Gastric Cancer, Pancreatic Cancer
Conditions
Keywords
CAR-T
Brief summary
A Phase 1b/2, open label, multi-center, clinical study of Chimeric Antigen Receptor T Cells (CAR-T) targeting claudin18.2 in patients with advanced gastric, pancreatic or other specified digestive system cancers
Detailed description
This is an open label, multi-center, Phase 1b/2 clinical trial to evaluate the safety and efficacy of autologous claudin18.2 chimeric antigen receptor T-cell therapy in patients with advanced gastric, pancreatic or other specified digestive system cancers. Following consent, patients must have tumor tissue evaluated by CLDN18.2 IHC assay. Patients meeting all eligibility criteria will undergo a leukapheresis procedure to collect autologous mononuclear cells for manufacture of investigational drug product (CT041). Following manufacture of the drug product, subjects will receive preconditioning prior to CT041 infusion. All subjects will be asked to continue to undergo long-term gene safety follow-up.
Interventions
BIOLOGICALCT041
treatment with anti-claudin18.2 chimeric antigen receptor T-cell infusion
Sponsors
CARsgen Therapeutics Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 dose escalation and expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
Inclusion criteria
Patients are eligible for screening for potential inclusion in the study (\* indicates inclusion criteria at Baseline (for subjects to be eligible for preconditioning)): 1. Voluntarily signed the ICF; 2. Age ≥ 18 and \< 76 years with pathologically/histologically confirmed diagnosis of adenocarcinoma of the stomach or gastroesophageal junction, referred to collectively as STAD, or pancreatic adenocarcinoma (PAAD);or biliary tract cancers (BTCs, including intrahepatic/extrahepatic cholangiocarcinoma and gallbladder cancer but not ampullary carcinoma); 3. Must have CLDN18.2-positive tumor expression as determined by the CLDN18.2 IHC assay; 4. Estimated life expectancy \> 4 months\*; 5. Failed or been intolerant of prior lines of systemic therapy: 1. For screening: * Leukapheresis can be performed for subjects with STAD who have progressed or were intolerant of at least 1 prior line of systemic therapy, or, * Leukapheresis can be performed for subjects with PAAD who are receiving first-line treatment, or, * Leukapheresis can be performed for subjects with BTC who are receiving first-line treatment. 2. Baseline\*: * Subjects with STAD who have progressed or were intolerant of at least 2 prior lines of systemic therapy, or, * Subjects with PAAD who have progressed or were intolerant of at least 1 prior line of systemic therapy, or, * Subjects with BTC who have progressed or were intolerant of at least 1 prior line of systemic therapy. For subjects with CCA with who has FGFR2 fusions or rearrangements, or IDH1-mutant must have received FDA-approved target therapies. 6. At least 1 measurable lesion per RECIST 1.1\*; 7. ECOG performance status of 0 or 1\*; 8. Sufficient venous access for leukapheresis collection and no other contraindications to leukapheresis; 9. Patients should have adequate CBC counts, renal and hepatic functions\*; 10. Women of childbearing age must undergo a serum pregnancy test with negative results before screening and infusion and be willing to use effective and reliable method of contraception\*; 11. Men must be willing to use effective and reliable method of contraception for at least 12-months after T-cell infusion\*; 12. Sufficient nutritional status.
Exclusion criteria
for screening (\* indicates
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b (Cohort A): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with specified advanced digestive system cancers (STAD, PAAD, or BTC). | up to year 15 | Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs). |
| Phase 1b (Cohort A): Identify the recommended Phase 2 dose (RP2D) of CT041 therapy in subjects with advanced STAD, PAAD, or BTC. | day 0 - day 28 | Incidence of dose-limiting toxicities (DLTs) |
| Phase 1b (Cohort A): Identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of CT041 therapy in subjects with STAD, PAAD, or BTC. | day 0 - day 28 | The highest dose below the dose where the escalation was stopped when the frequency or severity of DLTs exceeds predefined safety criteria. |
| Phase 1b (Cohort B): Determine the efficacy of CT041 by ORR in subjects with advanced STAD, PAAD, or BTC. | up to year 15 | Objective response rate by IRC assessment (RECIST v1.1) |
| Phase 2 (Cohort C): Determine the efficacy of CT041 by ORR in subjects with advanced STAD treated at the RP2D. | up to year 15 | Objective response rate by IRC assessment (RECIST v1.1) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b (Cohort B): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with specified advanced digestive system cancers (STAD, PAAD, or BTC). | up to year 15 | Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs). |
| Phase 2 (Cohort C): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with advanced STAD. | up to year 15 | Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs). |
| Phase 1b(Cohort B)/2: Duration of Response | up to year 15 | Duration of time from first response to progression of disease as determined by investigator and IRC assessment. |
| Phase 1b(Cohort B)/2: Time to Progression | up to year 15 | Duration of time in months from the date of CT041 infusion until disease progression, excluding deaths as determined by investigator and IRC assessment. |
| Phase 1b(Cohort B)/2: Disease Control Rate | up to year 15 | The incidence of a BOR of CR, PR, or SD based on investigator and IRC assessments using RECIST 1.1 criteria. |
| Phase 1b(Cohort B)/2: Progression free survival | up to year 15 | The time in months from the date of CT041 infusion to the earlier date of disease progression or death due to any cause as determined by investigator and IRC assessment. |
| Phase 1b/2: Overall survival | up to year 15 | The time in months from the date of CT041 infusion until the date of death by any cause. |
| Phase 1b/2: Objective Response Rate (ORR) per investigator assessment | up to year 15 | Rate of subjects experiencing an objective response (a binary variable indicating whether each subject experienced a ≥ partial response \[PR\] by Response Evaluation Criteria in Solid Tumors, version 1.1 \[RECIST 1.1\]), as determined by investigator assessment. |
| Phase 1b(Cohort B)/2: PK and bio-distribution of CT041 | Baseline - month 18 | CAR transgene copy number, peak value, AUC, in vivo persistence. |
| Phase 1b(Cohort B)/2: Health-related Quality of Life (HRQoL) in STAD patients (Cohorts B & C) | Baseline - month 18 | * Change from baseline in HRQoL as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30. * Change from baseline in HRQoL as measured by EORTC QLQ-OG25. |
| Phase 1b(Cohort B)/2: CLDN18.2 ICH Assay Performance | Baseline - month 18 | * Association of CLDN18.2 expression level versus tumor response * Association of CLDN18.2 expression versus clinical disease characteristics |
| Phase 1b(Cohort B)/2: Cytokine expression level in blood after CT041 infusion | Baseline - week 20 | Evaluate cytokine expression level in blood after CT041 infusion. |
| Phase 1b (Cohort B)/2: Anti-CT041 drug antibodies | Baseline - month 12 | Number of subjects with anti-CT041 drug antibodies |
| Phase 1b (Cohort B)/2: CT041 product characteristics | Baseline - month 18 | Association of CT041 product characteristics with clinical safety/efficacy/PK |
| Phase 1b (Cohort B)/2: Concordance analysis | up to year 15 | Concordance analysis of ORR of IRC assessment vs investigator assessment. |
| Phase 1b/2: Utilization of Hospital Resources | Day 0 to 3 months | Total days of hospitalization, including ICU days, during & after CT041 infusion as described below: * Infusion-related hospital re-admission within 3 months after infusion. * The number and percentages of subjects, and the number of hospitalizations due to non-infusion reasons. * All-cause re-admission within 3 months after infusion, and from infusion to data cutoff date among those who required rehospitalization * Duration of hospitalization in intensive care |
| Phase 1b (Cohort A): Duration of Response | up to year 15 | Duration of time from first response to progression of disease as determined by investigator |
| Phase 1b (Cohort A): Time to Progression | up to year 15 | Duration of time in months from the date of CT041 infusion until disease progression, excluding deaths as determined by investigator. |
| Phase 1b (Cohort A): Disease Control Rate | up to year 15 | The incidence of a BOR of CR, PR, or SD based on investigator assessments using RECIST 1.1 criteria. |
| Phase 1b (Cohort A): Progression free survival | up to year 15 | The time in months from the date of CT041 infusion to the earliest date of disease progression or death due to any cause as determined by investigator. |
Countries
Canada, United States
Outcome results
None listed