Phase I Evaluation of CART45RA-NKG2D and CART 19/22 T Cells in Refractory/Relapsed Acute Lymphoblastic Leukemia in Pediatric and Young Adult Cohorts
- Trial ID
- 2023-509723-41-00
- Protocol
- REALL_ CART
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase I clinical trial is to evaluate the **safety** and **feasibility** of two distinct CART cell therapies in children, adolescents, and young adults with refractory or relapsed acute lymphoblastic leukemia (ALL). Specifically, the trial aims to assess autologous CART-19/22 therapy in patients with CD19+/- CD22+/- B cell precursor ALL and allogeneic CART-NKG2D T therapy in patients with T-ALL. This evaluation is crucial for determining the potential of these therapies to address unmet clinical needs in this patient population.
Secondary objectives include:
- Assessing the expression of CD19/CD22 and NKG2DL on primary B- and T-ALL, respectively.
- Evaluating the persistence of CART19/22 and CARTs-NKG2D cells in patients' samples, including peripheral blood, bone marrow, and cerebrospinal fluid.
- Analyzing the peripheral blood cytokine profile from patients' serum on a weekly basis until evaluation.
- Identifying the DNA methylation profile of NKG2DL (MICA, MICB, and ULBPs 1-3) in primary T-cell malignancies' samples.
- Evaluating the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients undergoing CART-NKG2D therapy.
- Determining the overall response rate in both arms of the study.
Participants
The clinical trial involves participants diagnosed with **refractory/relapsed acute lymphoblastic leukemia** (ALL) in children, adolescents, and young adults. The study population includes both male and female subjects under the age of 30 at diagnosis and/or relapse. Participants are required to have a Lansky score (for those under 16 years) or a Karnofsky score (for those 16 years and older) of 50 or greater, indicating a general health status that allows for participation in the trial. The trial does not specifically target a vulnerable population. Participants must have a life expectancy greater than 12 weeks and meet certain hematological and organ function criteria. The selection process for the trial population is not detailed, as the sponsor has not provided information on the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include adequate venous access and the absence of contraindications for lymphoapheresis, as well as the ability to provide informed consent. The trial is designed to assess the safety and feasibility of autologous and allogeneic CART therapies in this patient population.
Plans and Procedures
The clinical trial is a **Phase I**, open-label, prospective, single-center, two-armed, non-randomized study designed to evaluate the safety and feasibility of **CART cell therapy** in patients with refractory or relapsed **acute lymphoblastic leukemia** (ALL). The trial targets children, adolescents, and young adults with unmet medical needs. The study involves two independent cohorts: one assessing autologous **CART-19/22 T cells** in patients with CD19+/- CD22+/- B-cell precursor ALL, and the other evaluating allogeneic **CART45RA-NKG2D cells** in patients with T-cell ALL. The trial is expected to commence recruitment on June 1, 2024, and conclude by December 31, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, life expectancy, and adequate organ function. The inclusion criteria specify that patients must be under 30 years at diagnosis or relapse, have a life expectancy greater than 12 weeks, and meet specific hematological and functional parameters. Following the screening, eligible participants will receive the investigational product via **intravenous infusion**. Subsequent follow-up visits will monitor the persistence of CART cells, cytokine profiles, and other secondary endpoints, such as the expression of CD19/CD22 and NKG2DL on primary ALL cells.
The expected duration of participant involvement will vary depending on individual response and the occurrence of any adverse events. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The end-of-study visit will involve a comprehensive assessment to evaluate the overall response rate and the presence of any long-term effects of the therapy. The trial aims to provide critical insights into the feasibility and safety of CART cell therapy in this patient population, with the potential to inform future therapeutic strategies for refractory or relapsed ALL.
Treatment
The clinical trial involves the administration of **CART45RA-NKG2D CELLS**, an experimental medication designed for the treatment of refractory/relapsed acute lymphoblastic leukemia. This investigational product is a **structurally diverse substance** categorized under cell therapy. The pharmaceutical form of CART45RA-NKG2D CELLS is an **intravenous infusion**, and it is administered via this route. The dosing schedule and frequency of administration are determined based on the specific protocol requirements of the trial. The product is not formulated for pediatric use, and its administration is monitored to ensure participant compliance and safety.
Another experimental treatment used in this trial is **CART 19/22 T CELLS**, which is also a **structurally diverse substance** classified as cell therapy. Similar to CART45RA-NKG2D CELLS, this product is administered as an **intravenous infusion**. The administration route and pharmaceutical form are consistent with the trial's protocol, ensuring standardized delivery of the treatment. The CART 19/22 T CELLS are not specifically formulated for pediatric patients, and compliance with the dosing regimen is closely monitored throughout the study.
In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is on evaluating the safety and feasibility of the experimental cell therapies in the specified patient population. The trial is designed to assess the therapeutic potential of these cell-based treatments in children, adolescents, and young adults with refractory/relapsed acute lymphoblastic leukemia, with a particular emphasis on those with unmet medical needs.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating the safety and feasibility of two types of **CART cell therapy**: autologous CART-19/22 for patients with CD19+/- CD22+ relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), and allogeneic CART-NKG2D T for those with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL). These assessments will be conducted in parallel within independent cohorts.
Secondary endpoints include the expression levels of CD19/CD22 and NKG2DL on primary B- or T-cell ALL, respectively. The persistence of CART19/22 and CARTs-NKG2D cells will be monitored in patient samples, including peripheral blood, bone marrow, and cerebrospinal fluid. Additionally, the peripheral blood cytokine profile will be analyzed from the patients' serum. The trial will also identify the DNA methylation profile of NKG2DL (MICA, MICB, and ULBPs 1-3) in primary T-cell malignancies' samples. The presence of soluble NKG2DL and antibodies such as ANTI-MICA and ANTI-MICB in the serum of patients undergoing CART-NKG2D therapy will be evaluated. Finally, the overall response rate in both arms of the trial will be assessed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age: Patients <30 years at diagnosis and/or relapse.
- Absolute lymphocyte count ≥ 100/μL.
- Adequate renal, hepatic, pulmonary, and cardiac function.
- Adequate venous access and absence of contraindications for lymphoapheresis.
- Patients with a seizure disorder may be enrolled if well controlled with anticonvulsants.
- Patient or patient's legal representative, parent(s), or guardian able to provide written informed consent.
- Diagnosis: o ARM A: CD19+/- CD22+ B-ALL with relapsed or refractory disease not responding to conventional chemotherapy and with no other curative therapy available. Treatment with previous CART CD19 therapy is permitted, but is not mandatory. / o ARM B: T-ALL with relapsed or refractory disease not responding to conventional chemotherapy and with no other curative therapy available.
- Patients diagnosed with ALL must be suitable for allogeneic HSCT and willing to proceed to transplant if the CART treatment induces complete remission and the investigator believes it is the best option.
- For ARM B there must be a suitable haploidentical donor (following local SOP).
- Lansky (age <16 years) or Karnofsky (age ≥16 years) score of 50 or greater.
- Life expectancy greater than 12 weeks.
- Absolute neutrophil count (ANC) ≥ 500/μL unless, in the opinion of the investigator, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy.
- Platelet count ≥ 50,000/μL unless, in the opinion of the investigator, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy.
Exclusion Criteria
- Enrolled in another clinical trial in the previous 4 weeks.
- Active infection requiring systemic medical therapy including clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV, adenovirus, BK-virus, HHV-6 or Aspergillus.
- Any of the following cardiac criteria: cardiac echocardiography with LVSF<30% or LVEF<40%; or clinically significant pericardial effusion.
- Presence of CNS-3 disease or uncontrolled seizure disorder.
- Active immunosuppressive therapy with the exception of prednisone 10 mg/day (or equivalent), within 7 days prior to enrolment.
- GFR <30 ml/min or bilirubin >3 times the upper limit of normality (unless due to Gilbert's syndrome).
- Any other condition that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial.
- Pregnant or lactating women.
- Sexually active patients must be willing to utilize one of the more effective birth control methods for at least 12 months after the infusion and until CAR-T cells are no longer present on two consecutive tests. Male partner should use a condom. Women of child-bearing potential are defined as all women physiologically capable of becoming pregnant. 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): o Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) o Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) o Intrauterine device (IUD) o Intrauterine hormone-releasing system o Bilateral tubal occlusion o Vasectomized partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success) o 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 for at least 12 months after the infusion and until CAR-T cells are no longer present on two consecutive tests.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Yet Recruiting | 01 Jun 2024 | 10 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CART45RA-NKG2D CELLS | Test | INTRAVENOUS INFUSION | INTRAVENOUS INFUSION | — | — | PRD10997227 |
CART 19/22 T CELLS | Test | INTRAVENOUS INFUSION | INTRAVENIOUS INFUSION | — | — | PRD10996964 |