Using engineered T cells to treat advanced sarcoma in young patients

A Phase I Trial of Memory T Cells Expressing an NKG2D Chimeric Antigen Receptor in Children, Adolescents and Young Adults With Advanced Sarcoma

This study is testing if special T cell treatments can help young patients with advanced sarcoma who haven't had success with regular treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: N/A to 30 Years
• Sex: All
• Sponsor: Instituto de Investigación Hospital Universitario La Paz (Academic / other)
• Drugs / interventions: CAR T, CAR-T, chemotherapy, chimeric antigen receptor
• Locations: 1 site (Madrid)
• Trial ID: NCT06087341 on ClinicalTrials.gov

What this trial studies

This Phase I clinical trial aims to evaluate the safety and effectiveness of NKG2D chimeric antigen receptor (CAR) memory T cell infusions in children, adolescents, and young adults with advanced sarcoma. The study will assess the maximum tolerated dose and dose-limiting toxicity of these infusions, both systemically and locally. By targeting the NKG2D receptor, which plays a crucial role in immune surveillance against tumors, the trial seeks to improve treatment outcomes for patients with high-risk sarcoma who have not responded to standard therapies.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 40 years or younger with advanced sarcoma that has recurred or is unresponsive to standard therapies and shows positive NKG2DL expression.

Not a fit: Patients with sarcoma that does not express NKG2DL or those who are not eligible for biopsy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve survival rates and quality of life for young patients with advanced sarcoma.

How similar studies have performed: While the use of CAR T cell therapies is gaining traction, this specific approach targeting NKG2D in pediatric sarcoma is relatively novel and has not been extensively tested in prior studies.

Eligibility criteria

Inclusion Criteria:

* Age: ≤ 40 years at the time of recurrence or progression with any type of sarcoma that has recurred or not responded to standard therapy and is deemed incurable by standard therapy.
* Positive NKG2DL expression in sarcoma samples. Ideally, they should have centralized histological verification of NKG2DL expression in sarcoma samples (positive expression is defined as at least 2+ expression (0-4+ scale) in \>50 percent of the tumor cells using anti-MICA and or anti-ULBP2). Patients will undergo biopsy following enrollment to obtain tissue to assess NKG2DL expression, with the following restrictions:

  * If the patient doesn´t have adequate accessible tumor for biopsy (at least 1 cm diameter).
  * Procedures employed to acquire biopsies for tumor lysates will be limited to percutaneous needle or core biopsies, thoracoscopic excision or open biopsies of readily accessible lesions. Pulmonary lesions may be biopsied but extensive surgery such as thoracotomy or laparotomy should not be employed.
  * Patients who require biopsy should not be enrolled if in the opinion of the principal investigator (PI), the tumor site places the patient at substantial related risk from the biopsy procedure.

In patients that fulfill any of these restrictions, when adequate archived tissue is available, this may be utilized to assess NKG2DL expression.

* Patient must have either measurable or evaluable tumor.
* The tumor must be accessible for intralesional administration of CAR T cells (only in ARM B).
* Life expectancy of at least 10 weeks in opinion of the principal investigator (PI).
* Lansky (age \<16 years) or Karnofsky (age \>=16 years) score of 50 or greater.
* Patients must have recovered from the acute toxic effects of all prior anticancer therapy (including chemotherapy and radiotherapy).
* Adequate bone marrow function defined by an absolute neutrophil count (ANC) of \>/= 1.000/μL, platelet count of \>/= 30.000/μL and hemoglobin of \>/= 9.0 g/dl, and absence of a regular red blood cell and platelet transfusion requirement.
* Patients should have a normal hepatic function with a total bilirubin \<2 times the upper limit of normal and serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) \< 2 times the upper limit of normal, and adequate renal function as defined by a serum creatinine ≤ 1.5 upper limit of normal.
* Patient or patient's legal representative, parent(s), or guardian able to provide written informed consent.
* Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the infusion. Male partner should use a condom.

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for at least 6 months after the NKG2D-CAR T infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests. Highly effective contraception methods include, as defined by the CTFG recommendations (available at h t t p s : / / w w w . h m a . e u / f i l e a d m i n / d a t e i e n / H u m a n \_ M e d i c i n e s / 0 1 -About\_HMA/Working\_Groups/CTFG/2014\_09\_HMA\_CTFG\_Contraception.pdf):

* Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
* Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
* Intrauterine device (IUD)
* Intrauterine hormone-releasing system
* Bilateral tubal occlusion
* Vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success)
* Sexual abstinence (only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject).

Sexually active males should use a condom during intercourse while taking study treatment and for at least 6 months after the infusion and until CAR-T cell are no longer present by qPCR on two consecutive tests.

Exclusion Criteria:

* Enrolled in another treatment protocol.
* Evidence of untreated and active infection or clinically significant systemic illness:

  * Cardiac disorder defined as LVFE \< 45% determined by ECHO.
  * Human Immunodeficiency Virus (HIV) positive test.
  * Presence of active or prior CMV, EBV, hepatitis B or C as indicated by serology.
  * Any significant pulmonary, hepatic or other organ dysfunction.
* Chronic corticosteroid dependence (except replacement therapy).
* Evidence of any toxicity grade ≥ 4 (according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0).
* Pregnant or lactating women.
* Medical history of epilepsy.
* Any other condition that, in the opinion if the PI, may interfere with the efficacy and/or safety evaluation of the trial.

Where this trial is running

Madrid

• Hospital Universitario La paz — Madrid, Spain (Recruiting)

Study contacts

• Study coordinator: Antonio Pérez Martínez

Conditions Advanced Sarcoma