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

Plain English Summary

Autologous B7-H3 Chimeric Antigen Receptor T Cells in Previously Treated Extensive-Stage Small Cell Lung Cancer With Recurrent or Refractory Disease is a Phase 1 clinical trial sponsored by National Cancer Institute (NCI) studying Extensive-Stage Small Cell Lung Cancer, Extrapulmonary Neuroendocrine Carcinoma, Recurrent or Refractory, Solid Tumors. This trial tests a new type of T-cell therapy designed to target and kill cancer cells in patients with advanced small cell lung cancer or similar rare cancers. It is for adults with small cell lung cancer or extrapulmonary neuroendocrine cancer that has returned or not responded to previous treatments. Participation involves a screening process, collection of the patient's own T-cells, chemotherapy, infusion of the modified T-cells, and extensive follow-up. Alternative treatments may include chemotherapy, radiation, immunotherapy, or other targeted therapies depending on the specific cancer and prior treatments. The trial aims to enroll 40 participants.

Official Summary

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....

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with specific types of lung or neuroendocrine cancer that has not responded to or has returned after initial treatment. Patients must have good enough organ function (heart, liver, kidney) and blood counts to tolerate the treatment. Individuals with active infections, certain prior cancer treatments, or specific allergies may not be eligible. This trial is studying Extensive-Stage Small Cell Lung Cancer, Extrapulmonary Neuroendocrine Carcinoma, Recurrent or Refractory, Solid Tumors, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures will show how safe the new T-cell therapy is and how well it controls or shrinks the tumors, indicating its potential to extend life or improve symptoms. The specific primary outcome measures are: Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells (Dose Limiting Toxicity (DLT) period (day 0 through day 28)); Determine disease control rate (DCR) (Until disease progression or 15 years, whichever occurs first). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial addresses a critical need for new treatments for aggressive small cell lung cancer and similar rare cancers that have limited options after initial therapy. This research targets Extensive-Stage Small Cell Lung Cancer, Extrapulmonary Neuroendocrine Carcinoma, Recurrent or Refractory, Solid Tumors, where improved treatment options are needed.

Investor Insight

This trial represents an investment in a cutting-edge cell therapy approach for a difficult-to-treat cancer, with potential for significant market impact if successful. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of CAR T-cell therapy, including potential side effects and the commitment required for treatment and follow-up. Be prepared for a hospital stay for chemotherapy and the T-cell infusion, followed by regular visits for up to 15 years to monitor your health and response to treatment. Understand that your own T-cells will be collected, modified in a lab, and then given back to you to fight the cancer. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 40 participants

Interventions

• 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.

Primary Outcomes

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

Secondary Outcomes

• 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)
• Overall Survival (OS) (Until death or 15 years, whichever occurs first)

Full Eligibility Criteria

* 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, cer

Trial Locations

• National Institutes of Health Clinical Center, Bethesda, Maryland, United States

Frequently Asked Questions

Related Conditions

• Small Cell Lung Cancer
• Extrapulmonary Neuroendocrine Carcinoma
• Lung Cancer
• Neuroendocrine Tumors
• Recurrent Cancer
• Refractory Cancer
• Solid Tumors
• Oncology
• Immunotherapy
• Cell Therapy

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