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Study of CD19 Specific Chimeric Antigen Receptor Positive T Cells (CAR-T) in ALL and NHL (ISIKOK-19)

Primary Purpose

Acute Lymphoblastic Leukemia, Non Hodgkin Lymphoma

Status
Unknown status
Phase
Phase 1
Locations
Turkey
Study Type
Interventional
Intervention
Car-T Cell Therapy
Sponsored by
Acibadem University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring CAR-T Cell, CD19, ALL, NHL, Cancer, Chimeric Antigen Receptor

Eligibility Criteria

3 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Been diagnosed with CD19 (+) B-Acute lymphoblastic lymphoma or CD19 (+) Non-Hodgkin Lymphoma
  • Having a measurable disease
  • Relapsed/ refractory (at least 2 cases to the ward; in relapse after autologous transplantation in NHL) disease
  • CD19 (+) expression in tumor cells by bone marrow/tissue or peripheral blood flow cytometry for relapse patients in the 3-month before the study period
  • Bone marrow relapse after allogenic stem cell transplantation and at least 6 months between CAR-T (ISIKOK-19 ©) cell infusion and stem cell transplantation
  • Philadelphia gene + B-ALL patient should have received second line treatment with tyrosine kinase inhibitor (TKI) or the usage of tyrosine kinase inhibitor (TKI) for the patient is contraindicated
  • Patient; lack of appropriate donor, complications due to previous stem cell transplantation, or rejection of stem cell transplantation as a treatment option after consultation with a physician, or lack of allogenic stem cell transplantation due to high tumor burden.

  • Lack of organ dysfunction:

    1. Maximum serum creatinine value: 1.7 mg / decilitre (male patients), 1.4 mg / decilitre (female patients)
    2. Liver function tests are within normal limits
    3. Bilirubin <2.0 mg / decilitre
    4. Central oxygen pressure in room air > 91% and no dyspnea
    5. Measurement of left ventricular ejection fraction ≥45% and left ventricular systolic function ≥28% by echocardiography during screening
  • Expected survival is ≥ 3 months
  • Performance condition: Karnofsky ≥ 50%
  • Consent to oral contraceptives
  • Approve treatment

Exclusion Criteria:

  • Concomitant history of cardiac, hepatic, neurologic, nephrologic, psychiatric, autoimmune and additional oncological diseases affecting physiological functions
  • Life expectancy <2 months
  • Hepatitis B, Hepatitis C, Human immunodeficiency virus infection

  • Before CAR-T (ISIKOK-19 ©) cell infusion

    1. Systemic steroid treatments, tyrosine kinase inhibitors, hydroxyurea, short-acting cytotoxic drugs should be stopped 72 hours before.
    2. 1 week ago, vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate (if <25 mg / m^2), cytosine arabinoside (if <100 mg / m^2), asparaginase and intrathecal treatments should be stopped.
    3. 2 weeks ago, salvage treatments (chemotherapy drugs other than lymphodepletion as part of the protocol, clofarabine, cytosine arabinoside (if> 100 mg / m^2), anthracyclines, methotrexate (if ≥25 mg / m^2), drugs used for graft versus host disease, long-acting growth factors, vincristine, immunomodulatory drugs should be stopped.
    4. Radiotherapy taken outside the central nervous system should be stopped 2 weeks prior.
    5. Any systemic treatment with pegylated asparaginase and donor lymphocyte infusion should be stopped 4 weeks prior.
    6. Anti-t cell therapies containing T cell lysis or toxic antibodies should be stopped 8 weeks before.
    7. Radiotherapy for the central nervous system should be stopped 8 weeks ago.
    8. Less than 3 months after stem cell transplantation
    9. Below 60% in tissue biopsies and / or CD19 expression in tumor cells by flow cytometric analysis in bone marrow is below 85%
  • Allergic to drugs that are used at any stage of treatment
  • Having received experimental drug treatment in the last month
  • Previously entered a cellular therapy and / or a gene therapy program
  • Disapproval of the storage of tissues and cells
  • Isolated disease that occurs outside the bone
  • A genetic disease associated with concomitant bone marrow failure
  • Active Grade 2-4 acute or diffuse chronic graft versus host disease
  • Being pregnant or breastfeeding
  • Disapproval the treatment
  • Patients with slow CAR-T cell expansion (the cell number is not doubled in 48 hours) and with less than 10% expression of CAR-T cells during production, < 60% cytotoxicity results in in-vitro study (i.e, patients whose product is inappropriate)

Sites / Locations

  • Acıbadem Labcell Cellular Therapy LaboratoriesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

A Low Dose

B High Dose

Arm Description

4 x 10^6 Car-T cell/ kg

6 x 10^6 Car-T cell/ kg

Outcomes

Primary Outcome Measures

Incidence of Adverse Events
Type, frequency and severity of adverse events (AEs) and laboratory abnormalities.

Secondary Outcome Measures

Complete Remission Rate
It is determined by the evaluation of complete remission (CR) obtained in the first 3 months.
Total Response Rate
CR obtained in the first 3 months is determined by evaluation of partial remission, incomplete partial remission and stable disease responses.
Duration of Remission (DOR)
Duration of remission (DOR) is defined as the duration from the date when the response criteria of CR or CRi is first met to the date of relapse or death due to underlying cancer, whichever occurs first.
Relapse Free Survival (RFS)
Relapse free survival (RFS) is measured by the time from achievement of CR or CRi whatever occurs first to relapse or death due to any cause during CR or CRi.
Progression Free Survival
Only in the NHL is the duration from CAR T cell infusion to progression
Event-Free Survival (EFS)
Event free survival (EFS) is the time from date of first Car-T cell infusion to the earliest of the following: Death from any cause Relapse
Overall Survival
Overall survival (OS) is the time from date of first Car-T Cell infusion to the date of death due to any reason.
Duration to maximum response
The duration from date of the first Car-T cell infusion to complete remission in ALL. The duration from date of the first Car-T cell infusion to complete remission and partial remission in NHL
The impact of baseline tumor burden on response
Best overall response will be summarized by baseline tumor burden (MRD, extramedullary disease, etc.)
The relationship between CRS/CRES efficiency
The relationship between CRS / CRES grades and total response rates are determined by correlation between DOR, RFS, EFS, PFS, OS.
The relationship between the total response and Car-T Cell persistence
The relationship between total response and the number of Car-T copies is determined by the correlation between DOR, RFS, EFS, PFS, OS
The relationship between Car-T Cell product content and responses
The relationship between Car-T Cell subgroups and total response are determined by the correlation between DOR, RFS, EFS, PFS, OS.
Car-T cell proliferation capability
The relationship between the Car-T Cell proliferation capability and the total response, are determined by the correlation between DOR, RFS, EFS, PFS, OS.
The relationship between MRD grade and clinical response
The relationship between MRD grade and total response are determined by correlation between DOR, RFS, EFS, PFS, OS.
The relationship between the incidence of immune response to Car-T cells and the persistence of Car-T cell
It is assessed as the relationship between antiserum effectivity against Car-T cells and Car-T cell copy number in blood.

Full Information

First Posted
December 16, 2019
Last Updated
January 23, 2020
Sponsor
Acibadem University
Collaborators
Acıbadem Atunizade Hospital, The Scientific and Technological Research Council of Turkey, Acıbadem Labcell
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1. Study Identification

Unique Protocol Identification Number
NCT04206943
Brief Title
Study of CD19 Specific Chimeric Antigen Receptor Positive T Cells (CAR-T) in ALL and NHL
Acronym
ISIKOK-19
Official Title
Phase I/ II Study of Cluster of Differentiation 19 (CD19) Specific CAR-T Cells (ISIKOK 19) in Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin Lymphoma (NHL)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Unknown status
Study Start Date
October 12, 2019 (Actual)
Primary Completion Date
January 1, 2021 (Anticipated)
Study Completion Date
January 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Acibadem University
Collaborators
Acıbadem Atunizade Hospital, The Scientific and Technological Research Council of Turkey, Acıbadem Labcell

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
It is a treatment that activates and strengthens the immune system against cancer. Recently, T cell receptors have been genetically rearranged by adaptive T cell therapies, which are promising in the fight against cancer, and are now able to recognize antigens on tumor cells. These modified T cell receptors are called chimeric antigen receptors. Many previous clinical studies have shown that different CAR-T cells are effective in relapse / refractory B cell cancers and NHL.
Detailed Description
Clinical trials of CAR-T cell therapy started at the end of 1990s. Phase I and II trials have still evaluated the efficacy and safety of CAR-T cells in hematological and solid cancers. The therapy involves drawing blood from patients and isolation of the T cells. Next, the T cells are genetically engineered in a laboratory by using virus or sleeping beauty to produce receptors on their surface named as chimeric antigen receptors. As the last step, the CAR-T cells are infused back into the patient. After infusion, it is expected that the CAR-T cells further increase in number in the patient's body and with the help of their engineered receptor to recognize and target the antigen on the surface of the cancerous cells for antitumor effect.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, Non Hodgkin Lymphoma
Keywords
CAR-T Cell, CD19, ALL, NHL, Cancer, Chimeric Antigen Receptor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
A Low Dose
Arm Type
Experimental
Arm Description
4 x 10^6 Car-T cell/ kg
Arm Title
B High Dose
Arm Type
Experimental
Arm Description
6 x 10^6 Car-T cell/ kg
Intervention Type
Biological
Intervention Name(s)
Car-T Cell Therapy
Intervention Description
Lymphodepletion Protocol: -6. Day: Cyclophosphamide 300 mg / m^2 i.v. -5. -4. and -3. Days: Fludarabine 30 mg / m^2 i.v. In addition, one day before the lymphodepletion protocol, xanthine oxidase enzyme inhibitor tablets received 100 mg / day p.o. and 0.9% sodium chloride solution 2000 ml / day i.v. infusion on protocol day received and continues for 2 weeks Car-T cells are administered in 3 split doses. Day 0: 20% or 40% (20% in patients with high tumor burden - in patients with bulky disease and / or more than 15% blast in bone marrow, 40% in patients with low tumor burden) Day 2: 30% or 50%, (the total amount of Car-T cell dose that should be given in the first 2 days should be 70%.) Third dose (%30);is given on the 7th day in the absence of cytokine release syndrome, or if cytokine release syndrome occurs, Car-T cells are given within 1 month if the number of copies falls below 5,000 / ml in 2 consecutive measurements.
Primary Outcome Measure Information:
Title
Incidence of Adverse Events
Description
Type, frequency and severity of adverse events (AEs) and laboratory abnormalities.
Time Frame
6 Months
Secondary Outcome Measure Information:
Title
Complete Remission Rate
Description
It is determined by the evaluation of complete remission (CR) obtained in the first 3 months.
Time Frame
3 Months
Title
Total Response Rate
Description
CR obtained in the first 3 months is determined by evaluation of partial remission, incomplete partial remission and stable disease responses.
Time Frame
3 Months
Title
Duration of Remission (DOR)
Description
Duration of remission (DOR) is defined as the duration from the date when the response criteria of CR or CRi is first met to the date of relapse or death due to underlying cancer, whichever occurs first.
Time Frame
6 Months
Title
Relapse Free Survival (RFS)
Description
Relapse free survival (RFS) is measured by the time from achievement of CR or CRi whatever occurs first to relapse or death due to any cause during CR or CRi.
Time Frame
6 Months
Title
Progression Free Survival
Description
Only in the NHL is the duration from CAR T cell infusion to progression
Time Frame
6 Months
Title
Event-Free Survival (EFS)
Description
Event free survival (EFS) is the time from date of first Car-T cell infusion to the earliest of the following: Death from any cause Relapse
Time Frame
6 Months
Title
Overall Survival
Description
Overall survival (OS) is the time from date of first Car-T Cell infusion to the date of death due to any reason.
Time Frame
6 Months
Title
Duration to maximum response
Description
The duration from date of the first Car-T cell infusion to complete remission in ALL. The duration from date of the first Car-T cell infusion to complete remission and partial remission in NHL
Time Frame
6 Months
Title
The impact of baseline tumor burden on response
Description
Best overall response will be summarized by baseline tumor burden (MRD, extramedullary disease, etc.)
Time Frame
6 Months
Title
The relationship between CRS/CRES efficiency
Description
The relationship between CRS / CRES grades and total response rates are determined by correlation between DOR, RFS, EFS, PFS, OS.
Time Frame
6 Months
Title
The relationship between the total response and Car-T Cell persistence
Description
The relationship between total response and the number of Car-T copies is determined by the correlation between DOR, RFS, EFS, PFS, OS
Time Frame
6 Months
Title
The relationship between Car-T Cell product content and responses
Description
The relationship between Car-T Cell subgroups and total response are determined by the correlation between DOR, RFS, EFS, PFS, OS.
Time Frame
6 Months
Title
Car-T cell proliferation capability
Description
The relationship between the Car-T Cell proliferation capability and the total response, are determined by the correlation between DOR, RFS, EFS, PFS, OS.
Time Frame
6 months
Title
The relationship between MRD grade and clinical response
Description
The relationship between MRD grade and total response are determined by correlation between DOR, RFS, EFS, PFS, OS.
Time Frame
6 Months
Title
The relationship between the incidence of immune response to Car-T cells and the persistence of Car-T cell
Description
It is assessed as the relationship between antiserum effectivity against Car-T cells and Car-T cell copy number in blood.
Time Frame
6 Months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Been diagnosed with CD19 (+) B-Acute lymphoblastic lymphoma or CD19 (+) Non-Hodgkin Lymphoma Having a measurable disease Relapsed/ refractory (at least 2 cases to the ward; in relapse after autologous transplantation in NHL) disease CD19 (+) expression in tumor cells by bone marrow/tissue or peripheral blood flow cytometry for relapse patients in the 3-month before the study period Bone marrow relapse after allogenic stem cell transplantation and at least 6 months between CAR-T (ISIKOK-19 ©) cell infusion and stem cell transplantation Philadelphia gene + B-ALL patient should have received second line treatment with tyrosine kinase inhibitor (TKI) or the usage of tyrosine kinase inhibitor (TKI) for the patient is contraindicated Patient; lack of appropriate donor, complications due to previous stem cell transplantation, or rejection of stem cell transplantation as a treatment option after consultation with a physician, or lack of allogenic stem cell transplantation due to high tumor burden. Lack of organ dysfunction: Maximum serum creatinine value: 1.7 mg / decilitre (male patients), 1.4 mg / decilitre (female patients) Liver function tests are within normal limits Bilirubin <2.0 mg / decilitre Central oxygen pressure in room air > 91% and no dyspnea Measurement of left ventricular ejection fraction ≥45% and left ventricular systolic function ≥28% by echocardiography during screening Expected survival is ≥ 3 months Performance condition: Karnofsky ≥ 50% Consent to oral contraceptives Approve treatment Exclusion Criteria: Concomitant history of cardiac, hepatic, neurologic, nephrologic, psychiatric, autoimmune and additional oncological diseases affecting physiological functions Life expectancy <2 months Hepatitis B, Hepatitis C, Human immunodeficiency virus infection Before CAR-T (ISIKOK-19 ©) cell infusion Systemic steroid treatments, tyrosine kinase inhibitors, hydroxyurea, short-acting cytotoxic drugs should be stopped 72 hours before. 1 week ago, vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate (if <25 mg / m^2), cytosine arabinoside (if <100 mg / m^2), asparaginase and intrathecal treatments should be stopped. 2 weeks ago, salvage treatments (chemotherapy drugs other than lymphodepletion as part of the protocol, clofarabine, cytosine arabinoside (if> 100 mg / m^2), anthracyclines, methotrexate (if ≥25 mg / m^2), drugs used for graft versus host disease, long-acting growth factors, vincristine, immunomodulatory drugs should be stopped. Radiotherapy taken outside the central nervous system should be stopped 2 weeks prior. Any systemic treatment with pegylated asparaginase and donor lymphocyte infusion should be stopped 4 weeks prior. Anti-t cell therapies containing T cell lysis or toxic antibodies should be stopped 8 weeks before. Radiotherapy for the central nervous system should be stopped 8 weeks ago. Less than 3 months after stem cell transplantation Below 60% in tissue biopsies and / or CD19 expression in tumor cells by flow cytometric analysis in bone marrow is below 85% Allergic to drugs that are used at any stage of treatment Having received experimental drug treatment in the last month Previously entered a cellular therapy and / or a gene therapy program Disapproval of the storage of tissues and cells Isolated disease that occurs outside the bone A genetic disease associated with concomitant bone marrow failure Active Grade 2-4 acute or diffuse chronic graft versus host disease Being pregnant or breastfeeding Disapproval the treatment Patients with slow CAR-T cell expansion (the cell number is not doubled in 48 hours) and with less than 10% expression of CAR-T cells during production, < 60% cytotoxicity results in in-vitro study (i.e, patients whose product is inappropriate)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ercument Ovalı, MD
Phone
+905325729174
Email
ercument.ovali@acibadem.com
First Name & Middle Initial & Last Name or Official Title & Degree
Siret Ratip, MD
Phone
+905326873789
Email
siret.ratip@acibadem.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ercument Ovali, MD
Organizational Affiliation
Director
Official's Role
Study Director
Facility Information:
Facility Name
Acıbadem Labcell Cellular Therapy Laboratories
City
Istanbul
ZIP/Postal Code
34758
Country
Turkey
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ercument Ovalı
Phone
+905325729174
Email
ercument.ovali@acibademlabcell.com.tr

12. IPD Sharing Statement

Learn more about this trial

Study of CD19 Specific Chimeric Antigen Receptor Positive T Cells (CAR-T) in ALL and NHL

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