- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06087341
A Phase I Trial of Memory T Cells Expressing an NKG2D Chimeric Antigen Receptor in Children, Adolescents and Young Adults With Advanced Sarcoma (CAR4SAR)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Contact
- Name: Antonio Pérez Martínez
- Phone Number: 917 27 75 76
- Email: aperezmartinez@salud.madrid.org
Study Locations
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Madrid, Spain, 442944
- Recruiting
- Hospital Universitario La Paz
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Contact:
- Antonio Pérez Martínez, MD
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
Accepts Healthy Volunteers
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: NKG2D-CAR memory T cells infusion
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.
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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.
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Experimental: Systemic and locally transduced NKG2D-CAR memory T cells infusion
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.
|
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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety: Dose-limiting toxicity (DLT) of NKG2D-CAR memory T cells
Time Frame: During the study treatment, until 28 days after the last study iv treatment administration
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During the study treatment, until 28 days after the last study iv treatment administration
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Safety: Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells
Time Frame: During the study treatment, until 28 days after the last study iv treatment administration
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The highest dose level if no Dose-limiting toxicitys are observed
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During the study treatment, until 28 days after the last study iv treatment administration
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Response rate
Time Frame: At day 60 after the treatment
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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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Rate of NKG2DL positive expression on primary sarcoma samples
Time Frame: 21 and 60 days after the treatment
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Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in peripheral blood at D21 and D60.
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21 and 60 days after the treatment
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Evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under therapy
Time Frame: During 60 days after the treatment
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The presence of anti-MICA antibodies will be determined in the serum of patients obtained at different times using LABScreen assay by Luminex Technology (LABScreen TM MICA and LSA-MIC single antigen, One Lambda and Diagnostica Longwood, respectively).
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During 60 days after the treatment
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Rate of NKG2D-CAR T cells persistence in peripheral blood
Time Frame: During 12 months after the treatment
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Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in peripheral blood at screening and then starting from D1.
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During 12 months after the treatment
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Rate of NKG2D-CAR T cells persistence in the tumor and metastasis site
Time Frame: 21 and 60 days after the treatment
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Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in the tumor samples at biopsy times (D21 and D60).
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21 and 60 days after the treatment
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Cytokine determination in the serum of patients
Time Frame: During 12 months after the treatment
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Obtain primary patient-derived cancer cells from accessible sarcomas
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During 12 months after the treatment
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Analysis of patient peripheral blood immune cell subpopulations
Time Frame: 21 and 60 days after the treatment
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Identify the immune cell phenotypes linked to CAR-T expansion and response provides an opportunity to understand the mechanisms of CAR-T success and craft approaches to improve CAR-T activity.
The changes in cell differentiation stages and exhaustion markers of immune populations will be done by spectral flow cytometry.
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21 and 60 days after the treatment
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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.
Time Frame: 21 and 60 days after the treatment
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Analyze the DNA methylation profile of MICA, MICB and ULBP1-3 genes in primary sarcoma samples from D0, D21 and D60, by pyrosequencing techniques.
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21 and 60 days after the treatment
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- CAR4SAR
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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