Autologous B7-H3 Chimeric Antigen Receptor T Cells in Previously Treated Extensive-Stage Small Cell Lung Cancer With Recurrent or Refractory Disease

Официальное название

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

Обзор

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....

Подробное описание

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:

* Age \>=18 years. * Histologically confirmed SCLC or EP-NEC that has recurred following or refractory to first-line therapy. * At least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

Design:

* This is a Phase I dose escalation/de-escalation study evaluating autologous B7-H3 CAR T cells in participants with R/R SCLC or EP-NEC. * Participants will undergo apheresis for T cell selection. Collected T cells will be transduced with a lentivirus encoding the B7-H3 CAR construct. Participants will receive a lymphodepletion regimen with the intent of enhancing the activity and proliferation of the infused autologous B7-H3 CAR T cells. * During study treatment, participants will have clinical assessments, laboratory evaluations, and imaging studies for safety and response assessment. Blood and tumor samples will be collected for correlative studies at various timepoints. * After study treatment completion, follow-up will be performed for up to 15 years.

Вмешательства

• Препарат Autologous B7-H3 CAR T
  For both dose escalation and expansion phases, B7-H3 CAR T cell infusion will be performed following lymphodepleting therapy. Up to 2 years post the initial infusion, participants will be offered the option for an additional infusion of B7-H3 CAR T cells at the same dose level as the initial dose, with or without LD if eligible.
• Препарат Cyclophosphamide
  For both dose escalation and expansion phases, FDA approved lymphodepleting agents, cyclophosphamide and fludarabine will be used on this study prior to the administration of T cells.
• Препарат Fludarabine
  For both dose escalation and expansion phases, FDA approved lymphodepleting agents, cyclophosphamide and fludarabine will be used on this study prior to the administration of T cells.

Первичные конечные точки

• Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells [Срок оценки: Dose Limiting Toxicity (DLT) period (day 0 through day 28)]
• Determine disease control rate (DCR) [Срок оценки: Until disease progression or 15 years, whichever occurs first]

Вторичные конечные точки (6)

• Assess safety of autologous B7-H3 CAR T cells infusion [Срок оценки: Study duration]
• Objective Response Rate (ORR) [Срок оценки: Until disease progression or 15 years, whichever occurs first]
• Duration of Response (DOR) [Срок оценки: Until disease progression or 15 years, whichever occurs first]
• Progression Free Survival (PFS) [Срок оценки: Until disease progression or 15 years, whichever occurs first]
• Overall Survival (OS) [Срок оценки: Until death or 15 years, whichever occurs first]
• Evaluate safety of re-treatment [Срок оценки: Study duration]

Критерии участия

• 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) 0-2.
• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• National Institutes of Health Clinical Center — Bethesda

Идентификаторы

NCT: NCT07509034 · 10001973 · 001973-C

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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