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

NCT06087341 | Recruiting Phase 1

• 1 other identifier: CAR4SAR
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

Phase I, open label, prospective, single-center, non-randomized, dose escalation clinical trial aiming to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of systemic transduced donor-derived NKG2D-CAR memory T cell infusions (Arm A), and of dual treatment, with both systemic and locally transduced donor-derived NKG2D-CAR memory T cell infusions (Arm B).

Conditions

Advanced Sarcoma

Outcome Measures

Primary Outcomes (3)

• Safety: Dose-limiting toxicity (DLT) of NKG2D-CAR memory T cells

  1. Any grade 3 or higher toxicity with an attribution of definitely or probably related to the infusion of the NKG2D CAR-T cells with the exception of Grade 3 fever and immediate hypersensitivity reactions occurring within 2hours of cell infusion that are reversible to a Grade 2 or less within 24 hours of cell administration with standard therapy; 2. Any lower grade toxicity that increases to a grade 3 or higher as a direct result of the NKG2D CAR-T cell infusion.

  During the study treatment, until 28 days after the last study iv treatment administration

• Safety: Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells

  The highest dose level if no Dose-limiting toxicitys are observed

  During the study treatment, until 28 days after the last study iv treatment administration

• Response rate

  This outcome will be evaluated by Immune-Related Response Criteria (iRECIST) v1.1. The efficacy will be measured by objective response rate (ORR) at D60 in both arms, which includes Complete Response (CR) and Partial Response (PR) based on Immune-Related Response Criteria iRECIST v1.1.

  At day 60 after the treatment

Secondary Outcomes (7)

• Rate of NKG2D-CAR T cells persistence in peripheral blood

  During 12 months after the treatment

• Rate of NKG2D-CAR T cells persistence in the tumor and metastasis site

  21 and 60 days after the treatment

• Rate of NKG2DL positive expression on primary sarcoma samples

  21 and 60 days after the treatment

• Cytokine determination in the serum of patients

  During 12 months after the treatment

• Analysis of patient peripheral blood immune cell subpopulations

  21 and 60 days after the treatment

Study Arms (2)

NKG2D-CAR memory T cells infusion

EXPERIMENTAL

If the primary tumor and/or metastases are not accessible, the patient will be included in Arm A.This group will receive an intravenous infusion of NKG2D-CAR memory T cells.

Other: NKG2D-CAR memory T cell

Systemic and locally transduced NKG2D-CAR memory T cells infusion

EXPERIMENTAL

If the primary tumor and/or metastases are accessible, the patient will be included in Arm B. This group will receive an intravenous infusion of NKG2D-CAR memory T cells and an intratumoral dose of NKG2D-CAR memory T cells.

Other: NKG2D-CAR memory T cell

Interventions

NKG2D-CAR memory T cell OTHER

Patients will be allocated in two groups: Arm A and Arm B. Both groups will receive an intravenous infusion of NKG2D-CAR memory T cells. Additionally, patients on Arm B will receive an intratumoral dose of NKG2D-CAR memory T cells (in accessible primary tumor and metastases). The distribution of patients on one arm or other will depend on their clinical characteristics described in the inclusion/ exclusion criteria. All patients will receive lymphodepleting chemotherapy prior to the infusion of NKG2D-CAR memory T cells according to the usual clinical practice in our center. Some patients will also receive low dose radiotherapy prior to infusion.

NKG2D-CAR memory T cells infusion; Systemic and locally transduced NKG2D-CAR memory T cells infusion

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Antonio Pérez Martínez: lead

Study Sites (1)

Hospital Universitario La paz

Madrid, 442944, Spain

RECRUITING

Central Study Contacts

Antonio Pérez Martínez

CONTACT

917 27 75 76; aperezmartinez@salud.madrid.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief of Pediatric Hemato-Oncology and Hematopoietic Transplantation Service

Model Details: Arm A: systemic transduced donor-derived NKG2D-CAR memory T cells infusion. Arm B: dual treatment, with both systemic and locally transduced donor-derived NKG2D-CAR memory T cells infusion.

Study Record Dates

• First Submitted: October 11, 2023
• First Posted: October 17, 2023
• Study Start: January 10, 2024
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): April 1, 2028
• Last Updated: April 12, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)