Clinical Trials /

A Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TST001 in Advanced or Metastatic Solid Tumors

NCT04495296

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TST001 in Advanced or Metastatic Solid Tumors
  • Official Title: Phase I Clinical Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TST001 - Claudin18.2 Monoclonal Antibody in the Treatment of Advanced Unresectable or Metastatic Local Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: TST001-1002
  • NCT ID: NCT04495296

Conditions

  • Advanced Cancer

Interventions

DrugSynonymsArms
TST001 injectionTST001 - Claudin18.2 monoclonal antibodyTST001 Injection

Purpose

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.

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:

        1. 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)".

        2. 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.
    

Trial Arms

NameTypeDescriptionInterventions
TST001 InjectionExperimentalTST001 Injection treatment. This phase 1 trial will include two stages, a dose escalation stage and an expansion stage.
  • TST001 injection

Eligibility Criteria

        Inclusion Criteria:

        The one who meet all inclusion criteria can be enrolled into the trial:

          1. Sign Informed Consent Form voluntarily. Understand the study and be willing to follow
             and be able to complete all trial procedures;

          2. Male or female aged at 18-75 (inclusive) years when ICF is signed;

          3. 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).

          4. ECOG score 0-1;

          5. Expected survival ≥ 3 months;

          6. 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);

          7. 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;

          8. (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:

          1. 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.

          2. 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);

          3. 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.

          4. 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.

          5. The subjects who received the treatment with CLDN18.2 monoclonal antibody or
             CLDN-18.2CART;

          6. 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);

          7. 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;

          8. The subjects who have previous serious allergic reaction or intolerance to any
             component of CAPOX or taxane drugs;

          9. 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;

         10. 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;

         11. (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.)

         12. 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.

         13. The subjects who received growth factor, transfusion or other blood products in
             treatment of anaemia or decreased platelet within 14 days before screening;

         14. The subjects who experienced clinically significant cardiac diseases within 6 months
             before the initial dosing of the investigational drug, including:

             i. 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);

         15. . 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.)

         16. 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;

         17. The subjects who are known to have > Grade 1 peripheral sensory neuropathy, unless a
             lack of deep tendon reflexes is the only neurological abnormality.

         18. The subjects suffering from serious or uncontrollable gastro-intestinal tract bleed;

         19. The subjects suffering from active infection requiring systemic treatment;

         20. The subjects who have HIV infection history or positive HIV viral test;

         21. 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)

         22. The subjects suffering from active autoimmune disorders who required systemic
             immunosuppressive therapy within the past 2 years;

         23. 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;

         24. Pregnant or lactating women;

         25. 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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Participant Safety as characterized by frequency and severity of adverse events(according to NCI CTCAE 5.0).
Time Frame:up to 30 days following last dose.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Area under plasma concentration vs time curve (AUC) for TST001
Time Frame:up to 30 days following last dose
Safety Issue:
Description:Changes in AUC over time in participants with TST001.
Measure:Peak plasma concentration (Cmax) for TST001
Time Frame:up to 30 days following last dose
Safety Issue:
Description:Cmax is the maximum plasma concentration.
Measure:Time to maximum observed plasma concentration (Tmax)
Time Frame:up to 30 days following last dose
Safety Issue:
Description:Tmax is the time in hrs/days it takes to reach Cmax after dosing with TST001
Measure:Terminal elimination half life (t1/2)
Time Frame:up to 30 days following last dose
Safety Issue:
Description:Time for the plasma level of TST001 to decrease b y 1/2 during the terminal elimination phase.
Measure:Immunogenicity
Time Frame:up to 30 days following last dose
Safety Issue:
Description:by measurement of Incidence of anti-drug antibodies (ADA)
Measure:Objective response rate (ORR)
Time Frame:up to 30 days following last dose
Safety Issue:
Description:as measured by RECIST 1.1
Measure:Duration of Response (DOR)
Time Frame:up to 30 days following last dose
Safety Issue:
Description: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.
Measure:Clinical Benefit Rate
Time Frame:up to 30 days following last dose
Safety Issue:
Description:(CBR: CR+PR+SD ≥ 18 weeks)
Measure:Progression free survival (PFS)
Time Frame:up to 30 days following last dose
Safety Issue:
Description:as measured by RECIST v1.1

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mabspace Biosciences (Suzhou) Co., Ltd.

Last Updated

July 29, 2020