Safety and Efficacy of Systemic Allogenic NK Cells in R/R Neuroblastoma

Official title

Evaluation of Safety and Efficacy Evaluation Post Intravenous Infusion of Activated NK Cells in Recurrent and Refractory High-risk Neuroblastoma Patients

Overview

The goal of this clinical trial is to assess safety and efficacy of systemic injection of allogenic NK cells in patients with refractory/recurrent high-risk neuroblastoma. Is the injection of allogenic nk cells safe in patients with R/R high-risk neuroblastoma? Is the injection of allogenic nk cells effective in patients with R/R high-risk neuroblastoma? We will compare the NK cell administration group with a control group that receives conventional treatment to determine whether the intervention is safe and effective

Detailed description

NK cells are isolated from healthy donors through the apheresis process and subsequently separated using the CLINIMACS device in a clean room environment. After quality assessment (sterility, viable cell count, purity, and phenotype of active cells), they are stored at -198°C until use. Upon need, the cells are thawed and washed, followed by checking their viability, count, and sterility. Children between the ages of 2 to 16 who meet the eligibility criteria will be added to the study. After admission, the cells are injected into the patient at a ratio of 5×10\^6 cells per kilogram of the patient's body weight. A total of 3 injections are administered to all patients. Based on the patient's response and recovery status, the need for additional injections is evaluated. If improvements in the patient's condition are observed after the last injection and confirmed by MRI MIBG, further 2 injections can continue. The intervals between injections vary based on the patient's standard treatment, and the cells are injected 10 days after the completion of each chemotherapy course.

Interventions

• Biological Allogenic NK cells infusion
  Natural Killer (NK) cells are extracted from a healthy donor through apheresis and processed in a clean room using the CLINIMACS device. After quality assessment, these cells are stored at -198°C until needed. When required, the cells are thawed, washed, and evaluated for viability and sterility before being administered to the patient at a dosage of 5 × 10\^6 cells per kilogram of body weight. Two further injections may be considered based on the patient's response and confirmed improvement via

Primary outcome measures

• NK Cell Infusion Safety [Time frame: After each injection to next injection and 2 weeks after last injection]

Secondary outcome measures (1)

• Response rate comparison between control and intervention groups [Time frame: 6 months and 12 months]

Eligibility criteria

Inclusion criteria

• High-risk neuroblastoma that is resistant to standard induction therapy based on COG (Children's Oncology Group) criteria (according to INRG criteria and having received at least 4 cycles of multi-drug induction chemotherapy, and not responding to conventional treatments).
• Evidence of relapse or progression of neuroblastoma after autologous peripheral blood stem cell transplantation or aggressive therapy.
• A minimum life expectancy of 6 months.
• Patients must have a pathological diagnosis of neuroblastoma and/or confirmation of tumor cells in the bone marrow with increased urinary catecholamines.
• Measurable residual disease based on imaging findings using Curie scoring or MIBG or PET imaging criteria (1: measurable tumor of at least 10 mm in one dimension on MRI or CT scan with positive uptake on I-123 MIBG scan ("MIBG avid") oOR 2): increased FDG uptake on 18F-FDG PET-CT or PET-MRI ("PET avid")).

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Exclusion criteria

• Insufficient bone marrow function: Platelet count > 50,000/µL, independent of transfusion (no platelet transfusion within one week). Absolute neutrophil count (ANC) maximum of 500 per microliter. Hemoglobin > 10 grams per deciliter.
• Insufficient liver function: Plasma bilirubin level more than 1.5 times the upper limit of normal (ULN). SGPT (ALT) at least three times the upper limit of normal (a level of 45 units per liter is considered the upper limit of normal).
• Insufficient kidney function: Creatinine clearance or estimated radioisotope GFR < 70 ml/min/1.73m². Plasma creatinine level more than 1.5 times the upper limit of normal based on age/gender.
• Insufficient central nervous system function if seizures are present, entry into the study is not possible and if seizures are not well controlled with anticonvulsant drugs.

3- Insufficient cardiovascular function Shortening fraction < 27% by ECHO OR Ejection fraction < 50% by ECHO or gated radionuclide study.

4- Insufficient pulmonary function evidence of dyspnea at rest. Exercise intolerance. Chronic need for oxygen and room air pulse oximetry < 94% if pulse oximetry evaluation is clinically indicated. Presence of current pleural or pericardial effusion.

5- Inability to tolerate new treatment due to emergency conditions. 6- Elevated catecholamines (more than twice the ULN) or sole involvement of bone marrow (bone marrow positive for NB as the only evaluable disease without confirmatory pathology report).

7- Receiving 0.5 mg/kg/day of systemic steroids (equivalent to prednisone) for at least 7 days before enrollment.

8- Receiving CYP3A4 inducers or inhibitors at least 7 days before study enrollment.

9- Diagnosis of any other malignancy alongside the diagnosis of neuroblastoma. 10- Diarrhea > Grade 2 (4 to 6 stools per day). 11- Significant illness not covered by exclusion criteria but interfering with the study process or increasing the intensity of treatment with NK cells.

12- Participation in another clinical trial. 13- Severe impairment of major organ functions, such as renal, cardiac, hepatic, neurological, pulmonary, or gastrointestinal toxicity above Grade 2 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 (CTC v5.0).

14- Inability to comply with protocol requirements. 15- Lack of confirmed and signed consent by the patient's guardians. 16- Evidence of HIV disease (Human Immunodeficiency Virus) or positive serology for HIV.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Iran · 1 center

• Rasoul Akram Hospital — Tehran

Identifiers

NCT: NCT06674265 · IR.ACECR.ROYAN.REC.1400.032

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗