CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Male or female subjects aged ≥ 18 years
2. For phase I part, subjects with histologically confirmed diagnosis of unresectable local advanced or metastatic solid tumor with expression of both PD-L1 and HLA-G positive are relapsed/refractory to at least two lines of standard-of-care therapy, or unwilling to undergo standard therapies.

   Relapse is defined as disease progression after last regimen; refractory is defined as intolerable or progressing disease (PD), or stable disease (SD) to the last regimen.

   For phase IIa part, subjects with histologically confirmed diagnosis of unresectable local advanced or metastatic BC, NSCLC, CRC or GBM with expression of both PD-L1 and HLA-G positive, and are relapsed/refractory to at least two lines of standard-of-care therapy, or unwilling to undergo standard therapies.

   Relapse is defined as disease progression after last regimen; refractory is defined as intolerable or progressing disease (PD) to the last regimen or stable disease (SD) without meaningful clinical benefit as determined by the investigator.

   The standard-of-care therapies of phase IIa for each disease are listed:

   BC: Subject failed to anthracycline-containing (such as Doxorubicin and Epirubicin), taxane-containing (such as Paclitaxel and Docetaxel), antimetabolites (such as Capecitabine, Gemcitabine and Fluorouracil) or platinum-based (such as Cisplatin and Carboplatin) chemotherapy, microtubule dynamic inhibitor (such as Eribulin and Vinorelbine) and/or targeted therapy such as antibody drug conjugate (such as Sacituzumab govitecan-hzi), PARP inhibitor, germline BRCA1/BRCA2 mutation (such as Olaparib and Talazoparib), HER2-targeted therapy for HER2-positive disease and endocrine therapy for hormone receptor-positive disease..

   NSCLC: Subject failed to targeted therapies (according to the genetic testing results), such as Gefitinib and Afatinib and/or platinum-containing, pemetrexed, docetaxel chemotherapy with or without Immune checkpoint inhibitors (such as PD-1 or PD-L1 inhibitor: Atezolizumab, Nivolumab, and Pembrolizumab). For subject with non-squamous cell carcinoma using Immune checkpoint inhibitor, subjects should be with EGFR/ALK/ROS-1 wild type; for subject with squamous cell carcinoma using Immune checkpoint inhibitor, subjects should be with EGFR/ALK wild type.

   CRC: Subject failed to chemotherapies (i.e. Folinicacid/ 5-fluorouracil/oxaliplatin (FOLFOX) and Folinicacid/ 5-fluorouracil/irinotecan (FOLFIRI)) and/or target therapies, including anti-EGFR (K-RAS and N-RAS wild type) (such as Cetuximab and Panitumumab) or anti-VEGF (such as Bevacizumab), Regorafenib and Lonsurf, according to the genetic testing results) GBM: Subject failed to chemotherapy (such as Temozolomide (TMZ)) Carmustine implant (such as Gliadel Wafer) and/or anti-VEGF (such as Bevacizumab) treatment
3. With at least one measurable lesion as defined by RECIST1.1 (for BC, NSCLC or CRC) or RANO (for GBM). For subjects with GBM, the maximum longest diameter (or perpendicular diameter for CNS lesions) not exceeding 3.0 cm (≤ 3.0 cm) at screening.
4. Able to understand and sign the informed consent form (ICF)
5. Have a life expectancy of \> 12 weeks
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
7. Recovered from any previous therapy related toxicity to ≤ grade 2 at screening
8. With adequate renal function: serum creatinine ≤ 1.5X upper limit of normal (ULN); estimated glomerular filtration rate (eGFR) \> 50 ml/min
9. With adequate liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3X ULN or ≤ 5 X ULN if liver metastases; and total bilirubin ≤ 1.5 X ULN or ≤ 3 X ULN if due to Gilbert's disease.
10. With prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5X ULN
11. With adequate hematopoietic function:

    * Absolute neutrophil count (ANC) ≥ 1,000 cells/μl
    * Platelets ≥ 75,000 counts/μl
    * Total white blood cell (WBC) ≥ 2,000 cells/μl
    * Hemoglobin ≥ 8 g/dL

Exclusion Criteria:

1. Has received autologous cell therapy or autologous tissue transplantation within 180 days before CAR001 infusion; or with a history of allogeneic or xenogeneic transplant, gene therapy or BiTE therapy
2. With known or suspected to be hypersensitivity to CAR001 or its excipients, such as DMSO or human serum albumin
3. With more than one kind of active diagnosed primary cancer
4. With active infection requiring systemic medication
5. With medical conditions who are receiving systemic steroid therapy \>10 mg prednisone/day or equivalent dose, or other immune-suppressants in the past 2 weeks
6. With active infection of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or human T-lymphotropic virus (HTLV) at the time of Screening. Suspected SARS-CoV-2 confirmed positive by PCR, or suspected tuberculosis infection.

   * Active HBV infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test during Screening. Subjects with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBc Ab) test at screening are eligible for the study if HBV deoxyribonucleic acid (DNA) test is ≤ 1000 copies/mL.
   * Active HCV infection, defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test during Screening. The HCV RNA test will be performed only for subjects who have a positive HCV test. Subjects with a history of treated HCV can be enrolled if negative by HCV PCR with investigator approval.
7. With acute cardiovascular disease; New York Heart Association (NYHA) classification ≥ 3; or history of myocardial infarction during the past 6 months; or has active uncontrolled arterial hypertension by medical history; Or cardiac LVEF ≤ 40%, evidence of pericardial effusion as determined by echocardiogram (ECHO), and clinically significant pleural effusion; or uncontrolled cardiac arrhythmia; or cardiac enzyme levels including N-terminal -pro B type natriuretic peptide (NT-proBNP) \> 450 pg/ml (age \<50 yrs); \> 900 pg/ml (age 50-75 yrs); \> 1,800 pg/ml (age \>75 yrs) by blood sampling. Per investigator's judgment, would not make participation appropriate
8. With historical or current auto-immune diseases, such as rheumatoid arthritis, type I diabetes, psoriasis or systemic lupus erythematosus
9. Has uncontrolled psychiatric disorder by medical history
10. Has central nerve system (CNS) diseases except GBM or stroke (acute stroke within 6 months is excluded)

    * With treated CNS metastases (by whole brain radiation therapy, surgery or radiosurgery, etc.) are permitted on study if all of the following are met:
    * CNS metastases have been clinically stable for at least 4 weeks and baseline scans show no evidence of new or worsening CNS metastases
    * With medical conditions who are on a stable dose of ≤10mg/day of prednisone or equivalent for at least 2 weeks
11. Has received any investigational therapy from another clinical study within the last 4 weeks prior to CAR001 infusion
12. Inability to undergo radiological assessment, such as MRI or CT for any reason
13. Has received radiotherapy or chemotherapy within 2 weeks prior to CAR001 infusion; or targeted therapy or monoclonal antibodies within 4 weeks before CAR001 infusion
14. With historical record indicating a high disease burden, such as \>5% bone marrow lymphoblasts or any peripheral blood lymphoblasts. Per investigator's judgement would not be eligible for participation.
15. Has experienced severe CRS during previous treatments
16. Not suitable to participate the trial as judged by the investigator
17. With spinal cord compression, primary or metastatic brain tumors causing new neurological symptoms or unstable neurological symptoms, or those experiencing mass effect due to tumors requiring intervention therapy
18. Has received any therapy that target HLA-G
19. Female subject of childbearing potential who:

    * Is lactating; or
    * Has a positive pregnancy test result at eligibility checking; or
    * Refuses to adopt at least two forms of birth control from signing informed consent to 1 year after the last administration of CAR001.
20. Male subject with a female spouse/partner who is of childbearing potential refuses to adopt at least two forms of birth control from signing informed consent to 1 year after the last administration of CAR001.

主要终点：Maximum Tolerated Dose (MTD) of CAR001 for Phase I part · MTD was determined by testing increasing doses once a week for 4 weeks via IV on dose escalation cohorts 1 to 5 with 3 to 6 participants each. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined as any AE ≥ grade 3 (CTCAE v5.0) that is considered to be causally related (possibly, probably, or definitely related) to CAR001 within 4 weeks. · 4 weeks after last dosing of CAR001；Objective Response Rate (ORR) of CAR001 for Phase IIa part · The rate of subjects with CR or PR based on RECIST1.1 in patients with NSCLC, TNBC or CRC; RANO in patients with GBM. Although there is no control group in this study, the ORR after CAR001 administration could be compared to baseline. · from visit 1 to 24-months of safety and efficacy follow-up period
次要终点：Safety - AEs and SAEs incidences over the study period；Safety - Vital signs assessments at each post-treatment；Safety - Laboratory examinations at each post-treatment；Safety - 12-lead electrocardiogram (ECG) assessments at each post-treatment；Safety - Physical Examination at each post-treatment；Efficacy - Progression Free Survival (PFS) rate；Efficacy - Overall Survival (OS) rate；Efficacy - Change of QoL from baseline

• CAR001 · EXPERIMENTAL · CAR001 cells mixed with normal saline will be administered to patients.

This study is composed of phase I and IIa parts. The dose-escalation phase I part aims to find the maximum tolerated dose (MTD) and to identify the safety of CAR001 in subjects with relapsed/refractory solid tumor; the dose-expansion phase IIa part aims to evaluate the potential efficacy of CAR001 in subjects with relapsed/refractory non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), colorectal cancer (CRC) or Glioblastoma multiforme (GBM).