Study of Anlotinib Hydrochloride and Toripalimab in Subjects With Unresectable or Metastatic Undifferentiated Pleomorphic Sarcoma

Inclusion Criteria:

1. Patients must have histologically confirmed Undifferentiated Pleomorphic Sarcoma withpathology review required for any outside samples. Only patients with untreated and rejected first-line standard chemotherapy withhigh-grade Undifferentiated Pleomorphic Sarcoma can be enrolled

2. Any other histology or standard of care therapy not specifically addressed will bereviewed by the principal investigator and pathologist for final determination ofeligibility.

3. Measurable disease as defined by RECIST v1.1

4. Radiographic progression as defined by RECIST v1.1, based on comparison between tworadiographic studies no greater than 3 months apart. or Inability to undergo completeresection of the disease by surgery.

5. Adequate organ function as defined: Hematological

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

7. Platelets ≥75,000 / mcL

8. 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 calculatedcreatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 Xinstitutional ULN. (GFR can also be used in place of creatinine or CrCl). Creatinineclearance should be calculated per institutional standard. Hepatic

9. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects withtotal bilirubin levels > 1.5 ULN.

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

11. Albumin >2.5 mg/dL Coagulation

12. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unlesssubject is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants.

13. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject isreceiving anticoagulant therapy as long as PT or PTT is within therapeutic rangeof intended use of anticoagulants.

14. Age ≥ 16 years.

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

16. Expected Survival Time: Over 3 months;

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

18. Female subject of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancy testwill be required.

19. Females of child bearing potential that are sexually active must agree to eitherpractice 2 medically accepted highly effective methods of contraception at the sametime or abstain from heterosexual intercourse from the time of signing the informedconsent through 120 days after the last dose of study drug. See Appendix G forprotocol-approved highly effective methods of contraceptive combinations. Subjects ofchildbearing potential are those who have not been surgically sterilized or have notbeen free from menses for > 1 year.

20. Negative test for pregnancy is required of females of child-bearing potential; Afemale of child bearing potential is any woman, regardless of sexual orientationor whether they have undergone tubal ligation, who meets the following criteria:

21. has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not beennaturally postmenopausal for at least 24 consecutive months (i.e., has had mensesat any time in the preceding 24 consecutive months or 730 days).

22. Conception while on treatment must be avoided

23. Male subjects should agree to use an adequate method of contraception starting withthe 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.

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

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

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

Exclusion Criteria:

1. Prior therapy with anlotinib. Patients who have received prior tyrosine kinaseinhibitor (TKI) therapy including imatinib, sunitinib, pazopanib, or similar. Patientswho have received immunotherapy including Programmed death 1 (PD-1)/Programmeddeath-ligand 1 (PD-L1) and CTLA-4.

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

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

4. If subject received palliative surgery, they must have recovered adequately from thetoxicity and/or complications from the intervention prior to starting therapy.

5. Additional known malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma of theskin that has undergone potentially curative therapy, or in situ cervical cancer.

6. Patients with end-organ dysfunction as defined in inclusion criterion (i.e. #6 above).

7. Patients with bone-only lesions.

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

9. Any major unhealed wound, ulcer, or fracture occurred in a patient who had undergonemajor surgery or trauma within 4 weeks and/or had any bleeding or bleeding episodeswhich the degree is bigger than CTCAE 3 grade within 4 weeks prior to enrollment.

10. Arteriovenous thrombosis events occurred within 6 months. Such as cerebrovascularaccidents (including transient ischemic attacks), deep vein thrombosis and pulmonaryembolism

11. History of steroid-related (non-infectious) pneumonia or current pneumonia.

12. Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis or leptomeningeal disease. Subjects with previously treated brainmetastases may participate provided they are stable (without evidence of progressionby imaging for at least four weeks prior to the first dose of trial treatment and anyneurologic symptoms have returned to baseline), have no evidence of new or enlargingbrain metastases, and are not using steroids for at least 7 days prior to trialtreatment. This exception does not include carcinomatous meningitis which is excludedregardless of clinical stability.

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

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 andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed.

15. Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 120 days after the last dose of trial treatment.

16. Any uncontrolled, intercurrent illness including but not limited to ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia

17. rolonged corrected QT (QTc) interval on Screening EKG >475 ms. Ejection Fraction <40%by 2D echocardiogram (ECHO) at Screening.

18. Any serious medical or psychiatric illness/condition including substance use disorderslikely in the judgment of the Investigator(s) to interfere or limit compliance withstudy requirements/treatment.

19. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment.