This Study is an Open-lable, Early Study to Evaluate the Safety, Feasibility, Cytokinetics, and Preliminary Efficacy of GC511B in DLL3+ Relapsed/Refractory Small Cell Lung Cancer.

An Early, First-in-Human, Investigator-Initiated, Open-label Study to Assess the Safety, Feasibility, Cytokinetics, and Preliminary Antitumor Activity of GC511B in Adult Trial Participants With DLL3+ Relapsed/Refractory Small Cell Lung Cancer

This is a First-in-Human, open-label, early dose-escalation clinical study to evaluate the safety and preliminary efficacy of GC511B CAR T cell injection in Adult with DLL3+ r/r SCLC trial participants.

This is a First-in-Human, open-label, early dose-escalation clinical study to evaluate the safety and preliminary efficacy of GC511B CAR T cell injection in Adult with DLL3+ r/r SCLC trial participants.

this study consists of two parts: dose escalation and dose expansion: Dose Escalation: This part consists of two stages:Stage 1: Accelerated titration design to explore the effective starting dose;Stage 2: Bayesian optimal interval (BOIN) design to explore the MAD/MTD.The BOIN design will start with aDL1 as determined in Stage 1 and continue until either 9 trial participants have been enrolled at a single dose level (DL) or the total number of trial participants reaches 11.Starting with BOIN stage DL3, the first and second trial participants were reinfused at least 2 weeks apart.During the dose-escalation phase, following each dose level (DL) and/or scheduled infusion time point, the Safety Review Committee (SRC) will evaluate all adverse events (AEs), serious adverse events (SAEs), laboratory safety data from subjects in the DLT observation period, as well as all other relevant available data, to determine the next DL to be explored and/or dosing schedule and to provide recommendations for subsequent study conduct.

Dose expansion : The dose expansion phase will be initiated at the defined RDE to further investigate the safety, feasibility, CK, immunogenicity, PD, and preliminary antitumor activity of GC511B monotherapy and/or combination therapy. Up to 4 expansion cohorts may be opened to evaluate specific DLs and indications with up to 20 response-evaluable trial participants included in each cohort.

Inclusion Criteria:

• 1.Trial articipant must be ≥ 18 years and ≤75 years of age at the time of signing the ICF.

Type of Subjects and Disease Characteristics

• 2.ECOG performance status 0-2.

• 3.Life expectancy ≥ 12 weeks.

• 4.At least 1 TL meeting RECIST v1.1 at screening. Tumor assessment by CT scan or MRI must be performed within 28 days prior to apheresis.

  1. A lesion can be considered TL if the lesion previously subjected to radiotherapy has a clear boundary, is measurable as per RECIST v1.1, and has clear progression during or after the latest treatment;
  2. If a fresh biopsy sample is selected at screening from a tumor lesion, the tumor lesion should not be selected as a TL unless imaging is performed at least approximately 2 weeks after the biopsy to allow time for healing. In a case where there is only one measurable TL, caution should be taken when obtaining biopsy tissues during the treatment period.

• 5.Archival or freshly biopsied tumor tissue for assessment of DLL3 expression levels can be provided.

• 6.Adequate organ function:

  a.Blood function: i.Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin therapy within 2 weeks prior to screening assessment); ii.Absolute neutrophil count ≥ 1.5×10^9/L and absolute lymphocyte count ≥ 0.6×10^9/L (without G-CSF use within 2 weeks prior to screening assessment);iii.Platelet count ≥ 75×10^9/L (without platelet transfusion or recombinant human thrombopoietin within 2 weeks prior to screening assessment).

  b.Hepatic function (based on normal values as defined by the clinical study site):i.Serum TBL ≤ 1.5 ×ULN;ii.ALT or AST ≤ 2.5×ULN in the absence of liver metastases; ALT and AST ≤ 5×ULN in the presence of liver metastases.

  c.Renal function (based on normal values as defined by the clinical study site): i.Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 60 mL/minute calculated using the Cockcroft-Gault formula, or creatinine clearance ≥ 60 mL/minute calculated using 24-hour urine.ii.Urine protein <++. For trial participants with proteinuria ≥ ++ on urine test paper at baseline, 24-hour urine must be collected and the content of protein in urine within 24 hours must be < 1 g.

  d.Coagulation function (based on normal values as defined by the clinical study site):i.PT≤1.5×ULN；ii.Thrombin time ≤ 1.5×ULN;iii.aPTT≤1.5×ULN。

  e.Cardiac function:i.New York Heart Association classification < class 3;ii.LVEF ≥ 50%.

• 7.Able to establish venous access and, in the judgment of the investigator, suitable for PBMC collection.

• 8.Women of childbearing potential must be non-lactating, and women of childbearing potential must have a negative result of highly sensitive serum pregnancy test during screening.

• 9.All trial participants of childbearing age (including women of childbearing age and males with partners) must agree to take medically acceptable effective contraception measures as mentioned in Appendix F throughout the treatment period and for 2 years after the last CAR-T product reinfusion or until a negative CAR copy test, whichever occurs later.

• 10.Male trial participants must agree not to donate sperm and female trial participants must agree not to donate eggs throughout the treatment period and for 2 years after the last CAR-T product reinfusion or until a negative CAR copy test, whichever occurs later.

• 11.Capable of signing ICF (as mentioned in Appendix A), which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

• 12.The trial participant has provided ICF before starting any study-specific activity/procedure.

• 13.Able to communicate well with the investigator, and willing to comply with the study plan and able to complete the study as required.

Exclusion Criteria:

• 1.Pregnant or breastfeeding females, or female trial participants with a positive pregnancy test result during the screening period (females not of childbearing potential are not required to receive a pregnancy test, such as metrectomy and/or bilateral oophorectomy, or amenorrhea for ≥ 12 months).

• 2. Trial participants who have received a live vaccine within 4 weeks prior to initiation of apheresis or who plan to receive any vaccine (other than coronavirus disease 2019 vaccine) during the study.

• 3.Trial participants has a history of other acquired or congenital immunodeficiency; trial participants received organ transplant or bone marrow transplant.

• 4.The trial participants has a serious arterial/venous thromboembolic event or cerebrovascular accident within 6 months before apheresis, such as deep venous thrombosis (excluding asymptomatic and untreated muscle venous thrombosis), pulmonary embolism, cerebral infarction, cerebral hemorrhage and except for myocardial infarction that is asymptomatic and does not require clinical intervention.

• 5.The trial participant has hereditary or acquired haemorrhage and thrombophilia (e.g., hemophilia, coagulation disorder, splenomegaly);

• 6.The trial participant has a QTc interval > 450 ms (males) or > 470 ms (females) during the screening period; the trial participant has a family or personal history of long or short QT syndrome;The trial participants had a history of unstable angina pectoris, severe arrhythmia, severe non-ischemic cardiomyopathy, or had undergone myocardial infarction or cardiovascular surgery within 6 months.

• 7.The trial participant has other diseases that may seriously endanger the safety of the trial participant or affect the completion of the study, such as peptic ulcer, intestinal obstruction, intestinal paralysis, pulmonary fibrosis, renal failure, and uncontrolled diabetes.

• 8.The trial participants has an active or ongoing infection requiring systemic intravenous treatment (the trial participant may start study treatment 2 weeks after completion of anti-infective therapy).

• 9.History of any autoimmune nervous system disorder, including but not limited to: multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, Guillain Barre syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy. Other active autoimmune or inflammatory disorders, including but not limited to inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), systemic lupus erythematosus, Sarcoidosis syndrome, granulomatosis with polyangiitis, autoimmune thyroid disease (Graves' disease) or rheumatoid arthritis. The following are exceptions to this criterion:

  1. The trial participant has vitiligo or autoimmune alopecia;
  2. The trial participant has autoimmune hypothyroidism (e.g., following Hashimoto's thyroiditis) and is stable on hormone replacement;
  3. Any chronic inflammatory or autoimmune skin disease that does not require systemic therapy;
  4. Trial participants without active disease in the past 5 years may be enrolled in the study, but must first consult with the investigator;
  5. Trial participants whose celiac disease is controlled by dietary management alone.

• 10. Trial participants with known life-threatening hypersensitivity or other intolerance to cyclophosphamide or fludarabine, or severe allergic constitution; trial participants with allergy to human serum albumin and dimethyl sulfoxide.

• 11.Active or chronic infectious diseases, including:

  1. HBV infection, defined as HBsAg positive or hepatitis B core antibody positive and HBV-DNA detectable;
  2. HCV infection, defined as HCV antibody positive and HCV-RNA detectable;
  3. HIV infection, defined as anti-HIV (1/2) positive;
  4. Syphilis infection, defined as TPPA positive with clinical or exposure evidence.

• 12.Prior receipt of anti-tumor therapies or participation in clinical studies;

  1. The trial participant has received prior CAR-T cell therapy or other gene-editing cell therapy;
  2. The trial participant participated in other clinical studies within 28 days prior to screening;
  3. Use of systemic corticosteroids (excluding inhaled corticosteroids) at a daily dose of ≥ 10 mg within 7 days prior to apheresis;
  4. Use of chemotherapy, immunotherapy, or targeted therapy within 4 weeks or less than 5 drug half-lives, whichever is shorter, prior to apheresis;
  5. Having received radical radiotherapy or radiotherapy with a bone marrow proportion greater than 30% at the radiotherapy site or whole brain radiotherapy within 4 weeks before apheresis, and having received local palliative radiotherapy aimed at alleviating symptoms within 2 weeks before apheresis;
  6. Trial participants who have received traditional Chinese medicine treatment for a clear anti-tumor indication within 2 weeks before apheresis.

• 13.Toxicities from prior anticancer therapy that have not recovered to National Cancer Institute CTCAE v5.0 Grade 0 or Grade 1 (excluding alopecia, pigmentation, and other Grade ≤ 2 long-term toxicities considered irreversible by the investigator).

• 14.Trial participants who previously discontinued administration due to adverse reactions such as immune-related pneumonitis, pituitary or thyroid dysfunction, or pancreatitis.

• 15.Trial participants who have undergone major surgical or interventional procedures within 4 weeks prior to apheresis and have not fully recovered (excluding tumor biopsy or paracentesis).

• 16.Evidence of interstitial lung disease or active pneumonitis. Cancer-related

• 17.Trial participants with transformed SCLC.

• 18.Trial participants with pleural effusion, ascites, or pericardial effusion that is symptomatic or requires drainage (Note: Trial participants with effusions not requiring drainage within 1 week prior to enrollment or who have stopped drainage without significant increase in effusions may participate in this study).

• 19.Trial participants with brain metastases and/or carcinomatous meningitis; subjects who previously received treatment for brain metastases may be considered if there is no evidence of disease progression confirmed by imaging within 28 days prior to apheresis, all neurological symptoms have recovered to baseline, and no radiotherapy, surgery, or steroid treatment has been received within 28 days prior to apheresis; Trial participants with carcinomatous meningitis should be excluded, whether clinically stable or not.

• 20.Trial participants with other malignancy within 5 years prior to apheresis, with the exception of malignancy expected to be cured with treatment (including, but not limited to, adequately treated thyroid cancer, in situ cancer of cervix, basal or squamous cell carcinoma of skin, or ductal carcinoma in situ of the breast treated by radical operation).

• 21.Trial participants have any other disease, metabolic abnormality, physical examination abnormality, or laboratory test abnormality that, in the opinion of the investigator, suggests a condition or disease that would not be suitable for study treatment and may affect the interpretation of the study results or put the trial participants at high risk.

• 22.Trial participants have inadequate compliance with the study in the opinion of the investigator or have other factors that would make the trial participants inappropriate for participation in the study.

• 23.Trial participants with a history or current diagnosis of uncontrolled psychosis.