Trial to evaluate CAR-T NKG2D CAR cell infusions in patients with advanced sarcoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospital Universitario La Paz

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Jan 2024 → ongoing

Decision date (initial)

2024-04-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513514-35-00

EudraCT number

2019-004310-33

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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 the efficacy of NKGD2-CAR memory T cells in patients’ tumor volume after therapy.

Secondary objectives 6

1. To determine NKG2DL expression in primary sarcoma samples.
2. To determine the persistence of NKG2D-CAR T cells in patient samples (peripheral blood and tumor).
3. To determine cytokines in the serum of patients.
4. To obtain primary patient-derived cancer cells from accessible sarcomas
5. To 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.
6. To evaluate the presence of soluble NKG2DL and anti-MICA antibodies in the serum of patients under therapy.8- Analysis of patient and donor peripheral blood immune cell subpopulations and finished cell product CART45RA-NKG2D.

Conditions and MedDRA coding

Sarcoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 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.
3. Patients must have either measurable or evaluable tumor.
4. The tumor must be accessible for intralesional administration of CAR T cells (only in ARM B).
5. Life expectancy of at least 10 weeks in opinion of the principal investigator (PI).
6. Lansky (age <16 years) or Karnofsky (age >=16 years) score of 50 or greater.
7. Patients must have recovered from the acute toxic effects of all prior anticancer therapy (including chemotherapy and radiotherapy).
8. 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.
9. 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.
10. Patient or patient's legal representative, parent(s), or guardian able to provide written informed consent.
11. 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.

Exclusion criteria 7

1. Enrolled in another treatment protocol.
2. 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.
3. Chronic corticosteroid dependence (except replacement therapy).
4. Evidence of any toxicity grade ≥ 4 (according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0).
5. Pregnant or lactating women.
6. Medical history of epilepsy.
7. Any other condition that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 11

1. Rate of NKG2D-CAR T cells persistence in peripheral blood.
2. Rate of NKG2D-CAR T cells persistence in the tumor and metastasis site.
3. Rate of NKG2DL positive expression on primary sarcoma samples.
4. Cytokine determination in the serum of patients.
5. Obtain primary patient-derived cancer cells from accessible sarcomas
6. 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.
7. Evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under therapy.
8. Analysis of patient peripheral blood immune cell subpopulations
9. Incidence and severity of adverse events (clinical and laboratory).
10. Incidence of SAEs.
11. Performance status.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospital Universitario La Paz

Sponsor organisation

Hospital Universitario La Paz

Address

Paseo De La Castellana 261

City

Madrid

Postcode

28046

Country

Spain

Scientific contact point

Organisation

Hospital Universitario La Paz

Contact name

Dr. Antonio Pérez Martínez

Public contact point

Organisation

Hospital Universitario La Paz

Contact name

Dr. Antonio Pérez Martínez

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

4 submissions — initial application plus substantial / non-substantial modifications