A Phase I Study to Assess the Safety and Antitumor Activity of Autologous B7-H3 Chimeric Antigen Receptor T Cells in Previously Treated Extensive-Stage Small Cell Lung Cancer With Recurrent or Refractory Disease
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells
研究概览
简要总结
Background:
Small cell lung cancer (SCLC) is the deadliest form of lung cancer. Extrapulmonary neuroendocrine cancer (EPNEC) is a similar type of cancer that develops anywhere other than the lungs. EPNEC is also deadly. B7-H3 is a protein often found in SCLC and EPNEC tumor cells. Researchers can modify a person s own T cells, or immune cells, to target B7-H3. When these modified T cells are returned to the body-a treatment called B7-H3 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells.
Objective:
To test B7-H3 CAR T cell therapy in people with SCLC or EPNEC.
Eligibility:
People aged 18 years and older with SCLC or EPNEC that either did not respond or returned after treatment.
Design:
Participants will be screened. They will have blood tests and tests of their heart function. They will have imaging scans.
Participants will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be altered to make them attack cells with B7-H3.
Participants will be in the hospital for at least 15 days. They will receive chemotherapy drugs to prepare their body for the treatment. These drugs will be given through a tube attached to a needle inserted into a vein.
The modified T cells will be infused through a vein. Participants will remain in the hospital until they are well enough to go home.
Follow-up visits will continue for 15 years....
详细描述
Background:
- Small cell lung cancer (SCLC) is the most lethal form of lung cancer with an average life expectancy of 7 to 11 months.
- Extrapulmonary neuroendocrine cancers (EP-NEC) are rare and aggressive orphan cancers that share morphological and transcriptomic similarities and potentially therapeutic vulnerabilities with SCLC, with no standard treatments at relapse.
- Currently available therapies for patients who have disease progression after first-line chemotherapy-immunotherapy yield limited clinical benefit. Most patients with recurrent/refractory (R/R) SCLC or EP-NEC die within months of disease progression.
- Chimeric antigen receptor (CAR) T cells recognize and kill target-expressing tumor cells.
- B7 homolog 3 (B7-H3, also known as CD276) is a surface molecule highly expressed in multiple solid tumor types, including SCLC and EP-NEC, with minimal expression in normal human tissues.
- B7-H3 targeted CAR T cells have shown preliminary evidence of safety and efficacy in B7-H3 expressing pediatric solid tumors and brain tumors.
Objective:
- Arm 1: To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells in participants with previously treated recurrent/refractory (R/R) extensive-stage small cell lung cancer (ES-SCLC) or extrapulmonary neuroendocrine cancer (EP-NEC).
- Arm 2: To determine Disease Control Rate (DCR).
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Age >=18 years old.
- •Histologically confirmed small cell lung cancer (SCLC) or extrapulmonary neuroendocrine cancers (EP-NEC) that has recurred following or is refractory to first-line therapy. Note: small cell cancers of non-lung primary sites are also eligible.
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-
- •Pulse oximetry >= 90% on room air.
- •Aspartate Transferase (AST) < 3 X institutional upper limit of normal (ULN). Note: in case of liver metastases <= 5 X ULN is acceptable.
- •Alanine Aminotransferase (ALT) < 3 X institutional ULN. Note: in case of liver metastases <= 5 X ULN is acceptable.
- •Total bilirubin <=2 X institutional ULN.
- •Creatinine <=1.5 X institutional ULN OR creatinine clearance (CrCl) >= 50 mL/min/1.73m^2 (calculated by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula or calculated eGFR provided by a laboratory).
- •Absolute Neutrophil Count (ANC) >= 750/mcL.
- •Platelet count >= 75,000/mcL.
- •An absolute lymphocyte count (ALC) >=300/mcL and CD3+ cell count >=150/mcL.
- •Normal cardiac ejection fraction as defined by >= 45% by echocardiogram (ECHO) at screening.
- •At least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 that has not been previously irradiated.
- •Recovered from acute toxic effects of all prior cancer therapy to Grade <2 per Common Terminology Criteria for Adverse Events (CTCAE) v.6.0 at least one week before apheresis excluding the parameters for ANC and ALC mentioned above.
- •The following criteria must be met prior to apheresis:
- •Chemotherapy and biologic/targeted agents:
- •>=14 days since the last dose of standard myelosuppressive chemotherapy.
- •>= 7 days since the completion of biologic agent, targeted agent, or tyrosine kinase inhibitor therapy.
- •>= 3 weeks or 5 half-lives (whichever is shorter) since prior therapy with a monoclonal antibody.
- •Radiotherapy:
- •>= 1 week since the last radiotherapy session.
- •No washout period required for palliative radiation to non-target lesions.
- •>= 3 weeks since hepatic radiation, chemoembolization, and/or radiofrequency ablation.
- •Steroids and immunosuppressive therapy:
- •Corticosteroids: >= 2 weeks since the therapeutic doses (> 0.5 mg/kg/day prednisone or equivalent). Note: Inhaled or topical steroids are not exclusionary.
- •Physiologic replacement doses (up to 5 mg/day prednisone equivalent) are allowed and can be adjusted based on participant's BMI if warranted.
- •>= 2 weeks since the other immunosuppressive medication (e.g., calcineurin inhibitors, methotrexate, rapamycin, thalidomide, etc.).
- •Anti-PD-1 and any investigational therapies:
- •>= 2 weeks since Anti-PD-1 monoclonal antibody therapy.
- •>= 2 weeks or 5 half-lives of the investigational product (whichever is shorter) since any investigational treatment or clinical trial participation.
- •Other criteria:
- •72 hours since small molecule tyrosine kinase inhibitors (e.g., EGFR inhibitors), PARP inhibitors, or KRAS G12C inhibitors.
- •Individuals of childbearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy.
- •Note: IOCBP is defined as any individual who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
- •Individuals able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 7 months after the last dose of study drugs. We also will recommend individuals able to father a child with partners of childbearing potential ask partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals able to father a child must not freeze or donate sperm within the same period.
- •Nursing participants must be willing to discontinue nursing from study treatment initiation through 6 months after the last dose of the study drug(s).
- •Ability of the participant to understand and the willingness to sign a written informed consent document.
排除标准
- •History of anaphylactic reactions attributed to anti-B7-H3 antibodies or compounds of similar chemical or biologic composition to autologous B7-H3 CAR T cells, cyclophosphamide, fludarabine, or other agents used in this study.
- •Infection exposure with the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) as defined below:
- •Positive serology for HIV.
- •Active HBV infection as demonstrated by test for hepatitis B surface antigen (HBsAg).
- •Positive serology for HCV.
- •Prior gene therapy using an integrating vector (except for autologous B7-H3 CAR T cells retreatment).
- •History of any previous allogeneic hematopoietic stem cell transplant.
- •Presence of fungal, bacterial, viral, or other infection is permitted if responding to active treatment.
- •Central Nervous System (CNS) disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that may impair the ability to evaluate neurotoxicity.
- •Pregnancy confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test in IOCBP at screening.
- •Uncontrolled intercurrent illness or medical condition(s) evaluated by medical history, physical exam, electrocardiogram (ECG) or situations that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study.
研究组 & 干预措施
Dose Expansion
Maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells.
干预措施: Autologous B7-H3 CAR T (Drug)
Dose Escalation
Escalating doses of autologous B7-H3 CAR T cells.
干预措施: Autologous B7-H3 CAR T (Drug)
Dose Expansion
Maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells.
干预措施: Cyclophosphamide (Drug)
Dose Escalation
Escalating doses of autologous B7-H3 CAR T cells.
干预措施: Fludarabine (Drug)
Dose Escalation
Escalating doses of autologous B7-H3 CAR T cells.
干预措施: Cyclophosphamide (Drug)
Dose Expansion
Maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells
时间窗: Dose Limiting Toxicity (DLT) period (day 0 through day 28)
The MTD/MAD is the dose level at which no more than 1 of up to 6 participants experience DLT during autologous B7-H3 CAR T cell treatment, and the dose below that at which at least 2 (of \<=6) participants have DLT as a result of treatment.
Determine disease control rate (DCR)
时间窗: Until disease progression or 15 years, whichever occurs first
DCR will be reported as a percentage of participants who achieve a complete response, partial response, or stable disease following autologous B7-H3 CAR T cells treatment.
次要结局
- Overall Survival (OS)(Until death or 15 years, whichever occurs first)
- Evaluate safety of re-treatment(Study duration)
- Assess safety of autologous B7-H3 CAR T cells infusion(Study duration)
- Objective Response Rate (ORR)(Until disease progression or 15 years, whichever occurs first)
- Duration of Response (DOR)(Until disease progression or 15 years, whichever occurs first)
- Progression Free Survival (PFS)(Until disease progression or 15 years, whichever occurs first)