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

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)

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.

Study Overview

• Status: Unknown
• Conditions: Acute Lymphoblastic Leukemia; Non Hodgkin Lymphoma
• Intervention / Treatment: Biological: Car-T Cell Therapy

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Turkey
  • Istanbul, Turkey, 34758
    • Recruiting
    • Acıbadem Labcell Cellular Therapy Laboratories

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: A Low Dose; 4 x 10^6 Car-T cell/ kg	Biological: Car-T Cell Therapy; 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.
EXPERIMENTAL: B High Dose; 6 x 10^6 Car-T cell/ kg	Biological: Car-T Cell Therapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events	Type, frequency and severity of adverse events (AEs) and laboratory abnormalities.	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission Rate	It is determined by the evaluation of complete remission (CR) obtained in the first 3 months.	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.	3 Months
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.	6 Months
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.	6 Months
Progression Free Survival	Only in the NHL is the duration from CAR T cell infusion to progression	6 Months
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	6 Months
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.	6 Months
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	6 Months
The impact of baseline tumor burden on response	Best overall response will be summarized by baseline tumor burden (MRD, extramedullary disease, etc.)	6 Months
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.	6 Months
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	6 Months
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.	6 Months
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.	6 months
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.	6 Months
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.	6 Months

Collaborators and Investigators

• Sponsor: Acibadem University
• Collaborators: The Scientific and Technological Research Council of Turkey; Acıbadem Labcell; Acıbadem Atunizade Hospital
• Investigators: Study Director: Ercument Ovali, MD, Director

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 12, 2019
• Primary Completion (ANTICIPATED): January 1, 2021
• Study Completion (ANTICIPATED): January 1, 2021

Study Registration Dates

• First Submitted: December 16, 2019
• First Submitted That Met QC Criteria: December 19, 2019
• First Posted (ACTUAL): December 20, 2019

Study Record Updates

• Last Update Posted (ACTUAL): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 23, 2020
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Cancer; NHL; ALL; CAR-T Cell; CD19; Chimeric Antigen Receptor
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: CD19-SP-CAR-T

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No