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

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.

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.

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

2. 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;

3. 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;

4. 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;

5. 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.