This is an open label Phase 1, First in Human trial of TST001, a recombinant humanized
anti-Claudin 18.2 (CLDN18.2) IgG1 monoclonal antibody. It is being tested against advanced
and/or metastatic solid tumors including gastric, gastroesophageal junction, pancreatic,
colon and NSCL cancers.
Part A of the trial will consist of two cohorts, one dosed every 2 weeks and one dosed every
3 weeks in a standard 3+3 design in 5 dose levels. The Q3W cohort will start when the Q2W
cohort has successfully completed the third dose level, at which time participants will be
assigned randomly into the cohorts, depending on which has an open slot when the patient
completes screening. Part A is the dose finding portion of the trial. A different dose may be
found for each of the two cohorts. 27 to 54 participants will be enrolled.
Part B of the trial consists of 3 cohorts of approximately 20 participants each. For Part B,
participants must have CLDN18.2 expressing tumors above (IHC) ≥ 2+ in ≥ 40% tumor cells to
qualify for participation. Cohort 1 is for participants with gastric and gastroesophageal
junction cancers and dosed every 2 weeks. Cohort 2 is for participants with any cancer except
gastric and gastroesophageal cancers, dosed every 2 weeks. Cohort 3 is for all cancers, but
dosed every 3 weeks. Participants will be randomly assigned 1:1 into Cohort 2 and 3. 60
participants will be enrolled.
The trial will last approximately 2 years, with assessments including safety labs, ECGs, MUGA
scans, PKs and PDs and CT/MRI tumor assessments, based on the Q2W and Q3W dosing schedules.
Inclusion Criteria:
- 1) Male or female ≥ 18 years. 2) Willing and able to provide signed and dated informed
consent prior to any study-related procedures and willing and able to comply with all
study procedures.
3) Patients with histologically or cytologically confirmed, locally advanced or
metastatic solid tumors.
4) Patients must be: a) progressed after standard therapies, b) intolerant of standard
therapies, or c) with a tumor type without standard therapy. d) Patients with HER2+
GC/GEJ cancer must have progressed after HER2-targeted therapy.
5) CLDN18.2 expression in tumor (Part B only): patients with locally advanced or
metastatic unresectable GC, GEJ cancer, or other solid tumor include but not limited
to pancreatic cancer, cholangiocarcinoma, ovarian cancer, and lung cancer. CLDN18.2
expression is determined by IHC assessed in central lab where expression 2+ membranous
staining in ≥40% of tumor cells.
6) Eastern Cooperative Oncology Group Performance Status (ECOG PS): Part A 0~1, Part B
0~2.
7) Life expectancy ≥ 3 months. 8) At least one measurable lesion per RECIST 1.1 (Part
B only). 9) Provide archived tumor tissue samples either formalin fixed paraffin
embedded block, OR at least 6 (Part A) or 10 (Part B) unstained slides.
10) Adequate hepatic function as evidenced by meeting all the following requirements:
- Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or
< 3.0 x ULN if liver metastases are present).
- Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 2.5 x ULN without
liver metastases (or ≤ 5 x ULN if liver metastases are present).
11) Estimated creatinine clearance (CrCL) ≥ 30 mL/min (Cockcroft-Gault Equation).
12) Adequate hematological function defined as:
- Absolute neutrophil count ≥ 1500/µL without growth factor support in the 2 weeks
prior to study entry.
- Hemoglobin ≥9 g/dL without transfusion in the 4 weeks prior to study entry.
- Platelet count ≥100,000/µL without transfusion in the 2 weeks prior to study
entry.
13) Coagulation tests, defined by the following:
- Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.
- International normalized ratio (INR) ≤2.0. Exception: INR >2 to ≤3 is acceptable
for patients on warfarin anticoagulation or direct oral anticoagulants without
active bleeding within 2 weeks prior to the first dose of the investigational
drug.
14) Recover to Grade 0-1 from adverse events related to prior anti-cancer therapy
except alopecia
Exclusion Criteria:
- 1) Symptomatic central nervous system metastases. Patients with asymptomatic CNS
metastases who are radiologically and neurologically stable for at least 4 weeks
following CNS-directed therapy, and who are on stable or decreasing doses of
corticosteroids equivalent to ≤10 mg/day are eligible for study entry.
2) Prior anticancer therapy:
1. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic
therapy, or targeted therapy) within 4 weeks prior to Cycle 1 Day 1, or
chemotherapy without delayed toxicity within the last 2 weeks preceding the first
dose of study treatment with ≤ grade 1 treatment related AEs.
2. Radiation therapy within 4 weeks prior to Cycle 1 Day 1; Liver-directed therapy
within 8 weeks prior to Cycle 1 Day 1, 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 Cycle 1 Day 1.
3. Prior treatment with an anti-CLDN18.2 antibody. 3) Major surgery within 8 weeks
prior to study entry; Minor surgery within 2 weeks prior to study entry.
4) Gastrointestinal abnormalities including:
1. Documented unresolved gastric outlet obstruction or persistent vomiting defined
as ≥3 episodes within 24 hours
2. Active peptic ulcer disease required treatment in the past 3 months
3. Gastrointestinal bleeding as evidenced by hematemesis, hematochezia, or melena in
the past 3 months without evidence of resolution documented by endoscopy or
colonoscopy
4. Documented active colitis within 4 weeks prior to study entry, including
infectious colitis, radiation colitis and ischemic colitis
5. History of ulcerative colitis or Crohn's disease 5) Allergy or sensitivity to
TST001 or known allergies to antibodies produced from Chinese hamster ovary
cells, which in the opinion of the investigator suggests an increased potential
for hypersensitivity to TST001.
6) History of a Grade 3-4 allergic reaction to treatment with another monoclonal
antibody.
7) Severe cardiovascular disease, including CVA, TIA, myocardial infarction, or
unstable angina, NYHA class III or IV heart failure or uncontrolled arrhythmia
within 6 months of study entry.
8) QTc ≥470ms at baseline; taking concomitant medications that would prolong the
QT interval; or with family history of long QT syndrome 9) Concurrent malignancy
within 5 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.
10) Prior stem cell, bone marrow or solid organ transplant. Exception: patients
who had a solid organ transplant > 5 years ago and are on no immunosuppressive
medications should be discussed with the Medical Monitor.
11) Active infection requiring intravenous therapy within 2 weeks prior to entry.
12) HIV infection with AIDS defining illness; Patients with a CD4+ T cell count >
350 cells/µL and no history of an AIDS-defining illness are eligible for entry.
13) Active viral (any etiology) hepatitis patients are excluded. Patients with
serologic evidence of chronic 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 Medical Monitor. Patients with a history of HCV
infection should have completed curative antiviral treatment and have a viral
load below the limit of quantification.
14) Women of childbearing potential, defines as all women physiologically capable
of becoming pregnant, unless they are using highly effective methods of
contraception (Appendix 3) during the intervention period and for 90 days after
the last dose of study intervention.
15) Men with a partner of childbearing potential who do not consent to use two
highly effective methods of birth control (Appendix 3) during treatment and for
an additional 90 days after the last administration of investigational drug. A
condom is required to be used by vasectomized men as well as during intercourse
with a male partner in order to prevent delivery of the drug via seminal fluid.
16) Any condition that the investigator or primary physician believes may not be
appropriate for participating the study.
