Safety, Tolerability and Pharmacokinetics of an Anti-PD-1 Monoclonal Antibody in Subjects With Advanced Malignancies

Inclusion Criteria:

1. 1. Willing to sign Informed Consent;
2. 2. Part A, must have a histologically or cytologically documented, incurable, or metastatic solid tumor that has progressed on, or been intolerant to, all standard systemic therapy options for the tumor type in the metastatic setting, or must have a tumor type for which no such standard systemic option exists;

3. Part B, must have a histologically or cytologically documented diagnosis of esophageal or gastric carcinoma, nasopharyngeal carcinoma (NPC), hepatocellular carcinoma (HCC), both soft tissue sarcoma (excluding leiomyosarcoma), chondrosarcoma, or with agreement of the sponsor, or other tumors who have received at least one line of standard systemic therapy for their respective tumor type in the metastatic setting with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent. Patient with MSI-H/dMMR Tumors are eligible to enroll.

1. Subjects with NPC must have received, or been intolerant to, a platinum-based combination as part of their prior therapy for advanced/metastatic disease;
2. Subjects with soft tissue sarcoma and chondrosarcoma must have radiographic evidence of progression within the previous 6 months and must have received at least 1 line of systemic therapy;
3. Subjects with esophageal cancer must have received, or been intolerant to, a platinum-based combination as part of their prior therapy for advanced/metastatic disease;
4. Subjects with gastric cancer must have received, or been intolerant to, a fluoropyrimidine-platinum combination as part of their prior therapy for advanced/metastatic disease;
5. Subjects with HCC must have received (or been intolerant to) sorafenib as part of their prior therapy for advanced metastatic disease.
6. 4. Measurable disease per RECIST v1.1 and irRECIST;
7. 5. ECOG performance status of 0 or 1;
8. 6. Adequate organ and marrow function;
9. 7. Willingness to provide consent for biopsy samples;
10. 8. For females of childbearing potential, use effective contraception from time of screening though 90 days post last dose of Toripalimab.

Exclusion Criteria:

1. 1. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study;
2. 2. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic therapy for cancer treatment. Concurrent use of hormones for non-cancer related conditions is acceptable (e.g., insulin for diabetes & hormone replacement therapy). Local treatment of isolated lesions for palliative intent is acceptable;
3. 3. Receipt of any investigational anti-cancer therapy within 4 weeks prior to first dose of Toripalimab;
4. 4. Current use or prior use of immunosuppressive medication within 4 weeks prior to first dose of Toripalimab, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids not to exceed 10mg/day of prednisone or equivalent;
5. 5. Part A: Prior exposure to immunotherapy such as but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccines. Part B: Exclusion of prior immunotherapy exposure will be limited to anti-PD-1, anti-PD-L1, or anti-PD-L2;
6. 6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation;
7. 7. Major surgery within 4 weeks prior to first dose of Toripalimab or still recovering from prior surgery;

8. Unresolved toxicities from prior anticancer therapy defined as having not resolved to baseline or to Grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria with the exception of alopecia;



8. 9. Active or prior documented autoimmune disease within the past 2 years. Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment within the past 2 years are not excluded;
9. 10. Known history of tuberculosis;
10. 11. Known to be human immunodeficiency virus (HIV) positive, hepatitis B, or hepatitis C positive;
11. 12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis);
12. 13. History of primary immunodeficiency;
13. 14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure according to NYHA Functional Classification ≥3, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring adverse events from Toripalimab, or compromise the ability of the subject to give written informed consent;
14. 15. Symptomatic or untreated central nervous system metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging metastases, and are off steroids;
15. 16. Receipt of live attenuated vaccination within 30 days prior to study entry or within 4 weeks of receiving Toripalimab;
16. 17. Pregnancy or breastfeeding women.