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IRCT20170122032121N7 IRCT 2023-07-22 Kian immune cell company Efficacy of allogenic NK cells IT injection in patients with high grade brain glioma Efficacy of the intrathecal injection of activated allogeneic natural killer cells in patients with High-grade gliomas; A multi-center phase II clinical trial 2023-06-22 anticipated 40 Complete https://irct.ir/trial/70113 interventional Randomization: Randomized, Blinding: Not blinded, Placebo: Not used, Assignment: Parallel, Purpose: Treatment, Randomization description: In this trial, patients will be stratified in 2 level: first level patient under 18 y/o and second level above 18 y/o. For random allocation in each stratum, permuted-block randomization method will be used. Ratio of patients in intervention group to patients in control group would be 3 to 1 and for randomization 5 foursome blocks in each stratum would be selected. Each block contains one patient in control group and 3 patients in intervention group. Required blocks will be designed and randomly selected using Sealed Envelope software and the patients would be placed in houses of each block in order of date of recruitment. 2 High grade brain glioma. Intervention 1: Intervention group: Patients in intervention group will receive 200 millions NK cells via intrathecal injection (LP or resorvor) for 3 times. In cases who have ongoing surgery or have been operated recently and have been planned for radiotherapy after surgery, if the patient condition would be suitable for IT injection, the first injection will be administered one or two weeks after the end of radiotherapy. The other doses would be injected in the period between courses of chemotherapy (one week after the end of last chemotherapy course). In cases who have passed surgery and radiotherapy and in the cases who are not eligible for surgery and radiotherapy (such as diffuse midline glioma cases) all three injections will be administered in the period between chemotherapy courses. CSF will be taken before each injection for intended assessments. The therapist physicians would be suggested to not prescribe corticosteroids or prescribe low dose of them from 3 days before to one week after NK cell injection to avoid their suppressing effects on NK cells. But this is not mandatory because of the risk of brain edema. Also therapist physicians would be suggested to prescribe immune checkpoint inhibitors if there is indication (PD-L1 expression or MSI) for prescription to intensify the cytotoxic effect of NK cells. Intervention 2: Control group: patients in control group will not receive any cells and just conventional treatments (surgery, radiotherapy and chemotherapy) will be ordered for them. Because of the risk of the adverse events, IT injection of the placebo will not be done for patients in control group. But if the study results 6 months after last injection of last patient would reveal that there is significant superiority in the intervention group, patients in the control group can be benefited with NK cell therapy for free. Patients in control group will be Followed-up till one year after recruitment for comparison with intervention group. Yes - There is a plan to make this available What will be shared: After concealment of personal information of participants, data of eligibility, CRFs and measured outcomes can be shared in case of request When: After publishing results in a scientific journal with no deadline To whom: Just to academic PIs Conditions: Any usage of data should be consulted and approved by the PIs Where to obtain: Applicant should send an e-mail to Dr.Mahdizadeh and propose their detailed requirements of the study data How to obtain: After sending an e-mail to Dr.Mahdizadeh, he will assess the authenticity of the applicant in almost 2 weeks. Then he will plan a meeting (visual or attendance) for the applicant with Dr.Ebrahimi in next month. The applicant can obtain approval of data sharing in this meeting and the data will be sent in next 14 days Comments:
public Hamid Mahdizadeh
Kian immune cell company, first floor, Royan RITAC center, Number 6, Keshvari alley, Banihashem square, Banihashem street, Resalat highway, Tehran, Iran
Tehran Iran (Islamic Republic of) 1665813339 +98 21 2233 8248 mahdizadehmd@yahoo.com Royan institute & Kian immune cell company scientific Hamid Mahdizadeh
Kian immune cell company, first floor, Royan RITAC center, Number 6, Keshvari alley, Banihashem square, Banihashem street, Resalat highway, Tehran, Iran
Tehran Iran (Islamic Republic of) 1665813339 +98 21 2233 8248 mahdizadehmd@yahoo.com Royan institute & Kian immune cell company Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) New diagnosed patients with grade 3 or 4 brain tumor, based on WHO classification, which are included in the one of the following conditions: • Astrocytoma, IDH-mutant • Oligodendroglioma, IDH-mutant • Glioblastoma, IDH-wild type • Diffuse midline glioma • Diffuse hemispheric glioma • Diffuse pediatric-type high-grade glioma, IDH-wild type Age range of 3 to 60 years old both sex Lansky/Karnofsky performance score above 60 Obtained informed consent of patients or parents or legal attendance in cases of pediatrics Hemoglobin above 10 gr/dL of blood Absolute granulocyte count (AGC) above 500 per microliter of blood Platelet count above 50000 per microliter of blood INR below 2 and PTT less than 1.5 times of maximum normal value Plasma bilirubin level less than 1.5 times of maximum normal value Plasma hepatic transaminases (ALT and AST) level less than 3 times of maximum normal value Plasma creatinine level less than 1.5 times of maximum normal value 3 years 60 years Both Evidence of radio necrosis in MRI or MRS Intolerance of new treatment due to emergency condition History of other malignancies History of any immunodeficiency diseases or any immune compromising conditions Rupture of cerebral shunt or unable to perform a lumbar puncture Pregnancy History of uncontrolled chronic diseases such as: Diabetes, CHF, liver cirrhosis, CKD, etc. C71 Malignant neoplasm of brain Treatment - Other Other Intervention group: Patients in intervention group will receive 200 millions NK cells via intrathecal injection (LP or resorvor) for 3 times. In cases who have ongoing surgery or have been operated recently and have been planned for radiotherapy after surgery, if the patient condition would be suitable for IT injection, the first injection will be administered one or two weeks after the end of radiotherapy. The other doses would be injected in the period between courses of chemotherapy (one week after the end of last chemotherapy course). In cases who have passed surgery and radiotherapy and in the cases who are not eligible for surgery and radiotherapy (such as diffuse midline glioma cases) all three injections will be administered in the period between chemotherapy courses. CSF will be taken before each injection for intended assessments. The therapist physicians would be suggested to not prescribe corticosteroids or prescribe low dose of them from 3 days before to one week after NK cell injection to avoid their suppressing effects on NK cells. But this is not mandatory because of the risk of brain edema. Also therapist physicians would be suggested to prescribe immune checkpoint inhibitors if there is indication (PD-L1 expression or MSI) for prescription to intensify the cytotoxic effect of NK cells. Control group: patients in control group will not receive any cells and just conventional treatments (surgery, radiotherapy and chemotherapy) will be ordered for them. Because of the risk of the adverse events, IT injection of the placebo will not be done for patients in control group. But if the study results 6 months after last injection of last patient would reveal that there is significant superiority in the intervention group, patients in the control group can be benefited with NK cell therapy for free. Patients in control group will be Followed-up till one year after recruitment for comparison with intervention group. Response rate comparison between control and intervention groups. Timepoint: 1 to 2 weeks after last injection with the follow up of 3, 6, and 12 months after last injection. Method of measurement: Using iRANO (Immunotherapy Response Assessment in Neuro-Oncology) checklist and using MRI and MRS. Safety. Timepoint: After each injection to next injection and 2 weeks after last injection. Method of measurement: Using CTCAEs (Common Terminology Criteria for Adverse Events) checklist. Overall survival and progression-free survival. Timepoint: After the end of the study. Method of measurement: using Kaplan-Meier method. Analysis of CSF including: hematology, biochemistry, culture, cytokine level and immunophenotype of cells. Timepoint: Before each injection, CSF sample will be taken from patients for analysis. Method of measurement: using microscope and slides, spectrophotometer, enzyme assay, ELISA and Flowcytometry. Royan institute Kian immune cell company Royan institute Approved 2023-02-28 Royan institute ethics committee Royan ethics committee, Royan alley, Hafez street, Banihashem square, Banihashem street, Resalat highway, Tehran, Iran Tehran Tehran Iran (Islamic Republic of)