Evaluation of T320, an Anti-Tissue Factor Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors

An Open-label, Multi-center Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Preliminary Efficacy of T320, an Anti-Tissue Factor Antibody-Drug Conjugate, in Patients With Advanced Solid Tumor

This is a first-in-human, non-randomized, open-label, multi-center, phase I study in patients with advanced solid tumor to evaluate the safety and tolerability, PK, immunogenicity, and preliminary anti-tumour activity of T320. This study consists of a dose escalation module and a backfill module. The trial process for each subject in both escalation and backfill module includes a screening period (28 days before the first T320 administration), a treatment period (from the first T320 administration to the end of reatment), a safety follow-up period (28 days after EOT/early withdrawal) and a progression follow-up period (every 12 weeks from safety follow-up visit). Patients will receive T320 administration once every 2 weeks (Q2W) and 28 days are set as one treatment cycle.

Inclusion Criteria:

• Voluntary to participate in the clinical study, sign a written informed consent form, and able to comply with clinical visits and study-related procedures.
• Age ≥18 years old upon signing the informed consent form.
• Have histologically and/or cytologically confirmed unresectable advanced solid tumour who are refractory to or intolerant of available standard-of-care therapy or have no effective standard treatment available.

Escalation module: preferred tumour types include cervix, ovary, endometrium, pancreatic, bladder, prostate, esophageal cancer, HNSCC, triple-negative breast cancer (TNBC), cholangiocarcinoma, and NSCLC. Backfill module: patients with cervix cancer, pancreatic cancer, HNSCC, NSCLC, ovarian and endometrial cancer.

• ECOG performance score of 0 ~ 2.
• Life expectancy ≥ 3 months.
• At least one measurable lesion per RECIST v1.1.
• Adequate organ function defined as following: a) Hematological status: neutrophil count (ANC) ≥ 1.5×109/L, platelet count (PLT) ≥ 90×109/L, and hemoglobin (HGB) > 9.0 g/dL (no blood transfusion or hematopoietic stimulating factor therapy within 14 days before the evaluation). b) Coagulation function: international normalized ratio (INR) ≤1.2 (without anticoagulant therapy) and activated partial prothrombin time (APTT) ≤1.25×ULN. c) Liver function: total bilirubin (TBIL) ≤ 1.5×ULN or ≤ 3×ULN in case of Gilbert's syndrome; alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5×ULN, if there is liver metastasis, ALT and AST ≤ 5×ULN. d) Renal function: creatinine clearance (Cockcroft-Gault) ≥ 60 mL/min. e) Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%; QTcF≤470 ms by Fridericia formula.
• Eligible patients with fertility (male and female) must agree to use reliable contraceptive methods with their partners during the trial period and at least 3 months after the last IP administration; female patients of childbearing age must have a negative serum pregnancy test within 7 days before the first investigational drug administration.
• Availability of tumour tissue sample (either an archival specimen or a fresh biopsy material) at screening.

Exclusion Criteria:

• Any anti-cancer therapy including chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment.

• Known past or current coagulation defects leading to an increased risk of bleeding or any known bleeding diathesis.

• History of Steven's Johnson's syndrome or Toxic Epidermal Necrolysis syndrome.

• Known to be allergic to T320 for injection or any of its excipients, or patients with allergic constitution.

• Known or suspected severe allergy/hypersensitivity (resulting in treatment discontinuation) to monoclonal antibodies.

• Known history of non-infectious pneumonitis (NIP)/interstitial lung disease (ILD) requiring systemic steroids, active NIP/ILD, or other severe lung disease.

• Presence of grade ≥ 2 peripheral neuropathy.

• Ongoing acute or chronic inflammatory skin disease.

• Presence of ocular surface disease (i.e., confluent superficial keratitis, cornea epithelial defect, corneal ulcer, stromal opacity, etc) or history of conjunctivitis.

• Presence of acute bacterial, viral or fungal infections.

• Untreated, unstable or uncontrolled central nervous system (CNS) metastases, except for: a) No evidence of cerebral edema and no systemic steroids or anticonvulsants requirement at screening and follow-up MRI scan performed within 28 days prior to the first dose of the IMP showing no progression of treated lesion(s) and no new lesion(s) appearing. b) Untreated asymptomatic brain metastasis and no need of local/systematic therapy currently.

• Any prior therapy with a conjugated or unconjugated auristatin derivative.

• Patient requiring concurrent treatment of strong inhibitors or inducers of cytochrome P450 3A4 (Table 3) within 2 weeks prior to the first dose and during the study treatment.

• Have previously received allogeneic hematopoietic stem cell transplantation or solid organ transplantation, or plan to receive allogeneic hematopoietic stem cell transplantation or solid organ transplantation during the study period.

• History of or currently central nervous system (CNS) lymphoma or other central nervous system diseases.

• Known to have any active infection of human immunodeficiency virus (HIV),hepatitis B virus (HBV) or hepatitis C virus (HCV). However, patients with the following conditions can be included in this study: a) Human immunodeficiency virus antibody (HIV-Ab) is negative, or HIVAb is positive but nucleic acid test shows an undetectable viral load (viral suppression is defined as having less than 200 copies of HIV per milliliter of blood) i.e., well-controlled HIV patients can be enrolled. b) Hepatitis B surface antigen (HBsAg) is negative; if HBsAg or HBcAb is positive, HBV-DNA (HBV deoxyribonucleic acid) < 1000 cps/mL. c) Hepatitis C virus antibody (HCV-Ab) is negative.

• Toxicity except for alopecia and fatigue caused by previous anti-tumour therapy has not been alleviated to grade 1 or below (CTCAE v5.0).

• History of other malignant tumor within 2 years before enrollment, except for skin basal cell carcinoma, skin squamous cell carcinoma, and carcinoma in situ that have undergone possible curative treatment and have not recurred within 5 years after the start of treatment.

• Have received any other investigational drug product within 28 days or 5 halflives of the previous investigational drug (if required) before screening.

• Have used live attenuated vaccines within 4 weeks before the first administration of dexamethasone or are expected to use live attenuated vaccines during the study period.

• Have used systemic immunosuppressive drugs within 4 weeks before the first administration, including but not limited to radiotherapy immunoconjugates, antibody-drug conjugates, immune/cytokines, monoclonal antibodies, etc. Except for continuous corticosteroids at a dose of <10 mg prednisone/day or equivalent.

• History of autoimmune diseases, including but not limited to myocarditis, pneumonia, myasthenia gravis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Wegener's granulomatosis, multiple sclerosis, vasculitis or glomerulonephritis.

• Have undergone major organ surgery (excluding needle biopsy) or had significant trauma within 4 weeks before the first administration of IP, or need to undergo elective surgery during the trial period.

• Have serious unhealable wound/ulcer/fracture within 4 weeks before the first administration of investigational drug.

• History of serious cardiovascular and cerebrovascular diseases, including but not limited to:1) Serious heart rhythm or conduction abnormalities, such as ventricular arrhythmia that requires clinical intervention, degree II-III atrioventricular block, etc. 2) Thromboembolic events requiring therapeutic anticoagulation, or subjects with venous filters. 3) Patients with Class III~IV cardiac insufficiency according to the New York Heart Association (NYHA) criteria. 4) Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other grade 3 and above cardiovascular and cerebrovascular events within 6 months before the first administration.

  5) Clinically uncontrollable hypertension (blood pressure cannot be controlled at systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg after standard antihypertensive treatment). 6) Any factors that increase the risk of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, or use of any concomitant drug that are known to or may prolong the QT interval.

• Substance use disorder that may interfere with the participant's involvement in the study or evaluation of the study result, as determined by the investigator.

• Patient with mental disorders that would affect participation in the trial or poor compliance.

• Women who are pregnant or breastfeeding.

• Patient who cannot tolerate venous blood sampling.

• The investigator believes that the subject has a history of other serious systemic diseases or is not suitable for participating in this clinical study for other reasons.