CART45RA-NKG2D CELLS for Sarcoma | Advanced sarcoma

Inclusion criteria

• {"criterion_text":"- 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.\n- Patient or patient's legal representative, parent(s), or guardian able to provide written informed consent.\n- 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.\n- 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: o If the patient does not have an adequate accessible tumor for biopsy (at least 1 cm diameter). o 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. o 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.\n- Patients must have either measurable or evaluable tumor.\n- The tumor must be accessible for intralesional administration of CAR T cells (only in ARM B).\n- Life expectancy of at least 10 weeks in opinion of the principal investigator (PI).\n- Lansky (age <16 years) or Karnofsky (age >=16 years) score of 50 or greater.\n- Patients must have recovered from the acute toxic effects of all prior anticancer therapy (including chemotherapy and radiotherapy).\n- 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.\n- 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."}

Exclusion criteria

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

Primary endpoints

• {"endpoint_text":"- The occurrence of Dose-limiting toxicities (DLTs) in all patients during the study treatment, until 28 days after the last study IV treatment administration and the Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells.","definition_or_measurement_approach":"DLTs observed during study treatment up to 28 days after the last IV administration; determination of Maximum Tolerated Dose (MTD) based on observed DLTs."}

Secondary endpoints

• {"endpoint_text":"- Rate of NKG2D-CAR T cells persistence in peripheral blood.","definition_or_measurement_approach":"Measurement of persistence of NKG2D-CAR T cells in peripheral blood (method not specified)."}
• {"endpoint_text":"- Rate of NKG2D-CAR T cells persistence in the tumor and metastasis site.","definition_or_measurement_approach":"Assessment of persistence of NKG2D-CAR T cells in tumor and metastasis sites (method not specified)."}
• {"endpoint_text":"- Rate of NKG2DL positive expression on primary sarcoma samples.","definition_or_measurement_approach":"Assessment of NKG2DL expression in primary sarcoma samples (positive defined in inclusion: at least 2+ on 0-4+ scale in >50% tumor cells using anti-MICA and/or anti-ULBP2)."}
• {"endpoint_text":"- Cytokine determination in the serum of patients.","definition_or_measurement_approach":"Measurement/determination of cytokine levels in patient serum (methods not specified)."}
• {"endpoint_text":"- Obtain primary patient-derived cancer cells from accessible sarcomas","definition_or_measurement_approach":"Collection of primary patient-derived cancer cells from accessible sarcomas (procedures and analyses not specified)."}
• {"endpoint_text":"- Identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPS 1-3) in primary sarcoma samples and DNA methylation profile of NKG2D-T cells before and after infusion.","definition_or_measurement_approach":"Profiling DNA methylation of specified genes in tumor samples and in NKG2D-T cells pre- and post-infusion (methods not specified)."}
• {"endpoint_text":"- Evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under therapy.","definition_or_measurement_approach":"Measurement of soluble NKG2DL and anti-MICA antibodies in serum (methods not specified)."}
• {"endpoint_text":"- Analysis of patient peripheral blood immune cell subpopulations","definition_or_measurement_approach":"Analysis of immune cell subpopulations in peripheral blood (methods not specified)."}
• {"endpoint_text":"- Incidence and severity of adverse events (clinical and laboratory).","definition_or_measurement_approach":"Recording and grading of adverse events (clinical and laboratory), likely using CTCAE v5.0 as referenced elsewhere for toxicity grading."}
• {"endpoint_text":"- Incidence of SAEs.","definition_or_measurement_approach":"Recording incidence of serious adverse events (SAEs) as per standard regulatory definitions (method not specified)."}
• {"endpoint_text":"- Performance status.","definition_or_measurement_approach":"Assessment of performance status (Lansky for age <16 or Karnofsky for age ≥16 as referenced in inclusion criteria)."}

Spain

Earliest CTIS Part Ii Submission Date

08-04-2024

Latest Decision Or Authorization Date

19-12-2025

Processing Time Days

620

Number Of Sites

1

Number Of Participants

18

Primary sponsor

Full Name

Hospital Universitario La Paz

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Spain