Clinical trial NCT04404595: Claudin18.2 CAR-T (CT041) in Patients with Gastric, Pancreatic Cancer, or Other Specified Digestive Cancers
Official title: Open-label, Multicenter, Phase 1b/2 Clinical Trial to Evaluate the Safety and Efficacy of Autologous Anti-claudin 18.2 Chimeric Antigen Receptor T-cell Therapy in Subjects with Advanced Gastric, Pancreatic, or Other Specified Digestive System Cancers
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Gastric Cancer
Pancreatic Cancer
Keywords: CAR-T
Lead sponsor: CARsgen Therapeutics Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2020-05-27
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 76
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 3+3 dose escalation and expansion
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 exclusion criteria for baseline as well):

1. Pregnant or lactating women\*;
2. HIV, active hepatitis C virus (HCV), active hepatitis B virus (HBV), or active syphilis infection;
3. Any active infection requiring systemic treatment\*;
4. AEs from previous treatment that have not recovered\*;
5. Patients who have clinically significant thyroid dysfunction;
6. Patients allergic to any drugs of the preconditioning regimen, tocilizumab, dimethyl sulfoxide (DMSO), or CT041 CAR-CLDN18.2 T-cell;
7. Patients who have received:

   1. prior cellular therapy such as (CAR T, TCR, tumor-infiltrating lymphocytes) within one year.
   2. organ transplantation.
   3. previous anti-claudin18.2 CAR T-cell therapy, mRNA-based cancer immunotherapy, or bispecific T cell engager.
8. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression;
9. Patients with heavy tumor burdens;
10. Unstable/active ulcer, anastomotic recurrence with full-thickness tumor infiltration or tumor involving any major vessels, digestive tract bleeding, or recent digestive surgery that may have increased risk of bleeding\*;
11. Patients who have a history of esophageal or gastric resection plus current evidence of locally recurrent tumor that involves any major blood vessels or that has evidence of recent bleeding or perforation\*;
12. Patients requiring anticoagulant therapy such as warfarin or heparin;
13. Patients requiring long-term antiplatelet therapy;
14. Use of prednisone \>/= 10mg daily or other equivalent steroids within 14 days before leukapheresis or preconditioning\*;
15. Anticancer treatment within approximately 2 weeks prior to leukapheresis or preconditioning\*;
16. Major surgery less than 1 week prior to leukapheresis or 3 weeks prior to preconditioning\*;
17. Patients who have clinically significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients\*;
18. Inadequate pulmonary function\*;
19. Patients known to have active autoimmune diseases;
20. Patients with second malignancies;
21. Patients have significant neurologic disorders;
22. Patients are unable or unwilling to comply with the requirements of clinical trial.

    Additional exclusion criteria solely for baseline (prior to conditioning regimen):
23. Fever \> 38.0°C;
24. Active illness or existing toxicity that would place the subject at undue risk;
25. Abrupt deterioration of clinical status or condition;
26. Subjects who have received a live attenuated vaccine 4 weeks before preconditioning.

Inclusion Criteria Before Infusion: There are no inclusion criteria at this timepoint.

Exclusion Criteria Before Infusion:

1. Patients who have clinically significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients;
2. Inadequate pulmonary function;
3. Active infection requiring systemic therapy or causing fever within 7 days prior to investigational infusion;
4. Active illness or toxicity that would place the subject at undue risk;
5. Abrupt deterioration of clinical status or condition;
6. New or worsening Grade ≥ 3 non-hematologic toxicities.

Primary outcomes:
measure: 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).
timeFrame: up to year 15
measure: Phase 1b (Cohort A): Identify the recommended Phase 2 dose (RP2D) of CT041 therapy in subjects with advanced STAD, PAAD, or BTC.
timeFrame: day 0 - day 28
measure: 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.
timeFrame: day 0 - day 28
measure: Phase 1b (Cohort B): Determine the efficacy of CT041 by ORR in subjects with advanced STAD, PAAD, or BTC.
timeFrame: up to year 15
measure: Phase 2 (Cohort C): Determine the efficacy of CT041 by ORR in subjects with advanced STAD treated at the RP2D.
timeFrame: up to year 15
Secondary outcomes:
measure: Phase 1b/2: Objective Response Rate (ORR) per investigator assessment
timeFrame: up to year 15
measure: Phase 1b (Cohort A): Duration of Response
timeFrame: up to year 15
measure: Phase 1b (Cohort A): Time to Progression
timeFrame: up to year 15
measure: Phase 1b (Cohort A): Disease Control Rate
timeFrame: up to year 15
measure: Phase 1b (Cohort A): Progression free survival
timeFrame: up to year 15
measure: 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).
timeFrame: up to year 15
measure: Phase 2 (Cohort C): Evaluate the safety and tolerability of CAR-CLDN18.2 T-cell therapy (CT041) in subjects with advanced STAD.
timeFrame: up to year 15
measure: Phase 1b(Cohort B)/2: Duration of Response
timeFrame: up to year 15
measure: Phase 1b(Cohort B)/2: Time to Progression
timeFrame: up to year 15
measure: Phase 1b(Cohort B)/2: Disease Control Rate
timeFrame: up to year 15
measure: Phase 1b(Cohort B)/2: Progression free survival
timeFrame: up to year 15
measure: Phase 1b/2: Overall survival
timeFrame: up to year 15
measure: Phase 1b/2: Utilization of Hospital Resources
timeFrame: Day 0 to 3 months
measure: Phase 1b(Cohort B)/2: PK and bio-distribution of CT041
timeFrame: Baseline - month 18
measure: Phase 1b(Cohort B)/2: Health-related Quality of Life (HRQoL) in STAD patients (Cohorts B & C)
timeFrame: Baseline - month 18
measure: Phase 1b(Cohort B)/2: CLDN18.2 ICH Assay Performance
timeFrame: Baseline - month 18
measure: Phase 1b(Cohort B)/2: Cytokine expression level in blood after CT041 infusion
timeFrame: Baseline - week 20
measure: Phase 1b (Cohort B)/2: Anti-CT041 drug antibodies
timeFrame: Baseline - month 12
measure: Phase 1b (Cohort B)/2: CT041 product characteristics
timeFrame: Baseline - month 18
measure: Phase 1b (Cohort B)/2: Concordance analysis
timeFrame: up to year 15
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Diego
country: United States
facility: UCSD
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Cancer Hospital
state: Minnesota
city: New Hyde Park
country: United States
facility: Northwell Cancer Institute
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Dallas
country: United States
facility: TX Oncology-Baylor Charles Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: Mayo
name: Harry H Yoon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Moffitt
name: Dae Won Kim, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Botta GP, Chao J, Ma H, Hahn M, Sierra G, Jia J, Hendrix AY, Nolte Fong JV, Ween A, Vu P, Miller A, Choi M, Heyman B, Daniels GA, Kaufman D, Jamieson C, Li Z, Cohen E. Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells. J Immunother Cancer. 2024 Feb 5;12(2):e007927. doi: 10.1136/jitc-2023-007927.