Advanced Sarcoma
Conditions
Interventions
Product Name: CART45RA-NKG2D Cells
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: CART45RA NKG2D cells
Other descriptive name: CART45RA NKG2D cells
Concentration unit: U/g unit(s)/
Sponsors
Dr. Antonio Pérez Martínez
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age: 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 doesn´t have 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. • 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) 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: o Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (eg: calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception o Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that hav
Exclusion criteria
Exclusion criteria: • Enrolled in another treatment protocol • 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 • Chronic corticosteroid dependence (except replacement therapy) • Evidence of any toxicity grade = 4 (according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.3) • 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To determine the safety and feasibility of a Phase I Clinical Trial on administering escalating doses of NKG2D-CAR memory T cells in children and young adults with advanced sarcoma. - To analyze NKGD2-CAR memory T cells efficacy on patients’ tumor volume after therapy.;Timepoint(s) of evaluation of this end point: 28 days after the last study treatment;Secondary Objective: - To determine NKG2DL expression on primary sarcoma samples. - To determine the persistence of NKG2D-CAR T cells in patient samples (peripheral blood and tumor). - To determine cytokines in the serum of patients. - To confirm the activity of NKG2D-CAR T cells against sarcoma primary cells and clonal coevolution during in vitro cultures. - To identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPS 1-3) in primary sarcoma samples. - To evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under therapy.;Primary end point(s): The primary aim of the study is to determine the safety, feasibility and clinical activity of NKG2D-CAR memory T cells in children and young adults with advanced sarcoma. • Safety: Dose-limiting toxicity (DLT) and Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells.: The primary outcome will be the occurrence of Dose-limiting toxicity (DLTs) in all patients during the study treatment, until 28 days after the last study treatment iv administration and the Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells . We define DLT as: (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 Fever Grade 3 and immediate hypersensitivity reactions occurring within 2hours of cell infusion that are reversible to a Grade 2 or less within 24hours 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 cells infusion. MTD is d | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Rate of NKG2D-CAR T cells persistence in the peripheral blood. Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in the peripheral blood at each visit time point. • Rate of NKG2D-CAR T cells persistence in the the tumor site metastasis. Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in the tumor samples at each visit time point. • Rate of NKG2DL possitive expression on primary sarcoma samples. Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in the peripheral blood at D21 and D60. • Cytokine determination in the serum of patients. • Confirmation of NKG2D-CAR T cells activity against autologous sarcoma primary cells and clonal coevolution during in vitro cultures. • Identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPS 1-3) in primary sarcoma samples. • Evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under therapy.;Timepoint(s) of evaluation of this end point: 28 days after the last study treatment | — |
Countries
Spain
Contacts
Public ContactIrene Garcia
UCICEC
Outcome results
None listed