Overview
The study is a first-in-human [FIH], open-label phase 1/2 study of TSN222 in subjects with advanced solid tumors or lymphomas. This study is comprised of a Phase 1 dose escalation and Phase 2 dose expansion component.
Description
Phase 1 Part:
Using the standard 3+3 design for dose escalation, the Phase 1 Part will evaluate the prespecified 6 sequential dose levels of 100 microgram (μg), 200 μg, 400 μg, 800 μg, 1600 μg, and 3200 μg of TSN222 as a single agent in subjects with advanced solid tumors or lymphomas.
The eligible subjects will receive TSN222 via i.t. injection on Days 1, 8 and 15 of every 28-day cycle until disease progression or unacceptable toxicity. The dose-limiting toxicity (DLT) observation period will be defined as the first 28 days after the first dose (i.e. the first cycle). Based on the standard "3+3" design, cohorts of 3 to 6 subjects each will be sequentially assigned to the predefined dose levels. Dose escalation will continue until up to the highest planned dose or the MTD or RP2D is determined.
Phase 2 Part:
Phase 2 part will evaluate the efficacy and safety of TSN222 as monotherapy at the preliminary RP2D(s) in 3 cohorts bellow:
Cohort 1: advanced squamous cell carcinoma of head and neck (HNSCC). Cohort 2: advanced melanoma. Cohort 3: advanced other types of solid tumors or lymphomas.
Eligibility
Inclusion Criteria:
Subjects must meet all the following inclusion criteria to be eligible for participation in
this study:
1. The subject fully understands the requirements of the study and voluntarily signs the
ICF.
2. At least 18 years of age at the time of informed consent.
3. Life expectancy of 3 months or more.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Willing to provide tumor tissues and accept tumor biopsies during study.
6. At least one measurable tumor lesion per RECIST v1.1 or Lugano 2014 response criteria
(only applicable for phase 2); note: the measurable lesions should be non-injected and
non-biopsied during study.
7. Subjects must meet the following criteria for each of the respective parts of the
study
Phase 1 part:
Has a pathologically documented unresectable locally advanced or metastatic solid tumor or
lymphoma that is refractory to or intolerable with standard treatment, or for which no
standard treatment is available.
Phase 2 part:
Cohort 1: Has pathologically confirmed diagnosis of unresectable locally advanced or
metastatic HNSCC that is considered incurable by local therapies, and is refractory to or
intolerable with at least one systemic treatment in the advanced setting.
Cohort 2: Has pathologically confirmed diagnosis of unresectable locally advanced or
metastatic melanoma that is refractory to or intolerable with at least prior two systemic
treatments in the advanced setting for BRAF mutant subjects, or at least one systemic
treatment in the advanced setting for BRAF non-mutant subjects.
Cohort 3: Has pathologically confirmed diagnosis of unresectable locally advanced or
metastatic other solid tumors or lymphomas that is refractory to or intolerable with at
least one systemic treatment in the advanced setting, or for which no standard treatment is
available.
9. Adequate bone marrow function: 10. Adequate renal function: estimated creatinine
clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula.
11. Adequate liver function: 12. Blood albumin ≥ 30g/L. 13. Adequate coagulation function:
14. Women of childbearing potential (WOCBP) and men must agree to follow instructions for
method(s) of contraception during the treatment period and for at least 6 months after the
last dose of TNS222. Contraception methods should be consistent with local regulations.
Refer to Appendix 6 for details and definitions of WOCBP, postmenopausal females and
contraception guidance.
Exclusion Criteria:
Subjects will be excluded if they meet any of the following criteria:
1. 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.
2. Prior history of active malignant disease other than that being treated in this study.
Exceptions: malignancies that were treated curatively and have not recurred within the
past 5 years (i.e., completely resected basal cell carcinoma and squamous cell
carcinoma of the skin; and completely resected carcinoma in situ of any type) (only
applicable to phase 2 part).
3. Any unresolved Grade 2 or higher toxicity from previous anticancer therapy except
alopecia and grade 2 peripheral neuropathy.
4. Prior systemic anti-cancer treatment (chemotherapy, biologic therapy, or targeted
therapy or herbal medicine) within 3 weeks or 5 half-lives (whichever is shorter)
prior to the first dose of study drug; or prior systemic anti-tumor immunotherapy
within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose of study
drug.
5. Radical radiation within 4 weeks prior to the first dose of study drug; palliative
radiotherapy to a non-target lesion within 2 weeks prior to the first dose of study
drug.
6. Has participated in a study of an investigational agent and received study therapy or
used an investigation device within 4 weeks prior to the first dose of study drug.
7. Major surgery within 4 weeks prior to first dose of study drug.
8. Severe infection within 4 weeks prior to the first dose of study drug, active
infection requiring oral or intravenous antibiotics within 2 weeks prior to the first
dose of study drug.
9. Active viral hepatitis.
10. History of human immunodeficiency virus (HIV) infection.
11. Known interstitial lung disease history, or current active pneumonitis, radiation
pneumonitis requiring hormonal therapy, or uncontrolled lung disease.
12. Symptomatic uncontrolled effusion in body cavities (e.g., pleural effusion, ascites
and pericardial effusion).
13. History of significant bleeding event (> 30ml) within 3 months before the first dosing
or hemoptysis (> 2.5 mL of bright red blood or at least 0.5 teaspoon per episode)
within 4 weeks before the first dosing；
14. Severe cardiovascular disease within 6 months of the first dose including
cerebrovascular accident, transient ischemic attack, myocardial infarction, or
unstable angina, New York Heart Association (NYHA) class III or IV heart failure or
uncontrolled arrhythmia.
15. Uncontrolled hypertension (systolic pressure >150mmHg or diastolic pressure > 90mmHg).
16. Has the average corrected QT interval by Fridericia's formula (QTcF) prolongation to >
480 millisecond (ms) based on 12-lead electrocardiograph (ECG) in triplicate, or with
a history of additional risk factors for torsade de pointes (e.g., heart failure,
hypokalemia, family history of long QT syndrome or unexplained sudden death under 40
years of age in first degree relatives).
17. Severe gastrointestinal disease, including but not limited to:
- Peptic ulcer disease in the past 3 months prior to the first dosing.
- Clinically significant gastrointestinal bleeding as evidenced by hematemesis,
hematochezia, or melena in the past 3 months prior to the first dosing without
evidence of resolution documented by endoscopy or colonoscopy.
- Active colitis requiring ongoing treatment within 4 weeks prior to the first
dosing, including infectious colitis, radiation colitis and ischemic colitis.
- History of ulcerative colitis or Crohn's disease.
18. Active autoimmune diseases or history of autoimmune diseases that may relapse, or
high-risk conditions (e.g., prior allogeneic hematopoietic stem cell transplantation
or organ transplantation that requires immunosuppression), with the following
exceptions: controlled type 1 diabetes, autoimmune hypothyroidism (provided it is
managed with hormone replacement therapy only).
19. 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:
- Topical, ocular, intra articular, intranasal, or inhalational corticosteroid with
minimal systemic absorption.
- Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for
contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g.,
delayed-type hypersensitivity reaction caused by contact allergen).
20. Receipt of any live vaccines within 4 weeks prior to first dose of study drug.
21. Females who are pregnant or nursing.
22. Has a history or current evidence of any severe condition, concurrent therapy, or
laboratory abnormality that might confound the interpretation of the study results,
interfere with the subject's participation for the full duration of the trial, or is
not in the best interest of the subject to participate, in the opinion of the
investigator.