A Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TST001 in Advanced or Metastatic Solid Tumors
Study Details
Study Description
Brief Summary
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 but not limited to gastric cancer/gastroesophageal junction adenocarcinoma, pancreas cancer, gallbladder carcinoma, bile duct carcinoma, lung cancer and ovarian carcinoma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
There are two parts in the study. Part I is mono-therapy dose escalation and dose expansion study, and Part II is dose escalation and dose expansion study of combination therapy.
Part I: Mono-therapy dose escalation and dose expansion study:
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Mono-therapy dose escalation regimen: The dose escalation study will be conducted using 3+3 dose escalation method at two dosing regimens, i.e."once every 2 weeks (Q2W)"and"once every 3 weeks (Q3W)".
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Mono-therapy dose expansion regimen: When the dose level in Q2W group in the mono-therapy dose escalation study is escalated to the MTD/MAD/RP2D, two expansion cohorts will be added at this dose level with about 30 (20-40) subjects with positive CLDN18.2 expression.
Group A: TST001 RP2 DG/GEJ adenocarcinoma with positive CLDN18.2 expression 20-40 Group B:
TST001 RP2D Non-G/GEJ adenocarcinoma with positive CLDN18.2 expression 20-40
Part II: Dose escalation and dose expansion study of combination medication
The dose escalation and dose expansion study will be conducted in the following two cohorts:
Group C - first line: TST001+CAPOX Positive CLDN18.2 expression GEJ C 20-40 Group D-second-line +: TST001+paclitaxel Positive CLDN18.2 expression G/GEJ 20-40
The trial will last approximately 3 years from the enrollment to the completion of both Par I and II studies, sample size approximate 165-210 subjects，with assessments including safety labs, ECGs, MUGA scans, PKs and PDs and CT/MRI tumor assessments, based on the Q2W and Q3W dosing schedules.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: TST001 Injection TST001 Injection treatment. This phase 1 trial will include two stages, a dose escalation stage and an expansion stage. |
Biological: TST001 injection
TST001 Injection with dose escalation stage of 0.3mg/kg up to 20mg/kg, as well as dose expansion stage with recommended dose level from dose escalation stage.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Participant Safety as characterized by frequency and severity of adverse events(according to NCI CTCAE 5.0). [up to 30 days following last dose.]
An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
- Maximum Tolerated Dose (MTD） [up to 28 days following first dose]
The maximum tolerated dose (MTD) is commonly estimated to be the maximum dose that can be determined through DLT of two among 6 subjects administered with TST001 Q2W in 28 days cycles.
- Maximum Tolerated Dose (MTD） [up to 21days following first dose]
The maximum tolerated dose (MTD) is commonly estimated to be the maximum dose that can be determined through DLT of two among 6 subjects administered with TST001 once every 3 weeks in 21 days cycles.
- Recommended Phase 2 Dose (RP2D) [up to 30 days following last dose]
The RP2D will be determined during the dose expansion stage of the study. RP2D will be determined using available safety and efficacy data.
- The incidence and case number of DLT (Dose Limiting Toxicity) in subjects administered with TST001 Q2W in 28 days cycles during observation period [up to 28 days following first dose]
DLT is short for Dose Limiting Toxicity. dose-limiting describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.
- The incidence and case number of DLT (Dose Limiting Toxicity) in subjects administered with TST001 once every 3 weeks in 21 days cycles during observation period [up to 21days following first dose]
DLT is short for Dose Limiting Toxicity. dose-limiting describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.
Secondary Outcome Measures
- Area under plasma concentration vs time curve (AUC) for TST001 [up to 30 days following last dose]
Changes in AUC over time in participants with TST001.
- Peak plasma concentration (Cmax) for TST001 [up to 30 days following last dose]
Cmax is the maximum plasma concentration.
- Time to maximum observed plasma concentration (Tmax) [up to 30 days following last dose]
Tmax is the time in hrs/days it takes to reach Cmax after dosing with TST001
- Terminal elimination half life (t1/2) [up to 30 days following last dose]
Time for the plasma level of TST001 to decrease b y 1/2 during the terminal elimination phase.
- Immunogenicity [up to 30 days following last dose]
by measurement of Incidence of anti-drug antibodies (ADA)
- Objective response rate (ORR) [up to 30 days following last dose]
as measured by RECIST 1.1
- Duration of Response (DOR) [up to 30 days following last dose]
DOR is defined as the time from the date of the first response CR (complete remission)/PR (partial remission) (whichever is first recorded) to the date of radiographical progression/death or date of censoring.
- Clinical Benefit Rate [up to 30 days following last dose]
(CBR: CR+PR+SD ≥ 18 weeks)
- Progression free survival (PFS) [up to 30 days following last dose]
as measured by RECIST v1.1
Eligibility Criteria
Criteria
Inclusion Criteria:
The one who meet all inclusion criteria can be enrolled into the trial:
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Sign Informed Consent Form voluntarily. Understand the study and be willing to follow and be able to complete all trial procedures;
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Male or female aged at 18-75 (inclusive) years when ICF is signed;
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Suffer from advanced unresectable or metastatic malignant local solid tumors confirmed by histological diagnosis and meet the criteria of the enrolled group as follows:
Part I: Mono-therapy dose escalation and expansion study:
Mono-therapy dose escalation study: The subjects for whom no standard treatment regimens are available or who is intolerable to standard treatments.
Mono-therapy dose expansion study: The subjects with positive CDLN18.2 expression in tumor tissue (which is defined as ≥40% tumor cells showing CLDN18.2 membrane dye ≥2+ through immunohistochemistry (IHC) test by the central laboratory) confirmed by the central laboratory at enrollment. There are 2 groups in Part I as follow:
Group A: The subjects with G/GEJ adenocarcinoma for whom no standard therapy regimens are available currently or who are intolerable to standard therapy regimens; Group B: The subjects with other malignant tumors (including but not limited to ductal adenocarcinoma of pancreas, bile duct carcinoma, lung cancer, ovarian carcinoma and other malignant solid tumors) for whom no standard therapy regimens are available currently or who are intolerable to standard therapy regimens; Part II: Dose escalation and expansion study of combination medication
Dose escalation study of combination medication (dose escalation part):
Group C: The subjects with HER2 negative G/GEJ adenocarcinoma without previous systemic chemotherapy. The subjects who have completed neoadjuvant chemotherapy or adjuvant chemotherapy within at least 6 months prior to the initial dosing of the study are allowed to be enrolled.
Group D: The subjects with G/GEJ adenocarcinoma at least with previous first-line systemic chemotherapy;
Dose expansion study of combination medication (dose expansion part):
The subjects with CDLN18.2 positive solid tumors (which is defined as ≥40% tumor cells showing CLDN18.2 membrane dye≥2+ through immunohistochemistry (IHC) test by the central laboratory) confirmed by the central laboratory will be enrolled.
Group C: The subjects with HER2 negative G/GEJ adenocarcinoma without previous systemic chemotherapy. The subjects who have completed neoadjuvant chemotherapy or adjuvant chemotherapy within at least 6 months prior to the initial dosing of the study are allowed to be enrolled.
Group D: The subjects with G/GEJ adenocarcinoma at least with previous first-line systemic chemotherapy; During the study, additional groups for the treatment of other solid tumors might be added according to the available clinical and pre-clinical study data (the inclusion criteria is to be determined).
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ECOG score 0-1;
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Expected survival ≥ 3 months;
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The results of the laboratory examination at screening must meet all the following criteria:
Absolute neutrophil count (ANC) ≥ 1.5×109/L; Absolute count (WBC) ≥ 2.5×109/L; Platelets ≥ 100×109/L; Haemoglobin ≥ 9 g/dL; International normalized ratio (INR) ≤ 1.5 times Upper Limit of Normal (ULN) / or activated partial thromboplastin time (APTT) ≤ 1.5 times ULN (for the test without anticoagulant); INR ≤ 2.5 times ULN / or APTT ≤ 2.5 times ULN (for the test with anticoagulant); Total Bilirubin ≤ 1.5 times ULN; AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN for the subjects with hepatic cancer or metastases to liver); Albumin ≥ 3.0 g/L; Serum creatinine ≤ 1.5 times ULN, or creatinine clearance rate ≥ 60 ml/min (creatinine clearance rate will be calculated by Cock-croft-Gault formula);
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Male and female of childbearing age should agree to take effective contraception measures (refer to Appendix 3. Contraception) from signing ICF till 3 months after the last dose; Blood β-HCG test for women of childbearing age within 70 hours prior to the initial dosing must be negative;
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(For dose expansion study only) There must be at least one assessable lesion conforming to the definition in RECIST v1.1;
Exclusion Criteria:
The subjects who meet any one of the following criteria cannot participate in the study:
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The subjects with advanced unresectable or metastatic local G/GEJ adenocarcinoma who are supposed to be enrolled into the combination therapy group with CAPOX have previously received systemic chemotherapy. The subjects will be eligible provided that they have completed neoadjuvant chemotherapy or adjuvant chemotherapy within at least 6 months prior to the initial dosing of the study; The subjects with advanced unresectable or metastatic local G/GEJ adenocarcinoma who are supposed to be enrolled into the combination therapy with paclitaxel have previously received paclitaxel treatment.
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The subjects who received radiotherapy within 4 weeks prior to the initial dosing of the investigational drug (the subjects who received local radiotherapy for bone metastases treatment with the radiotherapy related AE resolved to ≤ Grade 1 will be eligible);
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The subjects who received other anti-tumor medication or radiotherapy within 4 weeks prior to the initial dosing of the investigational drug; The medication (such as Zoledronic Acid) for bone metastases related events will not influence on the enrollment.
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The subjects who received major surgery (exclusive of aspiration biopsy) within 8 weeks prior to the initial dosing of the investigational drug, or who are expected to undergo major surgery, or who are in the conditions such as severe unhealed wound, trauma, ulcer.
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The subjects who received the treatment with CLDN18.2 monoclonal antibody or CLDN-18.2CART;
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The subjects who have previous serious allergic reactions, or are intolerable to the known component of TST001 or other monoclonal antibodies (including humanized or chimeric antibodies);
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The subjects who are known to have immediate or delayed hypersensitivity to, be intolerable to or be forbidden from any component of the investigational drugs;
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The subjects who have previous serious allergic reaction or intolerance to any component of CAPOX or taxane drugs;
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The subjects who manifest the symptoms of brain or leptomeningeal metastases;
The subjects with central nerve system (CNS) metastasis who meets the following conditions can be enrolled:
The subjects with brain metastasis who are naive to any treatment and have no symptom, or who are in progressive free status persisting for at least 8 weeks after treatment demonstrated by imaging data and do not require hormone or anti epilepsy treatment at least within 8 weeks;
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The subjects suffering from body cavity effusion (hydrothorax, ascites and pericardial effusion) that requires local treatment or repeated drainage and is not well controlled at the discretion of the investigator;
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(For dose expansion study only) The subjects suffering from co-existent malignant tumors. (The following tumor history at 5 years ago that has been cured will not influence on the enrollment: non-melasma, skin carcinoma, in situ cancer or non-invasive tumors.)
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The adverse reactions caused by previous treatment have not resolved to ≤ Grade 1 as per CTCAE v5.0 (exclusive of alopecia and anaemia) before the initial dosing of the investigational drug. If the adverse reaction has no clinical influence, the Sponsor and investigator will decide whether the subject can be enrolled in the study after discussion.
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The subjects who received growth factor, transfusion or other blood products in treatment of anaemia or decreased platelet within 14 days before screening;
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The subjects who experienced clinically significant cardiac diseases within 6 months before the initial dosing of the investigational drug, including:
- Myocardial infarction, ii. Unstable angina pectoris, iii. Cerebrovascular accident or iv. Other acute and uncontrollable cardiac diseases; Clinically significant ventricular arrhythmia history (such as persisting ventricular tachycardia, ventricular fibrillation and torsade de pointes); New York Heart Association (NYHA) Class III or IV congestive cardiac failure; QTc ≥470 (female) or QTc ≥450 (male) or medical history or family history of congenital long-QT syndrome ; The subjects with heart rhythm disorders who requires the treatment with antiarrhythmic drugs (The subjects who suffer from atrial fibrillation with heart rate controllable more than 1 month before the initial dosing of the investigational drug will be eligible);
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. The subjects who are known to have dihydropyrimidine dehydrogenase (DPD) deficiency. (Note: DPD deficiency screening should be performed according to local standard.) (The screening will be performed only in the subjects receiving CAPOX.)
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The subjects who experienced gastric haemorrhage recently or have the risk of gastric haemorrhage or gastric perforation demonstrated by evidences will be excluded from the study at the discretion of the investigator. The subjects suffering from obstruction pyloric and persistent repeated vomiting;
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The subjects who are known to have > Grade 1 peripheral sensory neuropathy, unless a lack of deep tendon reflexes is the only neurological abnormality.
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The subjects suffering from serious or uncontrollable gastro-intestinal tract bleed;
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The subjects suffering from active infection requiring systemic treatment;
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The subjects who have HIV infection history or positive HIV viral test;
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The subjects who are known to have the history of hepatitis C or chronic active hepatitis B;
Except for:
HBV virus carriers or the subjects with hepatitis B infection that is stable after medications (HBV-DNA titer should be no more than 1000 copies [cps]/mL or 200 IU/mL) The subjects with hepatitis C infection that is stable after medications (HCV-RNA test negative)
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The subjects suffering from active autoimmune disorders who required systemic immunosuppressive therapy within the past 2 years;
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The subjects who received systemic immunosuppressive therapy including glucocorticoid within 2 weeks before the initial dosing of the investigational drug; The subjects will be allowed to use hydrocortisone or similar drugs at physiologically alternative dose;
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Pregnant or lactating women;
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The subject with other conditions (such as psychological, geographic or medical conditions) that do not allow them to follow the study schedule and follow-up procedures. Or the subjects who are unsuitable to be enrolled into the study at the discretion of the investigator.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Beijing Cancer Hospital | Beijing | Beijing | China | 100036 |
| 2 | Fudan University Shanghai Cance Center | Shanghai | Shanghai | China | |
| 3 | First Affiliated Hospital of Zhejiang University | Hangzhou | Zhejiang | China |
Sponsors and Collaborators
- Mabspace Biosciences (Suzhou) Co., Ltd.
- Peking University Cancer Hospital & Institute
- First Affiliated Hospital of Zhejiang University
- Fudan University
- Henan Cancer Hospital
- Second Affiliated Hospital, School of Medicine, Zhejiang University
- Tianjin Medical University Cancer Institute and Hospital
- First Affiliated Hospital Bengbu Medical College
- The First People's Hospital of Jingzhou
- Sixth Affiliated Hospital, Sun Yat-sen University
- Beijing Friendship Hospital
- Tianjin Medical University General Hospital
- Hainan People's Hospital
- Hubei Cancer Hospital
- Jilin Provincial Tumor Hospital
- Jinan Central Hospital
- Liaoning Cancer Hospital & Institute
- Sichuan Cancer Hospital and Research Institute
- The Affiliated Hospital of Qingdao University
- The First Affiliated Hospital of Zhengzhou University
- The First Hospital of Jilin University
- Second Affiliated Hospital of Nanchang University
- Second Affiliated Hospital of Soochow University
- West China Hospital
- Fujian Cancer Hospital
- Zhejiang Cancer Hospital
- First Affiliated Hospital of Chongqing Medical University
- Xuzhou Central Hospital
- Suzhou Municipal Hospital
- First Hospital of China Medical University
- Fujian Medical University Union Hospital
- Bristol-Myers Squibb
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TST001-1002