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
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
110
treatment with anti-claudin18.2 chimeric antigen receptor T-cell infusion
City of Hope
Duarte, California, United States
University of Southern California
Los Angeles, California, United States
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).
Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs).
Time frame: up to year 15
Phase 1b (Cohort A): Identify the recommended Phase 2 dose (RP2D) of CT041 therapy in subjects with advanced STAD, PAAD, or BTC.
Incidence of dose-limiting toxicities (DLTs)
Time frame: day 0 - day 28
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.
The highest dose below the dose where the escalation was stopped when the frequency or severity of DLTs exceeds predefined safety criteria.
Time frame: day 0 - day 28
Phase 1b (Cohort B): Determine the efficacy of CT041 by ORR in subjects with advanced STAD, PAAD, or BTC.
Objective response rate by IRC assessment (RECIST v1.1)
Time frame: up to year 15
Phase 2 (Cohort C): Determine the efficacy of CT041 by ORR in subjects with advanced STAD treated at the RP2D.
Objective response rate by IRC assessment (RECIST v1.1)
Time frame: up to year 15
Phase 1b/2: Objective Response Rate (ORR) per investigator assessment
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.
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UCSD
San Diego, California, United States
UCSF
San Francisco, California, United States
Moffitt Cancer Center
Tampa, Florida, United States
University of Kansas Cancer Center
Kansas City, Kansas, United States
Karmanos Cancer Center
Detroit, Michigan, United States
Mayo Cancer Hospital
Rochester, Minnesota, United States
Northwell Cancer Institute
New Hyde Park, New York, United States
The Mount Sinai Hospital
New York, New York, United States
...and 6 more locations
Time frame: up to year 15
Phase 1b (Cohort A): Duration of Response
Duration of time from first response to progression of disease as determined by investigator
Time frame: up to year 15
Phase 1b (Cohort A): Time to Progression
Duration of time in months from the date of CT041 infusion until disease progression, excluding deaths as determined by investigator.
Time frame: up to year 15
Phase 1b (Cohort A): Disease Control Rate
The incidence of a BOR of CR, PR, or SD based on investigator assessments using RECIST 1.1 criteria.
Time frame: up to year 15
Phase 1b (Cohort A): Progression free survival
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.
Time frame: up to year 15
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).
Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs).
Time frame: up to year 15
Phase 2 (Cohort C): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with advanced STAD.
Incidence of adverse events (AEs), AEs of special interest (cytokine release syndrome \[CRS\], neurotoxicity, secondary malignancy), serious adverse events (SAEs).
Time frame: up to year 15
Phase 1b(Cohort B)/2: Duration of Response
Duration of time from first response to progression of disease as determined by investigator and IRC assessment.
Time frame: up to year 15
Phase 1b(Cohort B)/2: Time to Progression
Duration of time in months from the date of CT041 infusion until disease progression, excluding deaths as determined by investigator and IRC assessment.
Time frame: up to year 15
Phase 1b(Cohort B)/2: Disease Control Rate
The incidence of a BOR of CR, PR, or SD based on investigator and IRC assessments using RECIST 1.1 criteria.
Time frame: up to year 15
Phase 1b(Cohort B)/2: Progression free survival
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.
Time frame: up to year 15
Phase 1b/2: Overall survival
The time in months from the date of CT041 infusion until the date of death by any cause.
Time frame: up to year 15
Phase 1b/2: Utilization of Hospital Resources
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
Time frame: Day 0 to 3 months
Phase 1b(Cohort B)/2: PK and bio-distribution of CT041
CAR transgene copy number, peak value, AUC, in vivo persistence.
Time frame: Baseline - month 18
Phase 1b(Cohort B)/2: Health-related Quality of Life (HRQoL) in STAD patients (Cohorts B & C)
* 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.
Time frame: Baseline - month 18
Phase 1b(Cohort B)/2: CLDN18.2 ICH Assay Performance
* Association of CLDN18.2 expression level versus tumor response * Association of CLDN18.2 expression versus clinical disease characteristics
Time frame: Baseline - month 18
Phase 1b(Cohort B)/2: Cytokine expression level in blood after CT041 infusion
Evaluate cytokine expression level in blood after CT041 infusion.
Time frame: Baseline - week 20
Phase 1b (Cohort B)/2: Anti-CT041 drug antibodies
Number of subjects with anti-CT041 drug antibodies
Time frame: Baseline - month 12
Phase 1b (Cohort B)/2: CT041 product characteristics
Association of CT041 product characteristics with clinical safety/efficacy/PK
Time frame: Baseline - month 18
Phase 1b (Cohort B)/2: Concordance analysis
Concordance analysis of ORR of IRC assessment vs investigator assessment.
Time frame: up to year 15