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

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.