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

Inclusion Criteria:

• 1. Able to understand and willing to sign the Informed Consent Form;
• 2. Male or female ≥ 18 years;
• 3. Subjects with histologically or cytologically confirmed advanced unresectable ormetastatic solid tumor, including lymphoma that have progressed following priortreatment. In Part A, subjects must have received, or be ineligible for or intolerantof all available approved or standard therapies known to confer clinical benefitincluding immunotherapy, or for whom no standard therapy exists; in Part B, subjectswith advanced or metastatic solid tumors, including but not limited to lymphoma,melanoma, NSCLC, or other tumors with agreement of the Sponsor, who must have receivedat least one line of therapy for advanced or metastatic disease, but are not requiredto have received all standard therapies known to confer clinical benefit; In Part C,subjects must have received at least one line of therapy for advanced or metastaticdisease but are not required to have received all standard therapies known to conferclinical benefit; In Part D, subjects with advanced or metastatic solid tumors thatmay include but not limited to lymphoma, melanoma, NSCLC, RCC or UC who must havereceived at least one line of therapy for advanced or metastatic disease, but are notrequired to have received all standard therapies known to confer clinical benefit.
• 4. Measurable disease per RECISTv1.1 and iRECIST, or RECIL 2017 for lymphoma
• 5. ECOG performance status of 0 or 1 with life expectancy of 3 months in the opinionof the investigator.
• 6. Adequate organ and marrow function, as defined below:

1. Hemoglobin 8.0 g/dL within first 2 weeks prior to first dose of TAB004 (are notrequiring a transfusion within 14 days prior to dosing)
2. Absolute neutrophil count (ANC) 1.0 x 109 /L (1,000 /mm3)
3. Absolute lymphocyte count ≥ 0.6 x 109/L (600/mm3)
4. Platelet count 75 x 109 /L (75,000 /mm3), and not requiring platelet transfusionswithin the 5 days prior to dosing
5. Total bilirubin ≤ 1.5 x ULN except subjects with documented Gilbert's syndromewho must have a baseline total bilirubin ≤ 3.0 mg/dL
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN;for subjects with hepatic metastases, ALT and AST ≤ 5 x ULN
7. Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance (CrCl) or 24 hoururine CrCl ≥ 40 mL/minute Cockcroft-Gault formula will be used to calculate CrCl. 24-hour urine CrCl will be derived using the measured creatinine clearanceformula
8. International normalized ratio (INR) ≤ 2.0 and activated partial thromboplastintime (aPTT) ≤ 1.5 x ULN; applies only to subjects who do not receive therapeuticanticoagulation; subjects receiving therapeutic anticoagulation (such aslow-molecular weight heparin or warfarin) should be on a stable dose

• 7. Willingness to provide consent for biopsy samples (In Part A, fresh pre-treatmentbiopsies will be requested from subjects with safely accessible lesions. For subjectswho cannot provide a fresh pre-treatment biopsy, request for the most recentaccessible archival specimen will be required. In Part B, C and D, fresh pre-treatmentbiopsies will be required from subjects with safely accessible lesions. The mostrecent archival specimens will also be requested).
• 8. Females of childbearing potential who are sexually active with a nonsterilized malepartner must use effective contraception from time of screening, and must agree tocontinue using such precautions for 90 days after the final dose of TAB004 ortoripalimab; cessation of birth control after this point should be discussed with aresponsible physician. Periodic abstinence, the rhythm method, and the withdrawalmethod are not acceptable methods of birth control.
• 9. Females of childbearing potential are defined as those who are not surgicallysterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or completehysterectomy) or postmenopausal (defined as at least 12 months with no mensesconfirmed by follicle-stimulating hormone [FSH] levels. FSH testing will be conductedat the Screening visit to confirm post-menopausal status).
• 10. Subjects must use effective contraception. Nonsterilized males who are sexuallyactive with a female partner of childbearing potential must use effectivecontraception from Day 1 and for 90 days after receipt of the final dose of TAB004 ortoripalimab.

Exclusion Criteria:

• 1. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.
• 2. Any concurrent anti-cancer therapy, such as but not limited to chemotherapy,targeted therapy, radiotherapy, immunotherapy, or biologic therapy. Radiationtreatment for palliative intent is allowed provided that lesions other than thosereceiving radiation are available to measure response. Concurrent use of hormones fornon-cancer-related conditions (e.g., insulin for type 2 diabetes and hormonereplacement therapy) is acceptable. Note: Local treatment of isolated lesions for palliative intent is acceptable (e.g., bylocal surgery or radiotherapy).
• 3. Receipt of any investigational anticancer therapy within 28 days prior to the firstdose of TAB004 or, provided documentable, 5 half lives whichever is shorter, exceptfor lymphoma in which the exclusionary period is 2 weeks for immune checkpointinhibitors only.
• 4. Current or prior use of immunosuppressive medication within 2 weeks prior to thefirst dose of TAB004, with the exception of intranasal and inhaled corticosteroids orsystemic corticosteroids not to exceed 10 mg/day of prednisone or equivalent.
• 5. Prior exposure to anti-BTLA, or anti-HVEM antibodies for subjects enrolled intoPart A and B only; prior treatment with anti-PD-1 or anti-PDL-1is allowed,includingtoripalimab for all subjects.
• 6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• 7. Subjects with another malignancy, or history or other malignancy within 3 yearsthat is not expected to relapse. Subjects with non-melanomatous skin cancer orcervical cancer that has been curatively surgically resected are eligible.
• 8. Major surgery (as defined by the investigator) within 28 days prior to first doseof TAB004 or has not recovered to at least Grade 1 from adverse effects from suchprocedure, or anticipation of the need for major surgery during study treatment.
• 9. Unresolved toxicities from prior anticancer therapy, defined as having not resolvedto baseline or to NCI-CTCAE v5.0 Grade 0 or 1, or to levels dictated in theinclusion/exclusion criteria with the exception of neuropathies that are stable orimproving and alopecia. Subjects with irreversible toxicity that is not reasonablyexpected to be exacerbated by TAB004 may be included (e.g., hearing loss) afterconsultation with the medical monitor.
• 10. Active or prior documented autoimmune disease, such as but not limited to systemiclupus erythematosus, multiple sclerosis, inflammatory bowel diseases, rheumatoidarthritis, autoimmune hepatitis, systemic sclerosis, autoimmune vasculitis, autoimmuneneuropathies or type 1 insulin-dependent diabetes mellitus. Note: Subjects with the following are not excluded: vitiligo; alopecia; Grave's disease notrequiring systemic treatment other than thyroid hormone replacement (within the past 2years) psoriasis not requiring systemic treatment; controlled celiac disease; subjects witha history of autoimmune hypothyroidism requiring only thyroid hormone replacement therapy;And type 2 diabetes, provided that it is adequately controlled.
• 11. Clinically significant (intracranial, gastrointestinal) bleeding within 2 weeksprior to screening.
• 12. Known history of tuberculosis.
• 13. Subjects with history of or current drug-induced interstitial lung disease orpneumonitis ≥ Grade 2.
• 14. Subjects who have discontinued prior immune therapy due to immune mediated adversereaction(s).
• 15. Subjects who are known to be human immunodeficiency virus positive.
• 16. Subjects with evidence of hepatitis B or C virus infection, unless their hepatitisis considered to have been cured. (Note that subjects with prior hepatitis B virusinfection must have HBV viral load < 100 IU/mL before study enrollment, and must betreated according to local standards; hepatitis C virus infection must have, beforestudy enrollment, no detectable viral load and must be treated according to localstandards).
• 17. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,ulcerative colitis). Infection-related bowel inflammation, such as Clostridiumdifficile colitis, is not excluded provided that it has been fully resolved for ≥ 6weeks.
• 18. History of anaphylaxis, or eczema that cannot be controlled with topicalcorticosteroids asthma.
• 19. Adult asthma that is moderate or severe, or asthma that has required:hospitalization in the last 2 years; invasive mechanical ventilation ever; systemiccorticosteroids in the past year for exacerbations; or more than two short acting betaagonist (e.g., albuterol) administrations per month for breakthrough asthma symptoms.A history of childhood asthma or the presence of mild adult asthma that at baselinehas symptoms that can be controlled well with inhaled corticosteroids or short actingbeta agonists will not be excluded.
• 20. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure according to New York HeartAssociation Functional Classification ≥ 3, uncontrolled hypertension, unstable anginapectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatricillness/social situations that would limit compliance with study requirements,substantially increase risk of incurring adverse events from TAB004, or compromise theability of the subject to give written informed consent.
• 21. Untreated central nervous system and leptomeningeal metastases or requiringongoing treatment for these metastases, including corticosteroids. Subjects withpreviously treated brain metastases may participate provided they are clinicallystable for at least 28 days prior to study entry, have no evidence of new or enlargingmetastases, and are off steroids.
• 22. Receipt of live attenuated vaccination within 28 days prior to study entry orwithin 30 days of receiving TAB004.
• 23. Any condition or treatment or diagnostic test that, in the opinion of theinvestigator or sponsor, would interfere with evaluation of TAB004 or interpretationof subject safety or study results.
• 24. Pregnancy or breast feeding women.