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

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

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....

Study Overview

• Status: Not yet recruiting
• Conditions: Solid Tumors; Extensive-Stage Small Cell Lung Cancer; Recurrent or Refractory; Extrapulmonary Neuroendocrine Carcinoma
• Intervention / Treatment: Drug: Autologous B7-H3 CAR T; Drug: Cyclophosphamide; Drug: Fludarabine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Danielle F Pinkiert, R.N.; Phone Number: (240) 858-7566; Email: danielle.pinkiert@nih.gov
• Study Contact Backup: Name: Anish Thomas, M.D.; Phone Number: (240) 760-7343; Email: anish.thomas@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
      • Contact: National Cancer Institute Referral Office; Phone Number: 888-624-1937; Email: NCIMO_Referrals@mail.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• 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 percent 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.
• Absolute Neutrophil Count (ANC) >= 750/mcL.
• Platelet count >= 75,000/mcL.
• An absolute lymphocyte count (ALC) >=300/mcL and CD3 plus cell count >=150/mcL.
• Normal cardiac ejection fraction as defined by >= 45 percent 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.

• 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.

EXCLUSION CRITERIA:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation; Escalating doses of autologous B7-H3 CAR T cells.	Drug: 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.; Drug: 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.; Drug: 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.
Experimental: Dose Expansion; Maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells.	Drug: 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.; Drug: 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.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells	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.	Dose Limiting Toxicity (DLT) period (day 0 through day 28)
Determine disease control rate (DCR)	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.	Until disease progression or 15 years, whichever occurs first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess safety of autologous B7-H3 CAR T cells infusion	Safety will be reported based on the number (percentage) of participants experiencing adverse events per dose level as well as reporting specific grades and types of toxicity encountered per the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.	Study duration
Objective Response Rate (ORR)	The ORR will be reported among 13-16 participants, which includes both participants treated at the MTD/MAD during the dose escalation phase (3-6 participants) and the 10 participants treated during the dose expansion phase, along with a 95% two-sided confidence interval.	Until disease progression or 15 years, whichever occurs first
Duration of Response (DOR)	DOR will be reported using a Kaplan-Meier curve and 95% confidence interval for the median of each based on the participants at the final dose level.	Until disease progression or 15 years, whichever occurs first
Progression Free Survival (PFS)	PFS will be reported using a Kaplan-Meier curve and 95% confidence interval for the median of each based on the participants at the final dose level.	Until disease progression or 15 years, whichever occurs first
Overall Survival (OS)	OS will be reported based on those participants using a Kaplan-Meier curve and 95% confidence interval for the median OS.	Until death or 15 years, whichever occurs first
Evaluate safety of re-treatment	Safety will be reported based on the number (percentage) of participants experiencing adverse events per dose level as well as reporting specific grades and types of toxicity encountered per CTCAE v6.0.	Study duration

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Anish Thomas, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): June 9, 2026
• Primary Completion (Estimated): January 30, 2030
• Study Completion (Estimated): January 30, 2031

Study Registration Dates

• First Submitted: April 2, 2026
• First Submitted That Met QC Criteria: April 2, 2026
• First Posted (Actual): April 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: May 14, 2026

More Information

Terms related to this study

• Keywords: CAR-T; Immunotherapy; Phase I; B7-H3
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Recurrence; Small Cell Lung Carcinoma; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; fludarabine
• Other Study ID Numbers: 10001973; 001973-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD recorded in the medical record will be shared with intramural investigators upon request. This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review.
• IPD Sharing Time Frame: Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.
• IPD Sharing Access Criteria: Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No