CD19 Targeted CAR T Cell Therapy in Patients With Relapsed/ Refractory B Cell Acute Lymphoblastic Leukaemia (ALL)

Phase I Clinical Trial Evaluating Safety of CD19 CAR-T Cells in Patients With Relapsed or Refractory Acute B-cell Lymphoblastic Leukemia (R/R B-ALL)

This is a single-arm, open-label, phase I study (safety and dose escalation) of autologous Chimeric Antigen Receptor (CAR) T-cells targeting CD19 in patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL).

Study Overview

• Status: Not yet recruiting
• Conditions: Relapsed B Cell Acute Lymphoblastic Leukemia (ALL); Refractory B Cell Acute Lymphoblastic Leukemia (ALL)
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Mesna; Biological: CD19 CAR engineered autologous T-cells

Detailed Description

In this single-center, open-label, nonrandomized, no control, prospective clinical trial, pediatric or adolescent/young adult patients with CD19+ relapsed or refractory B cell acute lymphoblastic leukemia (R/R B-ALL) will be enrolled.

Eligible patients will receive CAR T product intravenously as a single or split dose following pre-conditioning by a lymphodepleting chemotherapeutic regimen and will then enter a 30-day follow-up period to monitor adverse events using the NCI CTCAE (version 5.0).

• Study Type: Interventional
• Enrollment (Anticipated): 22
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Tahereh Rostami, M.D; Phone Number: +9821-88004140; Email: trostami@sina.tums.ac.ir
• Study Contact Backup: Name: Naser Ahmadbeigi, Phd; Phone Number: +9821-82415103; Email: n-ahmadbeigi@sina.tums.ac.ir

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • Gene therapy research center, Shariati hospital, Tehran university of medical sciences, Iran
    • Contact: Naser Ahmadbeigi, Phd; Phone Number: +9821-82415103; Email: n-ahmadbeigi@sina.tums.ac.ir
  • Tehran, Iran, Islamic Republic of
    • Research Institute for Oncology- Hematology and Cell Therapy (RIOHCT), Tehran University of Medical Sciences
    • Contact: Tahereh Rostami, M.D; Phone Number: +982188004140; Email: trostami@sina.tums.ac.ir

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

CD19+ ALL patients with any of the following:

1. Relapsed or Refractory CD19 positive B-cell acute lymphoblastic leukemia (R/R B-ALL) A. Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission B. Refractory disease despite salvage therapy C. 2nd or greater relapse D. Any relapse after allogeneic hematopoietic stem cell transplantation
2. Informed consent explained to and signed by patient/parents or legal guardian.
3. The Karnofsky (age ≥10 years)/Lansky (age <10 years) performance status score over 50 points.
4. Expected to survive for more than 3 months.
5. Patients with a history of prior allogeneic hematopoietic stem cell transplant (HSCT) must be at least 3 months from HSCT at the time of CD19 CAR-T cells infusion and also have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis.
6. Important organ function is satisfied: Heart ultrasound indicates cardiac ejection fraction ≥ 50%, no obvious abnormality in ECG; Adequate pulmonary function defined as forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing; creatinine clearance calculated by Cockcroft-Gault formula ≥ 50 ml/min/1.73m2; Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age; Total Bilirubin ≤ 3 times the upper limit of normal for age.
7. Absolute lymphocyte count ≥ 0.5 x 10⁹/L.
8. Hemoglobin ≥ 8 g/dl (can be transfused).
9. Platelet count ≥ 20,000/μL (can be transfused).
10. Meets eligibility criteria to undergo autologous apheresis.

Exclusion Criteria:

1. Isolated extra-medullary disease relapse.
2. Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network guidelines).
3. Severe, uncontrolled bacterial, fungal or viral infections (Active hepatitis B or C, history of HIV infection)
4. Pre-existing significant neurological disorder.
5. Active significant acute graft versus host disease (GVHD) or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppressants within 4 weeks of enrolment.
6. Pregnant or lactating female.
7. The patient did not agree to use effective contraception during the treatment period and for the following 1 year.
8. A history of other malignant tumors.
9. Receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/ kg/day of methylprednisolone, in the 7 days prior to CAR T-cell infusion
10. Receiving systemic immunosuppressive therapy in the 14 days prior to CAR T-cell infusion
11. Receiving intrathecal chemotherapy in the 7 days prior to CAR T-cell infusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CD19 CAR-T cells; Pediatric or adolescent/young adult patients with CD19+ relapsed or refractory B cell acute lymphoblastic leukemia (R/R B-ALL)

Drug: Cyclophosphamide; Given IV; Drug: Fludarabine; Given IV; Drug: Mesna; Given IV; Biological: CD19 CAR engineered autologous T-cells; Given IV Following preconditioning with lymphodepleting chemotherapy (cyclophosphamide and fludarabine) patients will be treated with CD19 Chimeric Antigen Receptor (CAR) T cells as a single or split dose (day 0, 1 and 2, CAR cells will be intravenously infused at the 10%, 30% and 60% ratio respectively). Dosing of CD19 CAR-T cells will follow a dose-escalation schema, with dose changes based on dose-limiting toxicities.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) and Dose-limiting Toxicities (DLT) of CD19 CAR-T cells	Patients will be continually assessed for unexpected adverse events using the NCI CTCAE (version 5.0) or unexpected early mortality 30 days post-infusion. The primary objectives for the Phase I study portion are to determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with CD19 CAR-T cells in pediatric, adolescent and young adult patient's ≤ 25 years of age, with relapsed/refractory CD19+ ALL.	Within 30 days after the last dose of CD19 CAR-T cells

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who achieve complete morphological remission	Number of patients who achieve complete morphological remission (Complete Response (CR) or Complete Response with Incomplete count recovery (CRi) in the bone marrow)	Within 30 days post CD19 CAR-T cells

Collaborators and Investigators

• Sponsor: Sabz Biomedicals
• Collaborators: Gene Therapy Research Center, Shariati Hospital, Tehran University of Medical Sciences, Iran; Research Institute for Oncology- Hematology and Cell Therapy (RIOHCT), Tehran University of Medical Sciences, Iran
• Investigators: Principal Investigator: Tahereh Rostami, M.D, Research Institute for Oncology- Hematology and Cell Therapy (RIOHCT), Tehran University of Medical Sciences, Tehran, Iran; Study Director: Naser Ahmadbeigi, PhD, Gene Therapy Research Center, Shariati hospital, Tehran University of Medical Sciences, Tehran, Iran

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2021
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: November 22, 2020
• First Submitted That Met QC Criteria: November 28, 2020
• First Posted (Actual): December 4, 2020

Study Record Updates

• Last Update Posted (Actual): March 19, 2021
• Last Update Submitted That Met QC Criteria: March 17, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: CAR T cell; CD19+ B-cell Acute Lymphoblastic Leukemia; Relapsed/Refractory B cell acute lymphoblastic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: CD19 CAR T Cells for R/R ALL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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