiographic studies no greater than 6 months apart.

10. Inability to undergo complete resection of the disease by surgery.

11. Adequate organ function as defined:

- Hematological

- Absolute neutrophil count (ANC) ≥1,000 / microliter (mcL)

- Platelets ≥75,000 / mcL

- Hemoglobin ≥8 g/dL without transfusion or erythropoietin (EPO) dependency
(within 7 days of assessment)

- Renal

- Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or
calculated creatinine clearance ≥ 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN. (GFR can also be used in place of
creatinine or CrCl). Creatinine clearance should be calculated per
institutional standard.

- Hepatic

- Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects
with total bilirubin levels > 1.5 ULN.

- Aspartate Aminotransferase (AST/SGOT) and Alanine Transaminase (ALT/SGPT) ≤
2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.

- Albumin >2.5 mg/dL

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤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.

- 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.

12. Age ≥ 16 years.

13. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

14. Patients must consent and be willing to undergo three core needle biopsies at
baseline, prior to starting Cycle 3, and at off-study. At least one tumor site must be
amenable to biopsy in the judgment of the interventional radiologist.

15. Female subject 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.

16. Females of child bearing potential that are sexually active must agree to either
practice 2 medically accepted highly effective methods of contraception at the same
time or abstain from heterosexual intercourse from the time of signing the informed
consent through 120 days after the last dose of study drug. See Appendix G for
protocol-approved highly effective methods of contraceptive combinations. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.

- Negative test for pregnancy is required of females of child-bearing potential; A
female of child bearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
1. has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months or 730 days).

- Conception while on treatment must be avoided

17. 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.
Prior history of vasectomy does NOT replace requirement for contraceptive use.

18. Suitable venous access to allow for all study related blood sampling

19. Ability to understand and willingness to sign a written informed consent document.

20. For minors that are 16 to 18 years of age, assent and parental (or legally acceptable
representative) written informed consent must be obtained.

Exclusion Criteria:

1. Prior therapy with axitinib. Patients are permitted to have received prior tyrosine
kinase inhibitor (TKI) therapy including imatinib, sunitinib, pazopanib, or similar.
Patients may have received prior Programmed death 1 (PD-1)/Programmed death-ligand 1
(PD-L1) directed therapy.

2. Hypersensitivity to axitinib, pembrolizumab or any of its excipients.

3. Patients may not be receiving any other investigational agents (within 4 weeks prior
to Cycle 1, day 1).

4. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, day 1 or
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.

5. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation
therapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1
or at baseline) from adverse events due to agents administered more than 4 weeks
earlier. 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.

6. Additional known 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.

7. Patients with end-organ dysfunction as defined in inclusion criterion (i.e. #11
above).

8. Patients with bone-only lesions.

9. Patients with underlying immune deficiency, chronic infections including HIV,
hepatitis, or tuberculosis (TB) or autoimmune disease.

10. Patients with underlying hematologic issues including bleeding diathesis, known
previous GI bleeding requiring intervention within the past 6 months, active pulmonary
emboli or deep vein thromboses (DVT) that are not stable on anticoagulation regimen.

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

12. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis or leptomeningeal disease. 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. This exception does not include carcinomatous meningitis which is excluded
regardless of clinical stability.

13. Concomitant (or receipt of) treatment with medications that may affect the metabolism
of pembrolizumab and/or axitinib within 7 days prior to Cycle 1, day 1 of axitinib.

14. 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 allowed.

15. 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.

16. Any uncontrolled, intercurrent illness including but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia

17. Prolonged corrected QT (QTc) interval on Screening EKG >475 ms.

18. Ejection Fraction <40% by 2D echocardiogram (ECHO) at Screening.

19. Any serious medical or psychiatric illness/condition including substance use disorders
likely in the judgment of the Investigator(s) to interfere or limit compliance with
study requirements/treatment.

20. 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.