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Antibodies

Antibodies, Monoclonal

Immunomodulating Agents

Immunoglobulins

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)

Toripalimab

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

Shanghai Junshi Bioscience Co., Ltd.

Antineoplastic Agents

KX2-361

Protein Kinase Inhibitors

Enzyme Inhibitors

Tubulin Modulators

Antimitotic Agents

David Cutler, MD

The purpose of this study is to determine the safety and tolerability of the study drug KX2-361 and to determine how much of the study drug enters the bloodstream, in patients with advanced malignancies that have not responded to conventional therapies.

Safety, Tolerability & PK of KX2-361 in Subjects w Adv. Malignancies Refractory to Conventional Therapies

A Phase 1 Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KX2-361 in Subjects With Advanced Malignancies That Are Refractory to Conventional Therapies

The Maximum Tolerated Dose is defined as one dose level below where two or more subjects experienced a dose limiting toxicity (DLT).

Patient incidence of adverse events will be displayed by dose group and by system organ class. Adverse events will also be summarized by severity and relationship to the study drug. Laboratory parameters assessed will include vital signs, history and PE, assessment of toxicity, complete blood count w differentials and reticulocytes, serum chemistry (incl. RDB, LFT serum amylase and serum lipase), PT (or INR/PTT), urinalysis, and ECG assessment.

Plasma concentrations of KX2-361 will be analyzed to determine profile pharmacokinetic outcome measures, e.g. Cmax, Tmax, AUCt, AUC0-inf, t½, CL, and Css etc.

Activity response for the Dose Escalation Cohort portion of the study will be assessed by the investigator according to the RECIST criteria, CHESON criteria, or the Modified RANO criteria. The Expansion Cohort will utilize the Modified RANO criteria only for response measurements.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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 & PK of KX2-361 in Subjects w Adv. Malignancies Refractory to Conventional Therapies	NCT02326441	Advance Maligna...	KX2-361	18 Years -	Athenex, Inc.
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.

Spots Global Cancer Trial Database for advance malignancies