A Phase I Clinical Trial of CART cell therapy for refractory/ relapsed acute lymphoblastic leukemia with unmet needs in children, adolescents and young adults: feasibility and safety study (REALL_CART)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Para La Investigacion Biomedica Del 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]

Decision date (initial)

2024-05-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

In this umbrella trial, we will determine in parallel within independent cohorts:
1- The safety and feasibility of autologous CART-19/22 in children, adolescents and young adults with a CD19+/- CD22+/- relapse/ refractory disease for a r/r B cell precursor ALL.
2- The safety and feasibility of allogeneic CART-NKG2D T in children, adolescents and young adults with r/r T-ALL.

Secondary objectives 6

1. Expression of CD19/CD22 and NKG2DL on primary B- and T- ALL, respectively.
2. Persistence of CART19/22 and CARTs-NKG2D cells in patients’ samples (peripheral blood, bone marrow and cerebrospinal fluid (if available).
3. Peripheral blood cytokine profile from the patients’ serum (weekly until evaluation).
4. Identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPs 1-3) in primary T-cell malignancies’ samples.
5. Evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under CART-NKG2D therapy.
6. Overall rate response in both arms

Conditions and MedDRA coding

Refractory/ relapsed acute lymphoblastic leukemia in children, adolescents and young adults.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age: Patients <30 years at diagnosis and/or relapse.
2. Absolute lymphocyte count ≥ 100/μL.
3. Adequate renal, hepatic, pulmonary, and cardiac function.
4. Adequate venous access and absence of contraindications for lymphoapheresis.
5. Patients with a seizure disorder may be enrolled if well controlled with anticonvulsants.
6. Patient or patient's legal representative, parent(s), or guardian able to provide written informed consent.
7. 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.
8. 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.
9. For ARM B there must be a suitable haploidentical donor (following local SOP).
10. Lansky (age <16 years) or Karnofsky (age ≥16 years) score of 50 or greater.
11. Life expectancy greater than 12 weeks.
12. 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.
13. 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 9

1. Enrolled in another clinical trial in the previous 4 weeks.
2. 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.
3. Any of the following cardiac criteria: cardiac echocardiography with LVSF<30% or LVEF<40%; or clinically significant pericardial effusion.
4. Presence of CNS-3 disease or uncontrolled seizure disorder.
5. Active immunosuppressive therapy with the exception of prednisone 10 mg/day (or equivalent), within 7 days prior to enrolment.
6. GFR <30 ml/min or bilirubin >3 times the upper limit of normality (unless due to Gilbert's syndrome).
7. Any other condition that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial.
8. Pregnant or lactating women.
9. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. In this umbrella trial, we will determine in parallel within independent cohorts: 1- The safety and feasibility of autologous CART-19/22 in children, adolescents and young adults with a CD19+/- CD22+ relapse/ refractory disease for a r/r B-ALL. 2- The safety and feasibility of allogeneic CART-NKG2D T in children, adolescents and young adults with r/r T-ALL.

Secondary endpoints 6

1. Expression of CD19/CD22 and NKG2DL on primary B- or T- cell ALL, respectively.
2. Persistence of CART19/22 and CARTs-NKG2D cells in patients’ samples (peripheral blood, bone marrow, cerebrospinal fluid).
3. Peripheral blood cytokine profile from the patients’ serum.
4. Identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPs 1-3) in primary T-cell malignancies’ samples.
5. Evaluate the presence of soluble NKG2DL and ANTI-MICA and ANTI-MICB antibodies in the serum of patients under CART-NKG2D therapy.
6. Overall rate response in both arms.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Para La Investigacion Biomedica Del Hospital Universitario La Paz

Sponsor organisation

Fundacion Para La Investigacion Biomedica Del Hospital Universitario La Paz

Address

Paseo Castellana 261

City

Madrid

Postcode

28046

Country

Spain

Scientific contact point

Organisation

Fundacion Para La Investigacion Biomedica Del Hospital Universitario La Paz

Contact name

Dr. Antonio Pérez Martínez

Public contact point

Organisation

Fundacion Para La Investigacion Biomedica Del Hospital Universitario La Paz

Contact name

Dr. Antonio Pérez Martínez

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Application history

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