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

Advanced Malignancies Clinical Trial

Official title: A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAB001 in Subjects With Advanced Malignancies

Status Active, not recruiting

Clinical Trial Summary

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.

Clinical Trial Description

OVERVIEW: This is a Phase 1, multi-center, open-label, dose-escalation study of TAB001, a humanized monoclonal IgG4 antibody targeting the Programmed Death -1 (PD-1). It is estimated that up to 258 subjects with advanced malignancies will be enrolled in the study. Subjects must have an advanced solid malignancy that is refractory to standard therapy or for which no standard therapy exists.

The study has 2 parts. In Part A, up to 18 subjects will be enrolled who have not received prior immunotherapy for their cancer. Three dose levels are planned and include: 80, 240 and 480 mg/dose. Part A will be the traditional 3 + 3 design with 3 or 6 subjects per dose level (cohort) and will receive their assigned dose every 14 days in the absence of a dose limiting toxicity (DLT) that would prevent further dosing. Subjects will be assigned to a dose level in the order of study entry.

If no DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at the next higher dose level. If 1 of 3 subjects in a dose level experiences a DLT, that dose level will be expanded to 6 subjects. If only 1 of the 6 subjects has a DLT, then the next cohort of 3 subjects will be treated at the next higher dose level. If 2 or more DLTs occur within a cohort, then that dose level will be above the maximum tolerated dose (MTD), and the previous lower tolerated dose level will be considered the MTD.

In Part B, up to 240 subjects will be enrolled. Solid tumors may include, but will not be limited to, esophageal and gastric carcinoma, nasopharyngeal carcinoma, hepatocellular carcinoma sarcomas, both soft tissue sarcoma (excluding leiomyosarcoma) and chondrosarcoma, or with agreement of the sponsor, or other tumors that have received at least one line of therapy in the metastatic setting.

Tumor response will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

In the absence of confirmed disease progression and intolerable toxicities, subjects will be allowed to continue TAB001 administration every 14 days in Part A or every 21 days in Part B.

DOSAGE AND ADMINISTRATION TAB001 doses are 80, 240 and 480 mg in Part A and 240 mg in Part B. TAB001 will be administered as a 60-minute i.v. infusion for the first 2 doses and may be decreased at the investigators discretion to 30 minutes in subsequent infusions.

SAFETY EVALUATIONS Assessment of safety will be determined by vital sign measurements, clinical laboratory tests, Eastern Cooperative Oncology Group (ECOG) performance status evaluations, diagnostic imaging, physical examinations, electrocardiograms, and the incidence and severity of adverse events.

Safety will also include evaluations of immune safety and immunogenicity. Particular attention will be given to adverse events that may follow enhanced T-cell activation such as dermatitis and colitis, uveitis, or other immune-related adverse events (irAEs).

An irAE is a clinically significant adverse event of any organ that is associated with drug exposure, of unknown etiology, and is consistent with an immune-mediated mechanism.

EFFICACY EVALUATIONS will include overall response, disease control, duration of response, progression free survival, and overall survival.

PHARMACOKINETIC EVALUATIONS Pharmacokinetic parameters include AUC, Cmax, CL, Vd and t½z.

STATISTICAL METHODS The sample size for this study is not determined from power analysis. In Part A, it is based on the 3+3 design for dose escalation and safety evaluation requirements.

Descriptive statistics will include: mean, standard deviation, median, and minimum and maximum values for continuous variables; frequencies and percentages for categorical variables.

The efficacy parameters will be summarized using descriptive statistics. All safety and pharmacokinetic parameters will be summarized using descriptive statistics. ;

Related Conditions & MeSH terms

• Advanced Malignancies
• Neoplasms

• NCT number: NCT03474640
• Study type: Interventional
• Source: Shanghai Junshi Bioscience Co., Ltd.
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: March 14, 2018
• Completion date: August 2023