Clinical trial NCT05166070: An Exploratory Clinical Study of RD133 in Subjects With Relapsed or Refractory MSLN-Positive Solid Tumors
Official title: An Exploratory Clinical Study to Evaluate the Safety and Efficacy of RD133 in Subjects With Relapsed or Refractory MSLN-Positive Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Solid Tumor
Keywords: mesothelin-positive solid tumor
CAR-T
Lead sponsor: The First Affiliated Hospital with Nanjing Medical University
Sponsor class: OTHER
Collaborators: name: Shanghai IASO Biotechnology Co., Ltd
First posted: 2021-12-21
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The study is a single center, open label, non-controlled, exploratory study. The "3+3"dose escalation design will be implemented to evaluate the safety and tolerability of RD133 in the treatment of subjects with relapsed/refractory MSLN-positive solid tumors.
Primary purpose: TREATMENT

Brief summary: This study is a single-center exploratory clinical trial. It is estimated that 9-24 subjects will be enrolled. The "3+3" dose escalation design is adopted. The main purpose is to evaluate the safety of RD133 in the treatment of subjects with relapsed or refractory MSLN-positive solid tumors and explore the Recommend phase II dose of RD133 in the treatment of patients with relapsed/refractory MSLN-positive solid tumors.

Detailed description: Leukapheresis procedure will be performed to manufacture RD133 chimeric antigen receptor (CAR) modified T cells. Bridging therapy is allowed between PBMC collection and lymphodepletion. Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, subjects will receive a single dose infusion of RD133 at 1.0, 3.0, or 6.0x 10\^6 CAR+ T cells/Kg. Subjects will be followed in the study for a minimum of 2 years after RD133 infusion. Long-term follow-up for lentiviral vector safety will be followed for up to 15 years after RD133 infusion.

Eligibility criteria: Inclusion Criteria:

1. The subject must personally sign the written informed consent form approved by the ethics committee before the start of the study;
2. ≥18 years of age;
3. Have received at least 2 prior standard treatments, and achieved no response to the last-line treatment;
4. \>25% Mesothelin positive rate on tumor cell membrane confirmed by prior immunohistochemistry of tumor tissue or freshly punctured tissue;
5. Expected survival ≥ 12 weeks;
6. ECOG score ≤ 2;
7. At least one measurable target lesion that meets the RECIST v1.1 standard;
8. Female or male subjects with fertility should agree to practice an effective method of contraception from the day of signing the ICF until 365 days after the infusion. Effective method of contraception is defined as: abstinence or contraceptive methods with an annual failure rate of \<1% specified in the plan. ；
9. Before being enrolled in the group, the subject must have proper organ function and meet all of the following criteria:

9.1 The absolute value of neutrophils≥1.0×10\^9/L (granulocyte colony stimulating factor (G-CSF) support is allowed, but must be without supportive treatment within 7 days before the examination); 9.2 Platelet count ≥75×10\^9/L (must be without blood transfusion support \[including blood component transfusion\] or thrombopoietin \[TPO\], or other treatments for the purpose of increasing platelets within 7 days before the examination); 9.3 Hemoglobin ≥9 g/dl (must be without blood transfusion support \[including blood component transfusion\] within 7 days before the examination); 9.4 Bilirubin value ≤1.5×upper limit of normal (ULN) (except bile duct obstruction caused by tumor compression); 9.5 Creatinine clearance rate ≥60 ml/min; 9.6 ALT or AST ≤2.5×upper limit of normal (ULN) (with liver involvement ≤5×ULN); 9.7 The results of echocardiography indicate that the cardiac ejection fraction is ≥ 50%, without obvious pericardial effusion; 9.8 Stable coagulation function: INR ≤ 1.5, APTT ≤1.2×ULN (except tumor-related anticoagulation therapy); 9.9 \>91% basic blood oxygen saturation in the natural indoor air environments.

Exclusion Criteria:

1. Subject who has received any of the following prior treatments:

   1.1 Subject with acute or chronic graft-versus-host disease (GVHD) who need systemic treatment within 4 weeks before enrollment; 1.2 Subject who has received gene therapy before enrollment; 1.3 Subject who needs systematic immunosuppressive therapy (except topical drugs) to control autoimmune diseases (eg: Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, etc.), immunodeficiency or other diseases in the first 2 years after enrollment; 1.4 Subject who has been injected with live vaccines within 4 weeks before enrollment; 1.5 Subject has received other interventional clinical research drugs within 12 weeks before apheresis.
2. Subject with central metastasis or complete intestinal obstruction;
3. Subject with moderate or more severe hydrothorax and ascites which are hard to control by conventional treatment and require continuous catheter drainage;
4. With an active malignant tumor in the past 5 years, unless it is a curable tumor and has been obviously cured, such as basal or squamous cell carcinoma, cervical or breast carcinoma in situ, etc.
5. Subject with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and abnormal HBV DNA test results in peripheral blood (abnormal HBV DNA test results are defined as: HBV DNA quantitative level higher than the lower limit of the detection center or higher than normal range of the detection center; or qualitative HBV DNA test positive); Hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA positive; Human immunodeficiency virus (HIV) antibody positive; Cytomegalovirus ( CMV) DNA test positive; syphilis test RPR positive.
6. With an uncontrollable active infection (except genitourinary system infection and upper respiratory tract infection \<CTCAE Grade 2).
7. Severe heart disease: including but not limited to unstable angina, myocardial infarction (within 6 months before screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ grade 3), severe arrhythmia.
8. Subject with hypertension that cannot be controlled by medication.
9. The toxicity of previous treatment has not been relieved to baseline or ≤1 (NCI-CTCAE v5.0, except for hair loss and laboratory abnormalities without clinical significance).
10. Major surgery within 2 weeks before enrollment, or has surgery planned during the time the subject is expected to be infused with RD133 or within 12 weeks after RD133 infusion (except planned surgery under local anesthesia).
11. Subject who has a solid organ transplant.
12. Women who are pregnant or breastfeeding.
13. Subject with previous central nervous system diseases (such as cerebral aneurysm, epilepsy, stroke, Alzheimer's disease, mental illness, etc.) or mental disorders.
14. Other unstable systemic diseases judged by the investigator: including but not limited to severe liver, kidney, or metabolic diseases that require medication.
15. Known to have life-threatening allergic reactions, hypersensitivity reactions or intolerances to RD133 cell preparations or its components.
16. Subject with hemorrhage, severe thrombosis judged by the Investigator, or hereditary/acquired hemorrhage and severe thrombosis (including hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc.), or are receiving thrombolytic or anticoagulant.
17. The researcher believes that other situations are not suitable for inclusion in the group.

Primary outcomes:
measure: Type and incidence of dose-limiting toxicity (DLT) by dose group
timeFrame: 2 years post infusion
measure: Type and incidence of adverse events (AEs) and serious adverse events (SAEs) by dose group
timeFrame: 2 years post infusion
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 2 years post infusion
measure: Objective response rate (ORR)
timeFrame: 2 years post infusion
measure: Duration of response (DoR)
timeFrame: 2 years post infusion
measure: Time to response (TTR)
timeFrame: 2 years post infusion
measure: Disease control rate (DCR)
timeFrame: 2 years post infusion
measure: Progression-free survival (PFS)
timeFrame: 2 years post infusion
measure: Overall survival (OS)
timeFrame: 2 years post infusion
measure: Transgene Levels of RD133
timeFrame: 2 years post infusion
measure: Chimeric Antigen Receptor T (CAR-T) Positive Cell Concentration
timeFrame: 2 years post infusion
Other outcomes:
measure: Concentrations of TGF-β
timeFrame: 2 years post infusion
measure: Expression of biomarker in tumor tissue
timeFrame: 2 years post infusion
measure: Immunogenicity of RD133
timeFrame: 2 years post infusion
measure: replication competent lentivirus (RCL)
timeFrame: 2 years post infusion
measure: Exploratory analysis of MSLN level in peripheral blood
timeFrame: 2 years post infusion
measure: Exploratory analysis of MSLN level in tumor tissues and efficacy
timeFrame: 2 years post infusion
measure: T/B/NK cell ratio in peripheral blood
timeFrame: 2 years post infusion
measure: Systemic Cytokine Concentrations
timeFrame: 2 years post infusion
Locations:
city: Nanjing
country: China
facility: The First Affiliated Hospital with Nanjing Medical University
state: Jiangsu
Study officials:
affiliation: The First Affiliated Hospital with Nanjing Medical University
name: Lingxiang Liu
role: PRINCIPAL_INVESTIGATOR
References: