MC# 21-37

• At least 18 years of age at the time of signing the Informed Consent Form (ICF) prior to initiation of any study specific activities/procedures
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

Dose Escalation Cohort

• Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumors
• Subject who has tumor progression during or after prior therapy and for whom no standard therapy exists that would confer clinical benefit
• Subjects have evaluable disease per RECIST v1.1

Dose Expansion Cohort

• Histologically or cytologically confirmed diagnosis of locally advanced or metastatic HPV+ malignancies, including cervical cancers, P16+ Oropharyngeal cancers, anal cancers, vulvar, vaginal, penile, and squamous cell rectal cancers and other solid tumors (e.g. lung,
  esophagus) that are known HPV+
• HPV related malignancy that is not amenable to potentially curative resection and have received prior standard of care therapy(ies) unless the subject is not eligible to receive standard therapy
•  Prior documentation of tumor sample HPV status is acceptable for enrollment. For patients without documentation, HPV status will be determined by an HPV-specific test with fresh or archived tissue.
• At least 1 measurable lesion as outlined by RECIST v1.1
• Willing to provide newly obtained or archived tumor tissue samples either formalin fixed paraffin embedded block, OR at least 10 unstained slides. Newly obtained tumor tissue is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on
  Cycle 1, Day 1; subjects for whom newly obtained samples cannot be provided (e.g., inaccessible or subject safety concern) may submit an archived specimen (within 1 year) FFPE tissue blocks are preferred to slides.

Both Escalation and Expansion Cohorts

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Demonstrate adequate organ function as defined below.  All screening laboratories should be performed within 7 days of initiating TST005.
• Hematological
  • Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, without the use of hematopoietic growth factors 2 weeks prior to study entry
  • Platelets ≥ 100 × 10⁹/L, without transfusion in the 2 weeks prior to study entry
  • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion in the 2 weeks prior to study entry
• Renal
  • Creatinine ≤ 1.5 × the upper limit of normal (ULN) OR
  • Creatinine clearance (CrCl) using Cockcroft and Gault equation > 45 mL/min for subject with creatinine level > 1.5 × institutional ULN (Glomerular filtration rate (GFR) can also be used instead of creatinine)
• Hepatic
  • Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 × ULN.  For subjects with documented Gilbert's disease, total bilirubin ≤ 3.0 mg/dL is allowed.
    • Note: for subjects requiring stent placement for signs and symptoms of biliary obstruction, subjects may be allowed to enter the study if the total bilirubin is > 1.5 × ULN, but is trending down, following consultation with the Sponsor’s Medical Monitor (or designee)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
• Coagulation
  • International Normalized Ratio (INR) aPTT ≤ 1.5 × ULN
  • Activated Partial Thromboplastin Time (aPTT) INR ≤ 2.0
    • Exception: INR > 2 to ≤ 3 is acceptable for subjects on warfarin anticoagulation or direct oral anticoagulants without active bleeding within 2 weeks prior to the first dose of the investigational product
• Contraception
  • Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
  • Women of childbearing potential (WOCBP) must have negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to receiving the first administration of TST005
  • WOCBP and men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception from 30 days prior to the first TST005, for the duration of the treatment with TST005 plus 120 days post-treatment completion.  Contraception methods should be consistent with local regulations.  Refer to Appendix 4, Section 10.4 for details and definitions of WOCBP, postmenopausal females and contraception guidance.

Both Escalation and Expansion Cohorts

• Concurrent malignancy within 3 years prior to entry other than adequately treated cervical carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma, prostate cancer not requiring treatment (with or without resection), ductal carcinoma in situ of the breast, or ≤ T1 urothelial carcinoma
• Untreated or symptomatic central nervous system (CNS) metastases
  • Note: Subjects with asymptomatic treated CNS metastases are eligible provided they have been clinically stable and not requiring steroid for at least 4 weeks following CNS -directed therapy are eligible for study entry
• Any unresolved Grade 2 or greater toxicity from previous anticancer therapy except alopecia
• Active leptomeningeal disease
• Active autoimmune diseases or history of autoimmune diseases that may relapse, with the following exceptions:
  • Controlled type 1 diabetes
  • Hypothyroidism (provided it is managed with hormone-replacement therapy only)
  • Controlled celiac disease
  • Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia)
  • Any other disease that is not expected to recur in the absence of external triggering factors
• Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of investigational product, with the following exceptions:
  • Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
  • Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption
  • Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen)
• History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases, including but not limited to pulmonary fibrosis, active pneumonitis
• Severe cardiovascular disease, including cerebrovascular accident, transient ischemic attack, myocardial infarction, or unstable angina, New York Heart Association class III or IV heart failure or uncontrolled arrhythmia within 6 months of first dose
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy within 2 weeks of screening
• Clinically significant bleeding within three months of the first dose
• Uncontrolled hypertension, defined as systolic ≥150 mm Hg or diastolic ≥90 mm Hg maintained over time and despite antihypertensive treatment
• Patients with QTcF > 480 ms on screening ECG or with a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
• Pregnant or nursing
• Active viral (any etiology) hepatitis subjects are excluded. Subjects with serologic evidence of chronic hepatitis B virus (HBV) infection (defined by a positive hepatitis B surface antigen test and a positive anti-hepatitis core antigen antibody test) who have a viral load below the limit quantification (HBV DNA titer < 1000 cps/mL or 200 IU/mL) and are not currently on viral suppressive therapy may be eligible and should be discussed with the Sponsor’s Medical Monitor (or designee).  Note: subjects with a history of hepatitis C virus (HCV) infection should have completed curative antiviral treatment and have a viral load below the limit of quantification to be eligible to enroll into the study.
• Known human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
• A serious nonmalignant disease (e.g., psychiatric, substance abuse, uncontrolled intercurrent illness, etc.) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
• Any other condition that, in the opinion of the Investigator, would prohibit the subject from participating in the study
• Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose (i.e., with use of disease modifying agents, systemic corticosteroids or immunosuppressive drug)
  • Subjects with Type 1 diabetes mellitus (TD1M), hypothyroidism requiring only hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll
• A history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• < 4 weeks after any major procedures/surgery; clinically significant unhealed wound; any unhealed ulceration in GI prior to first dose of TST005
• History of severe immune-related adverse effects from checkpoint inhibitor (CPI) therapy (NCI CTCAE Grade 3 or 4) with the exception of endocrinopathy managed with replacement therapy or subjects who discontinued CPI therapy for CPI-associated toxicity or intolerability

Prior Therapy

• Dose Escalation phase: More than one prior checkpoint inhibitor therapies (approved or investigational) in the advanced setting.  One prior checkpoint inhibitor therapy is allowed; this can include but not limit to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody, or drugs specifically targeting T cell co-stimulation or checkpoint pathway.  Dose Expansion phase: Received any prior checkpoint inhibitor therapies (approved or investigational) in the advanced setting.  This can include but not limit to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody, or drugs specifically targeting T cell co-stimulation or checkpoint pathway.
• Prior treatment with any therapy target TGF-β or TGF-β receptors pathway
• Medications that are known to prolong the QT/QTcF interval including Class Ia and Class III antiarrhythmics at the time of informed consent.  Non-antiarrhythmic medications which may prolong the QT/QTcF interval are allowed provided the subject does not have additional risk factors for TdP (refer to Appendix 5, Section 10.5).
• Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, or targeted therapy) within 4 weeks or 5 half-lives (whichever is shorter) prior to first dose of TST005
• Any herbal medicine or Chinese patent medicines used to control cancer ≤ 2 weeks before the first dose of TST005
• Radiation therapy within 4 weeks prior to first dose of TST005; Liver-directed therapy within 8 weeks prior to first dose of TST005, including but not limited to stereotactic body radiotherapy (SBRT), transarterial chemoembolization (TACE), and radiofrequency ablation (RFA); palliative radiotherapy to a single area of metastasis (not a target lesion) within 2 weeks prior to first dose of TST005
• Received a live vaccine within 30 days prior to the first dose of TST005.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Prior stem cell, bone marrow or solid organ transplant.  Exception: subjects who had a solid organ transplant > 5 years ago and are on no immunosuppressive medications should be discussed with the Sponsor’s Medical Monitor (or designee)

Prior/Concurrent Clinical Study Experience

• Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of TST005
  • Note: Subjects participating in an observational study are an exception to this criterion and may qualify for the study with Sponsor approval

Other

• Allergy or sensitivity to antibodies produced from Chinese hamster ovary cells, which in the opinion of the Investigator suggests an increased potential for hypersensitivity to TST005
• History of a Grade 3/4 allergic reaction or infusion related reaction to treatment with another monoclonal antibody