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

The primary objective is to assess the safety and tolerability of Toripalimab in subjects with various advanced malignancies and to evaluate the recommended Phase 2 dose.

The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of Toripalimab, 2) evaluate antitumor activity of Toripalimab; 3) determine the immunogenicity of Toripalimab; 4) evaluate overall survival.

The exploratory objectives are to: 1) evaluate biomarkers that may correlate with activity of Toripalimab, 2) evaluate pharmacodynamic effects of Toripalimab on its target receptor, programmed cell death 1 (PD-1), as well as effects on the immune system. 3) evaluate the utility of PD-L1 \& additional exploratory markers as biomarkers that could aid in selection of appropriate subjects for TAB001 therapy, and 4) identification of additional biomarkers correlating with response to treatment with TAB001.

OVERVIEW: This is a Phase 1, open-label, 2-part (Part A = dose-escalation, Part B = multiple disease-specific cohort expansion) study to evaluate the safety, tolerability, PK, immunogenicity, and antitumor activity of toripalimab administered intravenously (IV) every 2 weeks (Q2W) of each 28-day cycle in Part A or 240 mg IV every 3 weeks (Q3W) of each 42-day cycle in Part B in adults with advanced solid tumors with disease progression following standard therapy or for which no standard therapy existed.

Part A used a 3+3 design and enrolled cohorts of 3-6 patients sequentially at escalating doses of 80, 240 an 480 mg Q2W to determine the MTD or MFD and the RP2D; up to 18 patients could be enrolled in the dose-escalation phase. Once a dose-limiting toxicity (DLT) occurred among the first 3 patients, the dose cohort would be expanded to a total of 6 patients. Patients who did not complete the 28-day DLT evaluation period for reasons other than toxicity were to be replaced. Dose escalation was to continue to the highest planned dose level (480 mg) or until identification of the MTD or the MFD. In addition, any cohort that had not exceeded the MTD could be expanded up to a maximum of 10 patients for further evaluation of safety and efficacy. Part A enrollment was limited to immunotherapy-naïve patients (defined as no prior exposure to immunotherapy, including but not limited to, anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies; prior use of tumor vaccines was permitted).

In Part B, toripalimab administered at the RP2D, based on Part A, was to be evaluated for safety and antitumor activity. Enrollment was limited to patients who had not received a prior anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody. Up to 280 patients with specified solid tumors could be enrolled in the cohort expansion phase with a maximum of 40 patients to be enrolled in each disease-specific cohort with the exception of the sarcoma cohort, in which a maximum of 80 patients could be enrolled.

The tumor status of all patients was to be evaluated by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). In Part A, radiological assessment of tumor response status was to be performed approximately every 8 weeks (± 10 days) for the first 12 months and approximately every 12 weeks (± 10 days) thereafter, unless the investigator determined it was more appropriate to continue the radiological assessments approximately every 8 weeks. In Part B, radiological assessment of tumor response status was to be performed approximately every 9 weeks (± 10 days) for the first 12 months and approximately every 18 weeks (± 10 days) thereafter, unless the investigator determined it was more appropriate to continue the radiological assessments approximately every 9 weeks.

Patients received toripalimab Q2W (± 2 days) in Part A or Q3W (± 2 days) in Part B, until documentation of confirmed progressive disease (a repeat scan was to be conducted within 4 weeks ± 2 days in Part A and within 6 weeks ± 2 days in Part B to confirm disease progression per irRECIST), unacceptable toxicity, withdrawal of consent, intercurrent illness preventing further administration of toripalimab, or if the investigator considered it in the best interest of the patient to discontinue toripalimab. If feasible, all patients were to be followed for progression-free survival (PFS) and overall survival (OS) (Part B only) until the end of the study.

AEs and serious adverse events (SAEs) were to be captured from the start of the first dose of toripalimab through 90 days after the last dose of toripalimab unless a patient received another experimental or anticancer therapy, in which case only related AEs or SAEs were to be collected through 90 days after the last dose of toripalimab.

Serum samples and tumor tissues were collected for PK, pharmacodynamics, anti-drug antibody (ADA) and biomarkers determination during the study.

Eligibility Criteria:
Inclusion Criteria:

1. Willing to sign Informed Consent;
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.
4. Measurable disease per RECIST v1.1 and irRECIST;
5. ECOG performance status of 0 or 1;
6. Adequate organ and marrow function;
7. Willingness to provide consent for biopsy samples;
8. For females of childbearing potential, use effective contraception from time of screening though 90 days post last dose of Toripalimab.

Exclusion Criteria:

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. 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. Receipt of any investigational anti-cancer therapy within 4 weeks prior to first dose of Toripalimab;
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. 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. Prior allogeneic bone marrow transplantation or prior solid organ transplantation;
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;
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;
10. Known history of tuberculosis;
11. Known to be human immunodeficiency virus (HIV) positive, hepatitis B, or hepatitis C positive;
12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis);
13. History of primary immunodeficiency;
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;
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;
16. Receipt of live attenuated vaccination within 30 days prior to study entry or within 4 weeks of receiving Toripalimab;
17. Pregnancy or breastfeeding women.