Small Cell Lung Cancer Extensive Stage
Conditions
Keywords
Extensive Stage-SCLC, DLL3 CAR-T, Bridge Radiotherapy
Brief summary
A study to evaluate the safety and feasibility of α-PD-L1/4-1BB DLL3 Chimeric Antigen Receptor (CAR)-T (BHP01) in patients with Relapsed/Refractory Small Cell Lung Cancer (SCLC) and determine the appropriate CAR-T cell dose. Next, In dose expansion phase, patients were assign two groups with/without bridge radiotherapy.
Detailed description
Small cell lung cancer (SCLC) accounts for about 15% of lung cancers, and two-thirds of cases are metastatic at the time of diagnosis. The inhibitory notch ligand delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of up to 85% of SCLC cells and minimally expressed in normal tissues, making it a compelling therapeutic target. This is a phase I, first-in-human, 3+3 dose escalation study to evaluate the safety and feasibility of BHP01 in patents with relapsed/refractory SCLC who progressed after at least 1 platinum based chemotherapy regimen.This is a dose escalation and dose expansion study. 12-21 patients with relapsed/refractory SCLC are planned to be enrolled (Group Pre-A/A/B/C). After the Dose-limiting toxicity (DLT) observation period of the related dose group finished.16 patients are planned to enroll in dose expansion phase who was assign two groups with/without bridge radiotherapy.
Interventions
DRUGα-PD-L1/4-1BB DLL3 CAR-T (BHP01)
Preconditioning with fludarabine, cyclophosphamide, based chemotherapy regimen at sub-clinical doses; Bridge radiotherapy with 15 Gray (Gy)/5 fractions; α-PD-L1/4-1BB DLL3 CAR-T (BHP01): the first dose was 5x10\^5/kg.
Sponsors
Sichuan University
Chengdu Brilliant Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with recurrent or refractory small cell lung cancer (SCLC) confirmed by histology or cytology who have relapsed or progressed after treatment with one previous platinum-based regimen; * Patients can provide sufficient tumor tissue (fresh or paraffin sections, etc.); * Age 18 \~70 (including boundary), for both men and women; * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; * Life expectancy ≥3 months; * At least one extracranial measurable lesion (RECIST v1.1) exists；for lesion after radiotherapy， must be confirmed that the lesion has progressed ; * Patients in limited-stage at the initial diagnosis must undergo radical thoracic radiotherapy and the time of tumor progression is not less than 1 months from the end of radiotherapy, or radical thoracic dose radiotherapy cannot be performed for specific reasons; The time elapsed since the completion of radiotherapy for brain metastases shall be no less than 1 months； * The test results of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C and syphilis were negative at screening (If hepatitis B core antibody (HBcAb) is positive, additional HBV DNA testing is required, and subjects whose test result is less than the reference value can be included in the study) ; * Female patients or male reproductive age patients and their partners should agree to effective contraception from sighing Informed Consent Form (ICF) to 6 months after the last BHP01 infusion.
Exclusion criteria
* Patients with known primary Central Nervous System (CNS) tumor, or meningeal metastasis, or patients with unstable CNS metastasis (symptomatic, requiring hormonal therapy within 4 weeks before investigational treatment, or no radiographic evidence of stabilization of the lesion for more than 4 weeks); * Received major surgical procedures （except for diagnosis） within 4 weeks before PBMCs collection, or are expected to require major surgical procedures during the study; * Received Chinese herbal medicine or Chinese patent medicine for anti-tumor indications within 7 days before Peripheral Blood Mononuclear Cells (PBMCs) collection; * Patients with a history of idiopathic pulmonary fibrosis, mechanical pneumonia (such as bronchiolitis obliterans), drug-induced pneumonia or idiopathic pneumonia, or evidence of active pneumonia by chest computer tomography (CT) at screening \[a history of radiation pneumonia (fibrosis) in the irradiated field may participate in this study\]; * Poorly controlled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once a month or more frequently); * Poorly controlled or symptomatic hypercalcemia (ionic calcium\> 1.5 mmol/L, calcium\> 12 mg/dL or corrected calcium\> ULN); * Presence of active or previous autoimmune diseases or immunodeficiencies, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, etc.; * Severe infection within 4 weeks before the start of PBMCs collection, including but not limited to hospitalization due to infection, bacteremia, severe pneumonia, or any active infection that may affect the patient's safety; * Serious cardiovascular and cerebrovascular diseases (such as heart disease ≥New York Heart Association class II, myocardial infarction or cerebrovascular accident), unstable arrhythmia or unstable angina pectoris within 3 months before PBMCs collection; * Previous treatment with DLL 3 target drugs or CAR-T or other gene-modified T cells; * Received any other Investigational drug within 28 days prior to PBMCs collection; * A history of mental illness; * Incapacitated persons or persons with limited capacity; * pregnant or lactating females; Males or females who are unwilling to use adequate contraception; Females of childbearing potential are required to undergo a pregnancy study during the screening period;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity (DLT) | day1-day28 | Safety |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | up to 1 year after the enrollment | The Objective Response Rate (ORR) is the percentage of participants who achieved a best overall response of Complete Response (CR) or Partial Response (PR) based on RECIST version 1.1. In the event of PR or CR, the subjects should confirm it no less than 4 weeks after the first evaluation. |
| Progression-free survival (PFS) | up to 1 year after the enrollment | The time from CAR-T administration to disease progression or death. |
| Disease control rate (DCR) | up to 1 year after the enrollment | The number of cases in which response (PR + CR) and stable disease (SD) are achieved from the start of cell infusion/the total number of evaluable cases (%). |
| Duration of response (DOR) | up to 1 year after the enrollment | The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause |
| Overall-Survival (OS) | up to 1 year after the enrollment | The period from the first infusion to any cause of death |
| CAR-T cell numbers | up to 1 year after the enrollment | Monitoring CAR-T cell numbers in blood to determine the persistence of CAR-T. |
Countries
China
Contacts
CONTACTJianxin Xue, MD
CONTACTZhuoran Yao, MD
PRINCIPAL_INVESTIGATORYou Lu, MD
West China Hospital
Outcome results
None listed