Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Bronchogenic

Bronchial Neoplasms

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

The subjects of A group will use 3 mg/kg doses every 2 weeks.Drug batch number is 20161002.

The subjects of B group will use 3 mg/kg doses every 2 weeks.Drug batch number is 20161108.

To compare the different drug batch number with different process

Toripalimab

Jie Wang, MD, PhD

This study was designed to evaluate the similarity of single-dose and parallel comparisons of recombinant humanized anti-PD-1 monoclonal antibody injections before and after process changes. It is designed to be a single-center, open and parallel controlled phase I study. Patients with advanced NSCLC will be enrolled.

After determining that the patient is qualified, the patient will be assigned to a batch of drug use in the order in which they are selected. The dosage of drug was set at 3 mg / kg. Planned to recruit subjects each 12 patients (24 cases) to participate in this study, taking into account a 20% dropout rate, so that the total of 15 patients (30 patients) subjects in each group in this study.

This study was divided into study phase (single-dose period) and follow-up stage (multiple-dose period).Each subject first conducted a single dose safety and pharmacokinetics (PK) study.If the subject did not develop adverse events that had significant clinical significance as suggested by the investigators within 28 days of the single dose and continued reorganization of the humanized anti-PD-1 monoclonal antibody injection to benefit the patient , and with the agreement of subjects, the subject will enter the follow-up phase (multiple-dose period). The same dose of recombinant humanized anti-PD-1 monoclonal antibody injection was administered once every 2 weeks and 4 consecutive cycles of treatment for one cycle of continuous period.Until the patient has developed tumor progression or an untolerated toxic side effect, the patient voluntarily exits the study or believes that the situation is not suitable for continuing treatment. There are follow-up of 90 days after treatment.

The Pharmacokinetics and Safety of Single-dose and Parallel Comparisons in Patients With NSCLC Treated With JS001

A Similar Phase I Study on the Pharmacokinetics and Safety of Single-dose and Parallel Comparisons in Patients With Advanced NSCLC Treated With Recombinant Humanized Anti-PD-1 Monoclonal Antibody (JS001) Before and After Process Change

Objective Response Rate (ORR) by irRC and RECIST 1.1

Duration of response (DOR) by irRC and RECIST 1.1

Disease control rate (DCR) by irRC and RECIST 1.1

Progression Free Survival (PFS) by irRC and RECIST 1.1

Overall Survival (OS) by irRC and RECIST 1.1

Time to response (TTR) by irRC and RECIST 1.1

Shanghai Junshi Bioscience Co., Ltd.

Immunomodulating Agents

Immunoglobulins, Intravenous

Recombinant humanized, IgG4κ (immunoglobulin gamma 4, kappa) monoclonal antibody (mAb) that specifically binds to the T cell immunoreceptor with Ig and ITIM domains (TIGIT))

TAB006

a human IgG4k monoclonal antibody that specifically binds to the programmed death 1 (PD-1)

Sheng Yao, PhD

The primary objective is to assess the safety and tolerability of TAB006 as monotherapy and in combination with toripalimab in subjects with selected advanced solid malignancies, including lymphoma, and to evaluate the recommended Phase 2 dose.

The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of TAB006 monotherapy and in combination with toripalimab and to describe the PK profile of toripalimab when administered with TAB006, 2) evaluate antitumor activity of TAB006 monotherapy and in combination with toripalimab; and 3) determine the immunogenicity of TAB006 monotherapy and in combination with toripalimab and to determine the immunogenicity of toripalimab when administered with TAB006.

OVERVIEW This is a Phase 1, multi-center, open-label, dose-escalation study of TAB006 in combination with toripalimab. TAB006 is a recombinant humanized, IgG4κ (immunoglobulin gamma 4, kappa) monoclonal antibody (mAb) that specifically binds to the T cell immunoreceptor with Ig and ITIM domains (TIGIT). Toripalimab is a human IgG4κ mAb that specifically binds to the programmed death 1 (PD-1). It is estimated that up to 208 subjects with advanced solid malignancies, including lymphoma will be enrolled in the study.

Subjects must have a histologically or cytologically confirmed advanced solid tumor, including lymphoma.

The study has 3 parts; Part A dose-escalation, Part B cohort expansion, Indication dose expansion.

Dose-Escalation Phase:

Patients who have experienced disease progression will be sequentially enrolled into 5 proposed dose cohorts in Part A and Part B (e.g., Part A Cohort 1, Part A Cohort 2, Part B Cohort 1, Part A Cohort 3, Part B Cohort 2). In Parts A and B, TAB006 is administered as an intravenous infusion (IV) over 60 minutes on Day 1 of each 21-day cycle. In Part B, TAB006 is administered first, then toripalimab is administered IV over 60 minutes for the first dose. If tolerated, subsequent doses of TAB006 and toripalimab will be administered over a minimum of 30 minutes and no longer than 4 hours, if clinically indicated .

Part A is closed to enrollment. Enrollment will begin with Part B, starting at the TAB006 60 mg dose level.

The DLT evaluation period is defined as 21 days following the first dose and inclusive of any dose delays \> 14 days between initiation of the first and second cycle (i.e., if the second cycle is not initiated on day 22). A patient is considered to be "DLT evaluable" if they received both TAB006 and toripalimab and complete all evaluations in the DLT evaluation period or are withdrawn within 21 days due to an AE meeting the definition of a DLT.

If that patient does not experience a Grade 2 drug-related AE during the DLT evaluation period, enrollment in the next cohort will proceed. If that patient experiences a Grade 2 drug-related AE, that dose cohort and all subsequent cohorts will revert to a 3+3 design.

* If 0 of the first 3 patients in a dose cohort experience a DLT during the DLT evaluation period, dose escalation may proceed to the next higher dose cohort with approval of the safety monitoring committee (SMC).
* If 1 of the 3 patients in a dose cohort experiences a DLT during the DLT evaluation period, that dose cohort will be expanded to at least 6 patients.
* If no more than 1 of 6 patients in the dose cohort experiences a DLT, dose escalation may proceed to the next planned dose cohort with the approval of the SMC.
* If 2 or more patients in a dose cohort experience a DLT during the DLT evaluation period, the MTD will have been exceeded, and no further patients will be enrolled into that dose cohort or higher dose cohorts.

The protocol may be amended, based on the recommendation of the SMC, to enroll additional patients in a previously tested lower-dose cohort or to add an intermediate-dose cohort.

Patients will be treated until unacceptable toxicity, disease progression per RECIST v1.1 or 2014 Lugano for lymphoma, withdrawal of consent, removal of the patient from study based on investigator's judgment of unacceptable risks to the patient, study termination by the Sponsor, or the completion of a total of 35 cycles (approximately 105 weeks) of study drug treatment.

Treatment beyond RECIST-defined progression \[i.e., immune unconfirmed progression (iUPD) per iRECIST\] is permitted only if the patient provides consent per IRB policy and, in the judgment of the investigator, the patient is clinically stable, defined as:

* No signs or symptoms indicating clinically significant progression of disease;
* No decline in Eastern Cooperative Oncology Group (ECOG) performance status; and Absence of symptomatic rapid disease progression requiring urgent medical intervention (e.g., symptomatic pleural effusion, spinal cord compression).

Patients who are treated beyond RECIST-defined progression may continue treatment until evidence of immune confirmed progression (iCPD) per iRECIST, unacceptable toxicity, withdrawal of consent, removal of the patient from study based on investigator's judgment of unacceptable risks, study termination by the Sponsor, or the completion of a total of 35 cycles (approximately 105 weeks) of study drug treatment.

Dose expansion phase:

There will be 9-24 patients in dose expansion phase (9 to 12 patients each in 1-2 selected dose cohorts in Part B \[TAB006 followed by toripalimab 240 mg Q3W\] to further evaluate safety, PK and preliminary evidence of anti-tumor activity to support the selection of RP2D of TAB006 alone or in combination with toripalimab.

Indication-specific Expansion Phase Up to four primary cancers will be identified for further study in the indication-specific expansion phase. Each indication-specific cohort will enroll approximately 40 patients with disease progression after at least one prior line of standard treatment or for whom there is no standard treatment. All patients will receive TAB006 at the RP2D in combination with toripalimab 240 mg Q3W in 21-day cycles.

Tumor response will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), or the New Response Evaluation Criteria in Lymphoma (RECIL) 2017.

DOSAGE AND ADMINISTRATION TAB006 doses are 18mg, 60mg, 180mg, 600mg and 1800mg. Toripalimab dose is 240mg. TAB006 alone or TAB006 plus toripalimab will be administered as a 60-minute i.v. infusion for the first dose 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. EFFICACY EVALUATIONS will include best overall response, objective response rate, duration of response or duration of stable disease, progression free survival and overall response.

PHARMACOKINETIC EVALUATIONS : Non-compartmental analysis will be conducted using WinNonlin. PK parameters of TAB006 including, but not limited to Tmax, Cmax, AUC, Vss, CL, t1/2, Cmin, The Cmin of toripalimab will also be reported. Dose proportionality for TAB006 will be assessed.

STATISTICAL METHODS Part A and Part B are based on the 3+3 design for dose escalation and safety evaluation requirements. Indication Phase, sample size is estimated using Simon's two-phase design minimax method.

All PK/Pharmacodynamic, immunogenicity, and safety data will be summarized and presented by cohort as well as overall for the study, using descriptive statistics (number of subjects, mean, median, standard deviation, minimum, and maximum) for continuous variables and using frequencies and percentages for discrete variables.

For analysis of ORR and DCR, 90% confidence intervals (CI) will be calculated using the Clopper-Pearson method. If the number of patients is higher than ten, 90% CI will be calculated using the Kaplan-Meier method for analysis of DoR, TTR, PFS, and OS.

A Clinical Study of TAB006 in Patients With Previously Treated, Advanced Malignancies

A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TAB006, as Monotherapy and in Combination With Toripalimab, in Patients With Previously Treated, Advanced Malignancies

The endpoints for characterization of potentially predictive biomarkers include changes in PBMC immunophenotypes and whole exome sequencing (WES); additional exploratory markers in the peripheral blood; and CD155, PD-L1 and/or microsatellite instability expression in tumor tissues, where provided.

The endpoints for characterization of safety and tolerability will be characterized by all of the following: the incidence and severity of dose limiting toxicity (DLT); immune-related and other adverse events (AEs) and serious adverse events (SAEs) graded per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0; incidence and severity of laboratory abnormalities, to include electrocardiogram (ECG) results, and abnormal findings on physical examination.

The endpoints for characterization of immunogenicity include the number and percentage of patients who develop detectable anti-drug antibodies (ADA) to TAB006 or toripalimab and, among those with confirmed ADA, the number and percentage with neutralizing antibodies (nAb).

TopAlliance Biosciences, Inc.

CTI Clinical Trial and Consulting Services

Symptoms and General Pathology

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Recurrence

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

humanized anti-PD-1 monoclonal antibody is to be injected intravenously 1mg/kg Q2w until disease progresses or unacceptable tolerability occurs

humanized anti-PD-1 monoclonal antibody is to be injected intravenously 3mg/kg Q2w until disease progresses or unacceptable tolerability occurs

humanized anti-PD-1 monoclonal antibody is to be injected intravenously 10mg/kg Q2w until disease progresses or unacceptable tolerability occurs

Dose escalation study evaluating three dose levels (1, 3 and 10 mg/kg) of JS001. Subjects will be assigned to a dose schedule in the order of study entry.

Junyuan Qi, MD, PhD

The primary objective is to assess the safety and tolerability of JS-001 in subjects with recurrent malignant lymphoma, and to evaluate its preliminary efficacy.

The secondary objectives are to: 1) characterize the single-dose and multi-dose pharmacokinetic (PK) profile of JS-001, 2) characterize the immunogenicity of JS-001; 3) assess the dose-efficacy relationship of JS-001 single agent, and 4) preliminarily evaluate biomarkers associated with the efficacy of JS-001.

Safety, Tolerability, Pharmacokinetics & Pharmacodynamics of Toripalimab for Patients With Recurrent Malignant Lymphoma

A Phase I Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Injection in Patients With Recurrent Malignant Lymphoma

Digestive System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Stomach Neoplasms

Esophageal Neoplasms

Carcinoma, Hepatocellular

Sarcoma

Nasopharyngeal Carcinoma

Chondrosarcoma

Stomach Cancer

Esophageal Cancer

Soft Tissue Sarcoma

Antineoplastic Agents

Immune Checkpoint Inhibitors

Immunologic Factors

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.

Toripalimab, Recombinant Humanized anti-PD-1 Monoclonal Antibody

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, 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.

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

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

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

The treatment effect of Toripalimab will be assessed using RECIST 1.1 to determine objective response rate.

The treatment effect of Toripalimab will be assessed using RECIST 1.1 to determine disease control rate.

The treatment effect of Toripalimab will be assessed using RECIST 1.1 to determine progression-free survival time.

Iqvia Pty Ltd

Skin and Connective Tissue Diseases

Melanoma

Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection

TAB004

Richard Curry, MD

Ke Hu

Maya Khalil, M.D.

Megan Hodges

Sam Sneed

Jennifer Segar, MD

Elizabeth Seja

Deborah Wong, M.D.,Ph.D.

Mehir Tharani

Warren Chow, MD

Cara Fowler

Rahul Aggarwal, MD

Phu Lam

Emma Barton-Judson

Mehmet Asim Asim Bilen, M.D

Alyssa Pratt

Mohammed Milhem, MD

Margaret Carder

Jiang Yixing, M.D.

Xin Gao, M.D.

Paula Strussione

Anthony Shields, M.D., Ph.D.

Katlyn Kraft

Andrew Davis, MD

Angela Pinto-Harkin

Xinhua Zhu, MD, PhD

Barbara Kleiber

Claire Verschraegen, M.D.

Early Phase Screening and Enrollment

Russell Schilder, MD

Martha Cruz, RN, MPH, BSN

Farrukh T. Awan, M.D.

Aung Naing, MD

Darcy Stagman

Vincent Ma, MD

The primary objective is to assess the safety and tolerability of TAB004 as monotherapy and in combination with toripalimab in subjects with selected advanced solid malignancies, including lymphoma, and to evaluate the recommended Phase 2 dose.

The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of TAB004 monotherapy and in combination with toripalimab and to describe the PK profile of toripalimab when administered with TAB004, 2) evaluate antitumor activity of TAB004 monotherapy and in combination with toripalimab; and 3) determine the immunogenicity of TAB004 monotherapy and in combination with toripalimab and to determine the immunogenicity of toripalimab when administered with TAB004.

The exploratory objectives are to: 1) evaluate pharmacodynamic effects of TAB004 on its target receptor BTLA, as well as effects on the immune system; 2) evaluate biomarkers that may correlate with activity of TAB004 as monotherapy and in combination with toripalimab; 3) evaluate the utility of BTLA ligand, herpesvirus-entry mediator (HVEM), and additional exploratory biomarkers that could aid in selection of appropriate subjects for TAB004 monotherapy and in combination with toripalimab.

OVERVIEW: This is a Phase 1, multi-center, open-label, dose-escalation study of TAB004, a recombinant humanized IgG4κ monoclonal antibody specific to BTLA when administered alone and in combination with toripalimab, a human IgG4k monocloncal antibody that specifically binds to the programmed death 1 (PD-1). It is estimated that up to 499 subjects with selected advanced solid malignancies (i.e.; non-small cell lung cancer \[NSCLC\], melanoma, renal cell carcinoma (RCC), urothelial carcinoma (UC), or other tumors), including lymphoma will be enrolled in the study.

Subjects must have a histologically or cytologically confirmed advanced unresectable or metastatic solid tumor, including lymphoma.

The study has 4 parts; Part A dose-escalation, Part B cohort expansion, Part C dose-escalation and Part D cohort expansion. In Part A, up to 24 subjects will be enrolled who must have received, or be ineligible for, or intolerant of, all available approved or standard therapies know to confer clinical benefit including immunotherapy, or for whom no standard therapy exists.

In Part B, C and D, subjects must have received at least one line of therapy for advanced or metastatic disease, but are not required to have received all standard therapies known to confer clinical benefit.

Part A is the monotherapy dose-escalation portion of the study. Four TAB004 dose levels are planned and include: 0.3, 1, 3 and 10 mg/kg. Part A will be the traditional 3 + 3 design with 3 to 6 subjects per dose level (cohort) and will receive their assigned dose every 21 days in the absence of a dose limiting toxicity (DLT) that would prevent further dosing.

Part B is the monotherapy cohort expansion portion of the study and will consist of up to 50 subjects in each advanced solid tumor indication (up to 200 subjects) that may include but not be limited to lymphoma, melanoma, NSCLC, or other tumors with agreement of the Sponsor.

Part C is the combination therapy dose-escalation portion of the study. Four dose levels are planned as follows: Cohort 1 - TAB004 20 mg and toripalimab 240mg; Cohort 2 - TAB004 70 mg and toripalimab 240 mg; Cohort 3 -TAB004 200 mg and toripalimab 240 mg; Cohort 4- TAB004 500 mg and toripalimab 240 mg. Part C will be the traditional 3 + 3 design with 3 to 6 subjects per dose level (cohort) and will receive their assigned doses every 21 days in the absence of a DLT that would prevent further dosing.

Part D is the combination therapy cohort expansion portion of the study. Up to 50 subjects will be enrolled in each advanced solid tumor indication (melanoma, NSCLC, RCC, UC, lymphoma) (up to 250 subjects). Doses of TAB004 and toripalimab will be determined based upon safety and efficacy data from Part C.

Tumor response will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), or the New Response Evaluation Criteria in Lymphoma (RECIL) 2017.

In the absence of confirmed disease progression and intolerable toxicities, subjects will be allowed to continue TAB004 (Part A and B) or TAB004 and toripalimab (Part C and D) administration every 21 days for up to 2 years.

DOSAGE AND ADMINISTRATION TAB004 doses are 0.3, 1, 3, 10 mg/kg, 20mg, 70mg, 200mg and 500mg. Toripalimab dose is 240mg. TAB004 alone or TAB004 plus toripalimab will be administered as a 60-minute i.v. infusion for the first dose 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. Blockade of BTLA pathway and PD-1 pathway by monoclonal antibodies has been demonstrated in several syngeneic mouse models to enhance specific T cell responses and inhibit tumor growth. In studies of BTLA deficient mice, diseases such as asthma, autoimmune involvement of the central nervous system, and systemic lupus erythematosus were exacerbated. Particular attention will be given to symptoms related to those diseases. The occurrence of adverse events that may follow enhanced T-cell activation such as pneumonitis, colitis, nephritis, severe skin reactions, endocrinopathies, or other immune-related adverse events (irAEs) will be evaluated for subjects receiving TAB004 alone or in combination with toripalimab.

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 best overall response, objective response rate, duration of response or duration of stable disease, progression free survival and overall response.

PHARMACOKINETIC EVALUATIONS Pharmacokinetic parameters include AUC0-inf, AUC0-last, AUC0-21d, Cmax, Cmin trough, Tmax, t1/2, CL, accumulation and Vss.

STATISTICAL METHODS Part A and Part C are based on the 3+3 design for dose escalation and safety evaluation requirements. In Part B and Part D, sample size is estimated using Simon's two-phase design minimax method.

All PK/Pharmacodynamic, immunogenicity, and safety data will be summarized and presented by cohort as well as overall for the study, using descriptive statistics (number of subjects, mean, median, standard deviation, minimum, and maximum) for continuous variables and using frequencies and percentages for discrete variables.

ORR and the associated 2-sided 95% exact confidence limits will be calculated. The proportion of subjects who have experienced best response as CR, PR, SD, or progressive disease (PD) will be provided by cohorts in Part B and Part D.

Safety, Tolerability and Pharmacokinetics of a Monoclonal Antibody Specific to B-and T-Lymphocyte Attenuator (BTLA) as Monotherapy and in Combination With an Anti-PD1 Monoclonal Antibody for Injection in Subjects With Advanced Malignancies

A First-in-Human, Multicenter, Open-Label, Phase 1 Dose-Escalation and Cohort Expansion Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAB004 as Monotherapy and in Combination With Toripalimabin Subjects With Advanced Solid Malignancies Including Lymphoma

BTLA ligand expression with ORR, PD-L1 expression with ORR

BTLA ligand expression with DCR,PD-L1 expression with DCR

BTLA ligand expression with PFS, PD-L1 expression with PFS

BTLA ligand expression with OS, PD-L1 expression with OS

Treatment-related adverse events as assessed by CTCAE v4.0

volume of distribution of steady state (Vss)

TopAlliance Biosciences

The subjects of expanded cohort 1 will use repeated doses every 2 weeks like multiple dose cohorts

The subjects of expanded cohort 2 will use repeated doses every 2 weeks like multiple dose cohorts

Dose escalation study evaluating three dose levels (1, 3 and 10 mg/kg) of JS-001.Each of the 3 dose levels will use 2 dose schedules: single dose, and repeated doses every 2 weeks. Subjects will be assigned to a dose schedule in the order of study entry.

JS001

Yuankai Shi, PhD.MD

The primary objective is to assess the safety and tolerability of JS-001 in subjects with various advanced or recurrent malignancies, including solid tumors and lymphomas, and to evaluate its preliminary efficacy.

The secondary objectives are to: 1) characterize the single-dose and multi-dose pharmacokinetic (PK) profile of JS-001, 2) characterize the immunogenicity of JS-001; 3) assess the dose-efficacy relationship of JS-001 single agent, and 4) preliminarily evaluate biomarkers associated with the efficacy of JS-001.

The exploratory objectives include to evaluate the consistency between biomarker detection results of archived tissue and fresh frozen tissue, and to assess the consistency of response using various response criteria (such as irRC, WHO, RECIST and irRECIST).

OVERVIEW This is a Phase 1, open-label, dose-escalation study of JS-001, a humanized monoclonal IgG4 antibody targeting the Programmed Death -1 (PD-1). It is estimated that 18-36 subjects with advanced or recurrent solid tumors or lymphomas will be enrolled in the dose-escalation study.

A 3+3 design will be utilized for this Phase 1 study. Three dose levels are planned and include: 1, 3, 10 mg/kg/dose. Each of the 3 dose levels will use 2 dose schedules: single dose, and repeated doses every 2 weeks. Subjects will be assigned to a dose schedule in the order of study entry.

The study will be the traditional 3 + 3 design with 3 or 6 subjects treated at this dose level and at all subsequent dose levels depending upon the incidence of DLTs. 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 cohort experiences a DLT, that cohort 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 MTD (the highest dose where no more than 1 of 6 subjects has experienced a DLT), and the previous lower (tolerated) dose level will be considered the MTD.

A DLT is defined as a Grade 3 drug-related adverse event occurring within 28 days after previous dose (excluding tumor flare defined as local pain, irritation, or rash localized at sites of known or suspected tumor or a transient Grade 3 infusion adverse event) using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 in a single dose cohort.

Tumor response will be evaluated using immune-related response criteria (irRC), , Response Evaluation Criteria in Solid Tumors (RECIST 1.1), , and International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphomas (for lymphomas only).

In the absence of confirmed disease progression and intolerable toxicities, subjects in the single dose cohorts and multiple dose cohorts will be allowed to continue JS-001 administration with the consent of the subject.

If there is an effective case in a given dose level and the safety is good (There is no more than Grade 2 adverse event (not included Grade 2), 6-14 subjects with soft tissue sarcoma will be enrolled in the dose level as expanded cohort. The subjects of expanded cohort will use repeated doses every 2 weeks like multiple dose cohorts to further evaluate safety and efficacy of JS-001 with soft tissue sarcoma. At the same time, 9-12 subjects with hodgkin lymphoma will be enrolled in 3 mg/kg/dose level as expanded cohort. The subjects of expanded cohort will use repeated doses every 2 weeks like multiple dose cohorts to further evaluate safety and efficacy of JS-001 with hodgkin lymphoma.

DOSAGE AND ADMINISTRATION JS-001 will be administered as a 60-minute i.v. infusion. Cohorts will include escalating dose levels of 1, 3, 10mg/kg/dose.

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 The primary efficacy endpoint is the best response rate (RR). Duration of response, progression-free survival, time to progression, and overall survival will also be analyzed.

PHARMACOKINETIC EVALUATIONS Pharmacokinetic parameters include AUC, Cmax, tmax, and t½, etc. STATISTICAL METHODS The sample size for this study is not determined from power analysis. 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.

Safety, Tolerability, Pharmacokinetics & Pharmacodynamics of an Anti-PD-1 mAb for Patients With Advanced Solid Tumors

A Phase I Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Injection in Patients With Advanced Solid Tumors

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Pharmacokinetics and Safety of Single-dose and Parallel Comparisons in Patients With NSCLC Treated With JS001	NCT03301688	NSCLC	Toripalimab	18 Years - 70 Years	Shanghai Junshi Bioscience Co., Ltd.
A Clinical Study of TAB006 in Patients With Previously Treated, Advanced Malignancies	NCT05253105	Previously Trea... Malignancies	TAB006 Toripalimab	18 Years -	Shanghai Junshi Bioscience Co., Ltd.
Safety, Tolerability, Pharmacokinetics & Pharmacodynamics of Toripalimab for Patients With Recurrent Malignant Lymphoma	NCT03316144	Malignant Lymph...	Toripalimab	18 Years - 65 Years	Shanghai Junshi Bioscience Co., Ltd.
Safety, Tolerability and Pharmacokinetics of an Anti-PD-1 Monoclonal Antibody in Subjects With Advanced Malignancies	NCT03474640	Advanced Malign...	Toripalimab, Re...	18 Years -	Shanghai Junshi Bioscience Co., Ltd.
Safety, Tolerability and Pharmacokinetics of an Anti-PD-1 Monoclonal Antibody in Subjects With Advanced Malignancies	NCT03474640	Advanced Malign...	Toripalimab, Re...	18 Years -	Shanghai Junshi Bioscience Co., Ltd.
A Clinical Study of TAB006 in Patients With Previously Treated, Advanced Malignancies	NCT05253105	Previously Trea... Malignancies	TAB006 Toripalimab	18 Years -	Shanghai Junshi Bioscience Co., Ltd.
Safety, Tolerability, Pharmacokinetics & Pharmacodynamics of Toripalimab for Patients With Recurrent Malignant Lymphoma	NCT03316144	Malignant Lymph...	Toripalimab	18 Years - 65 Years	Shanghai Junshi Bioscience Co., Ltd.
Safety, Tolerability and Pharmacokinetics of a Monoclonal Antibody Specific to B-and T-Lymphocyte Attenuator (BTLA) as Monotherapy and in Combination With an Anti-PD1 Monoclonal Antibody for Injection in Subjects With Advanced Malignancies	NCT04137900	Advanced Unrese... Metastatic Soli...	TAB004 Toripalimab	18 Years -	TopAlliance Biosciences
Safety, Tolerability, Pharmacokinetics & Pharmacodynamics of an Anti-PD-1 mAb for Patients With Advanced Solid Tumors	NCT02836834	Lymphoma Lung Cancer	JS001	18 Years - 65 Years	Shanghai Junshi Bioscience Co., Ltd.

Spots Global Cancer Trial Database for phase 1 trial