Protocol summary

Study aim
Cell therapy with Anti-CD19 CAR-NK Cells in patients with relapsed or incurable B-ALL.
Design
The trial is a single-arm interventional phase 1-2 research (Not randomized and not blinded) on 10 patients aimed to examine the safety and define the maximum tolerated dosage (MTD) of cord blood-derived CAR-NK cells in patients with relapsed or incurable B-ALL.
Settings and conduct
The study is a single-group clinical trial to evaluate the safety and maximum tolerated dose of allogeneic in-vitro manipulated Natural Killer Cells for relapsed or incurable B-ALL at the cancer immunology and immunotherapy research center of Tabriz University.
Participants/Inclusion and exclusion criteria
Inclusion: relapsed or incurable B-ALL, Signed written informed consent. Exclusion: Pregnant/lactating women; infections; use of immunosuppressors
Intervention groups
Main treatment + infusion of Anti-CD19 CAR-NK Cells. The preparation regimen includes cyclophosphamide and fludarabine. The CAR-NK cells are injected with a single dose of CAR-NK cells including either (10 million) or (50 million) or (100 million) cells per kilogram of the patient's body weight. Increasing the dose continues until reaching the maximum determined dose (100 million) or the occurrence of dose-limiting toxicity.
Main outcome variables
Incidence of dose-limiting toxicity; Assessment of Maximum Tolerated Dose; Overall Remission Rate; Progression-free survival; Duration of Response

General information

Reason for update
Acronym
IRCT registration information
IRCT registration number: IRCT20200413047063N5
Registration date: 2024-06-16, 1403/03/27
Registration timing: prospective

Last update: 2024-06-16, 1403/03/27
Update count: 0
Registration date
2024-06-16, 1403/03/27
Registrant information
Name
Masoud Soleimani
Name of organization / entity
Tarbiat Modares University
Country
Iran (Islamic Republic of)
Phone
+98 21 8288 4508
Email address
soleimani.masoud@gmail.com
Recruitment status
recruiting
Funding source
Expected recruitment start date
2024-06-19, 1403/03/30
Expected recruitment end date
2026-06-20, 1405/03/30
Actual recruitment start date
empty
Actual recruitment end date
empty
Trial completion date
empty
Scientific title
Cell therapy with anti-CD19 CAR-NK cells in patients with relapsed or resistant B-ALL
Public title
Immune cell therapy in patients with relapsed or resistant B-ALL
Purpose
Treatment
Inclusion/Exclusion criteria
Inclusion criteria:
Eligible diseases: Acute lymphocytic leukemia (ALL CD19+). Patients 3 years of age or older, and must have a life expectancy > 12 weeks. Eastern cooperative oncology group (ECOG) performance status of 0-2 or karnofsky performance status (KPS) score is higher than 60. Females of child-bearing potential must have a negative pregnancy test and all subjects must agree to use an effective method of contraception for up to two weeks after the last infusion of CAR NK cells. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements: White blood cell count (WBC) ≥ 2500c/ml, Platelets ≥ 50×10^9/L, Hb ≥ 9.0g/dL, lymphocyte (LY) ≥ 0.7×10^9/L, LY% ≥ 15%, Alb ≥ 2.8g/dL, serum lipase and amylase < 1.5×upper limit of normal, serum creatinine ≤ 2.5mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5×upper limit of normal, serum total bilirubin ≤ 2.0mg/dL. These tests must be conducted within 7 days prior to registration. Ability to give informed consent.
Exclusion criteria:
Pregnant or nursing women may not participate. Active HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at the time of screening. Serious illness or medical condition which would not permit the patient to be managed according to the protocol, including active uncontrolled infection, major cardiovascular, coagulation disorders, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive/restrictive pulmonary disease, or psychiatric or emotional disorders. History of severe immediate hypersensitivity to any of the agents including cyclophosphamide, fludarabine, or aldesleukin. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary. The existence of unstable or active ulcers or gastrointestinal bleeding. Patients need anticoagulant therapy (such as warfarin or heparin). Patients need long-term antiplatelet therapy (aspirin at a dose > 300mg/d; clopidogrel at a dose > 75mg/d). Patients using fludarabine or cladribine chemotherapy within 3 months prior to leukapheresis.
Age
From 3 years old
Gender
Both
Phase
1-2
Groups that have been masked
No information
Sample size
Target sample size: 10
Randomization (investigator's opinion)
Not randomized
Randomization description
Blinding (investigator's opinion)
Not blinded
Blinding description
Placebo
Not used
Assignment
Single
Other design features

Secondary Ids

empty

Ethics committees

1

Ethics committee
Name of ethics committee
Ethics Committee of Tabriz University of Medical Sciences
Street address
Tabriz University of Medical Sciences, Niyayesh Blvd., Molasadra Blvd.
City
Tabriz
Province
East Azarbaijan
Postal code
5166/15731
Approval date
2023-06-26, 1402/04/05
Ethics committee reference number
IR.TBZMED.REC.1402.259

Health conditions studied

1

Description of health condition studied
relapsed or incurable B Cell Acute Lymphoblastic Leukemia
ICD-10 code
C91.02
ICD-10 code description
Acute lymphoblastic leukemia, in relapse

Primary outcomes

1

Description
Incidence of dose-limiting toxicity (DLTs)
Timepoint
Daily during the first seven days after the injection and then weekly until 4 weeks
Method of measurement
History, Physical exam, and lab test

2

Description
Overall Remission Rate (ORR)
Timepoint
8 weeks after CAR-NK cells infusion
Method of measurement
Assessed using International lymphoma party (LWP) Group

Secondary outcomes

1

Description
Progression-free survival (PFS)
Timepoint
48 weeks after CAR-NK cells infusion
Method of measurement
Assessed using International Lymphoma Working Party (LWP) criteria

2

Description
Duration of Response (DOR)
Timepoint
48 weeks after CAR-NK cells infusion
Method of measurement
Assessed using International Lymphoma Working Party (LWP) criteria

Intervention groups

1

Description
Intervention group: A single infusion of Anti CD19 CAR NK cells, the patient is brought to the isolation room 4 days before receiving CAR-NK cells and gets a chemotherapeutic conditioning treatment (days - 4 to - 1). The preparation regimen includes cyclophosphamide at a dose of 30 mg/kg/day from day -3 to day -2 (for two days) and fludarabine at a dose of 30 mg/m2/day from day -4 to day -2 (for three days).On day zero, the CAR-NK cells, which have been prepared in the laboratory clean room, are injected with a single dose of CAR-NK cells including either (10 million) or (50 million) or (100 million) cells per kilogram of the patient's body weight. Increasing the dose continues until reaching the maximum determined dose (100 million) or the occurrence of dose-limiting toxicity.To evaluate the maximum tolerated cell dose, the 3+3 formula is used. The minimum initial safe dose includes ten million cells per kilogram of the patient's body weight, which is injected into the first three patients, and if no dose-limiting toxicity occurs, for the next three patients, the dose is increased by half a log (fifty million cells to per kilogram of the patient's body weight). The cell dose will be increased up to a maximum dose of 100 million cells per kilogram of body weight unless dose-limiting toxicity occurs. The definition of the maximum tolerated cell dose according to the ICMJE guidelines includes the highest cell dose, which is shown by a maximum of 2 out of 6 patients.Based on this, dose-limiting toxicity (DLT) is defined as follows:1- Acute and severe allergic reaction (grade 3 and 4) following the injection of CAR-NK cells2- Cytopenia lasting more than 28 days from the time of injection3- Acute GVHD of grade 2 to 44- Unexpected acute and severe toxicity (grades 3 and 4) Infusion of CAR-NK cells is performed in the inpatient department of the hospital and in the isolation room qualified for cell therapy. During this period, patients are under strict monitoring in terms of treatment side effects and toxicity related to the infusion of CAR-NK cells, and routine laboratory tests are performed daily (and more if needed).For the injection of these cells, the standard methods determined for lymphocyte injection (DLI), including the administration of appropriate premedication, the availability of the necessary drugs for anaphylaxis, and the careful monitoring of the patient within 4 hours after the injection.If any complication occurs during the infusion, the injection will be stopped and the necessary measures will be taken based on the CTCAE table and classification below.In grade 1, only the infusion is stopped.Grade 2-3; Stopping the infusion and treatment including corticosteroids and antihistaminesGrade 4: In addition to the above, it is recommended to carry out resuscitation and care measures in the ICU departmentStatistical Analysis: The collected data will be analyzed using appropriate statistical methods, including survival analysis, logistic regression, and correlation analyses, to determine the safety and efficacy outcomes and identify potential prognostic factors.Ethical Considerations: This study will be conducted in full compliance with ethical guidelines and regulations, ensuring patient confidentiality.
Category
Treatment - Other

Recruitment centers

1

Recruitment center
Name of recruitment center
Omid cell and tissue processing company
Full name of responsible person
Masoud Soleimani
Street address
West Qabadian St.
City
Tehran
Province
Tehran
Postal code
1968917313
Phone
+98 912 287 5993
Email
soleim_m@modares.ac.ir

Sponsors / Funding sources

1

Sponsor
Name of organization / entity
Omid cell and tissue processing company
Full name of responsible person
Masoud Soleimani
Street address
West Qabadian St.
City
Tehran
Province
Tehran
Postal code
1968917313
Phone
+98 912 287 5993
Email
soleim_m@modares.ac.ir
Web page address
Grant name
Grant code / Reference number
Is the source of funding the same sponsor organization/entity?
Yes
Title of funding source
Omid cell and tissue processing company
Proportion provided by this source
80
Public or private sector
Private
Domestic or foreign origin
Domestic
Category of foreign source of funding
empty
Country of origin
Type of organization providing the funding
Persons

2

Sponsor
Name of organization / entity
Tabriz University of Medical Sciences
Full name of responsible person
Ali Akbar Movasaghpour
Street address
Niayesh Blvd
City
Tabriz
Province
East Azarbaijan
Postal code
51665371
Phone
+98 912 638 9475
Email
movassaghpour@gmail.com
Grant name
Grant code / Reference number
Is the source of funding the same sponsor organization/entity?
Yes
Title of funding source
Tabriz University of Medical Sciences
Proportion provided by this source
20
Public or private sector
Public
Domestic or foreign origin
Domestic
Category of foreign source of funding
empty
Country of origin
Type of organization providing the funding
Academic

Person responsible for general inquiries

Contact
Name of organization / entity
Omid cell and tissue processing company
Full name of responsible person
Msoud Soleimani
Position
Professor
Latest degree
Ph.D.
Other areas of specialty/work
Hematology
Street address
West Qabadian St.
City
Tehran
Province
Tehran
Postal code
1968917313
Phone
+98 912 287 5993
Email
soleim_m@modares.ac.ir

Person responsible for scientific inquiries

Contact
Name of organization / entity
Omid cell and tissue processing company
Full name of responsible person
Masoud Soleimani
Position
Professor
Latest degree
Ph.D.
Other areas of specialty/work
Hematology
Street address
West Qabadian St.
City
Tehran
Province
Tehran
Postal code
1968917313
Phone
+98 912 287 5993
Email
soleim_m@modares.ac.ir

Person responsible for updating data

Contact
Name of organization / entity
Tabriz University of Medical Sciences
Full name of responsible person
Ali Akbar Movasaghpour
Position
Professor
Latest degree
Ph.D.
Other areas of specialty/work
Hematology
Street address
Niayesh Blvd
City
Tabriz
Province
East Azarbaijan
Postal code
51665371
Phone
+98 912 638 9475
Email
movassaghpour@gmail.com

Sharing plan

Deidentified Individual Participant Data Set (IPD)
Undecided - It is not yet known if there will be a plan to make this available
Study Protocol
Undecided - It is not yet known if there will be a plan to make this available
Statistical Analysis Plan
Undecided - It is not yet known if there will be a plan to make this available
Informed Consent Form
Undecided - It is not yet known if there will be a plan to make this available
Clinical Study Report
Undecided - It is not yet known if there will be a plan to make this available
Analytic Code
Undecided - It is not yet known if there will be a plan to make this available
Data Dictionary
Undecided - It is not yet known if there will be a plan to make this available
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