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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Advanced Malignancies

Intervention / Treatment
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* Biological: Toripalimab, Recombinant Humanized anti-PD-1 Monoclonal Antibody


Participation Criteria
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Eligibility Criteria
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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. Subjects with NPC must have received, or been intolerant to, a platinum-based combination as part of their prior therapy for advanced/metastatic disease; 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; 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; 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; 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Toripalimab 80 mg repeat dose every 14 days<br>3-6 subjects (Part A) | Biological: Toripalimab, Recombinant Humanized anti-PD-1 Monoclonal Antibody<br>* Toripalimab is a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, which selectively interferes with the combination of PD-1 with its ligands, PD-L1 and PD-L2, resulting in the activation of lymphocytes and elimination of malignancy theoretically.<br>* Other names: TAB001, JS001;|
| Experimental: Toripalimab 240 mg repeat dose every 14 days<br>3-6 subjects (Part A) | Biological: Toripalimab, Recombinant Humanized anti-PD-1 Monoclonal Antibody<br>* Toripalimab is a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, which selectively interferes with the combination of PD-1 with its ligands, PD-L1 and PD-L2, resulting in the activation of lymphocytes and elimination of malignancy theoretically.<br>* Other names: TAB001, JS001;|
| Experimental: Toripalimab 480 mg repeat dose every 14 days<br>3-6 subjects (Part A) | Biological: Toripalimab, Recombinant Humanized anti-PD-1 Monoclonal Antibody<br>* Toripalimab is a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, which selectively interferes with the combination of PD-1 with its ligands, PD-L1 and PD-L2, resulting in the activation of lymphocytes and elimination of malignancy theoretically.<br>* Other names: TAB001, JS001;|
| Experimental: Toripalimab 240 mg repeat dose every 21 days<br>240 subjects (Part B) | Biological: Toripalimab, Recombinant Humanized anti-PD-1 Monoclonal Antibody<br>* Toripalimab is a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, which selectively interferes with the combination of PD-1 with its ligands, PD-L1 and PD-L2, resulting in the activation of lymphocytes and elimination of malignancy theoretically.<br>* Other names: TAB001, JS001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Through Day 90 of last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The treatment effect of Toripalimab will be assessed using RECIST 1.1 to determine objective response rate. | Every 8 weeks (Part A) or every 9 weeks (Part B) through study completion, an average of 1 year | 
| Disease Control Rate (DCR) | The treatment effect of Toripalimab will be assessed using RECIST 1.1 to determine disease control rate. | Every 8 weeks (Part A) or every 9 weeks (Part B) through study completion, an average of 1 year | 
| Progression-Free survival (PFS) | The treatment effect of Toripalimab will be assessed using RECIST 1.1 to determine progression-free survival time. | Every 8 weeks (Part A) or every 9 weeks (Part B) through study completion, an average of 1 year | 
| Overall survival (OS) |  | Through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, check point inhibitor, PD-1 antibody, solid tumor, esophageal carcinoma, gastric carcinoma, nasopharyngeal carcinoma, hepatocellular carcinoma, soft tissue sarcoma, chondrosarcoma, orphan tumors, phase 1 trial