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

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.