CARTALL: Chimeric-Antigen Receptor (CAR) T-Cell Therapy for Relapsed/ Refractory T-Lineage Acute Lymphoblastic Leukaemia

Anti-CD7 Protein Expression Blocker (PEBL) Chimeric-Antigen Receptor (CAR) T-Cell Therapy for Relapsed/ Refractory T-Lineage Acute Lymphoblastic Leukaemia (CARTALL)

The objective of this study is to assess the safety and efficacy of anti-CD7 CAR T-cells in patients with refractory or relapsed T-lineage acute lymphoblastic leukemia (T-ALL).

Study Overview

• Status: Recruiting
• Conditions: Lymphoblastic Leukemia, Acute, Childhood; Lymphoblastic Leukemia; Lymphoblastic Leukemia, Acute Adult; Lymphoblastic Leukemia in Children; CAR; CAR T-Cell-Related Encephalopathy Syndrome; Refractory Leukemia
• Intervention / Treatment: Biological: CAR T-cell therapy

Detailed Description

A major obstacle to the development of effective CAR T-cells for T-cell malignancies is that the surface marker profile of malignant T-cells largely overlaps that of activated T lymphocytes. We developed a CAR T-cell approach that targets CD7, a T-cell marker highly expressed in all cases of T-cell ALL, including ETP-ALL. Its expression is also highly stable even in T-ALL cells exposed to chemotherapy. To prevent fratricide effect of the T cells, surface CD7 expression are effectively downregulated with the expression of an anti-CD7 Protein Expression Blocker (PEBL). Patients will receive anti-CD7 PEBL CART-cells. This will allow targeting the entire leukemia cell population to induce deeper and more durable remissions.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • Recruiting
    • Allen Yeoh Eng Juh
    • Contact: Allen Yeoh, M.D; Phone Number: +(65) 6772 2002; Email: paeyej@nus.edu.sg
    • Contact: Zhiwei Chen, BSc.; Phone Number: +(65) 6772 4406; Email: chen.zhiwei@nus.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis/ Disease define as:

  1. Relapsed T-cell acute lymphoblastic leukaemia/ lymphoma as defined by:

     Bone marrow disease = or > 0.01% by MRD as determined by flow cytometry

     Or CNS disease as defined as > 5 WBCs/ uL in CSF with morphological evidence of blasts or biopsy proven recurrence in the eye or brain

     Or Extramedullary relapse as defined by morphological evidence of blasts in the testis or any other extramedullary sites

  2. Induction failure as defined by:

     MRD = or > 1% by flow cytometry at the end of induction on day 33

     Or Failure to achieve morphological remission defined as > 5% blasts after standard induction chemotherapy

  3. Refractory disease as defined by:

     MRD = or > 0.01% by flow cytometry or molecular methods during 2 or more timepoints after induction therapy

• Minimum level of pulmonary reserve defined as Grade ≤ 1 dyspnoea and oxygen saturation (SpO2) of > 95% on room air
• Left ventricular systolic function (LVSF) ≥ 28% confirmed by echocardiogram, or left ventricular ejection fraction (LVEF) ≥ 45% confirmed by echocardiogram within 3 months of screening
• Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening
• Normal Age-adjusted eGFR Creatinine Clearance within 3 months of screening
• Alanine aminotransferase ≤ 5 times the upper limit of normal for age
• Patients with > 99% CD7 expression on blast cells will be eligible for anti-CD7 PEBL-CAR-T cell infusion.

Exclusion Criteria:

• Failure to meet any of the inclusion criteria
• Patients who test positive on urine pregnancy testing and are pregnant or are lactating
• Concomitant genetic syndromes associated with bone marrow failure states, such as Fanconi anaemia, Kostmann syndrome, Schwachman syndrome, or any other bone marrow failure syndrome with the exception of Down syndrome
• Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and no evidence of active disease
• Active or latent hepatitis B or hepatitis C infections within 8 weeks of screening, or any uncontrolled infection at screening
• Positive Human Immunodeficiency Virus (HIV) test within 8 weeks of screening
• Grade 2 to 4 acute graft-vs-host disease (GVHD) or extensive chronic GVHD
• Received an investigational medicinal product within 30 days of screening
• Central nervous system : Uncontrolled seizures or status epilepticus; increased intra-cranial pressure as evidenced by papilledema and CSF opening pressure > 20 cm water; decreased conscious state (any cause)

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: Single arm; Single arm Phase I Clinical Trial	Biological: CAR T-cell therapy; This is a single-centre, phase I study to determine the efficacy and safety of CAR T-cell therapy in patients with high-risk T-ALL, refractory or relapsed T-ALL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participant who are flow cytometry minimal residual disease (MRD) negativity at 1 month after Anti-CD7 PEBL CAR T-cell infusion.	MRD levels will be determined by flow cytometry. The target sensitivity of flow MRD is <0.01% when available.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participant who are minimal residual disease (MRD) negative with molecular base assay at the end of 1 month after Anti-CD7 PEBL CAR T-cell infusion.	MRD levels will be determined by molecular based MRD by Ig/TCR. PCR and oncogene fusion transcript (OFT).	30 days
Proportion of patient who shows CAR T-cell persistence by immunophenotyping using flow cytometry in bone marrow, peripheral blood and CSF samples at multiple study time points following CAR T cell infusion	Flow cytometry will be performed on bone marrow, peripheral blood and CSF samples at multiple study time points following CAR T cell infusion	1 month to 5 years

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Anticipated): September 8, 2021
• Primary Completion (Anticipated): November 1, 2026
• Study Completion (Anticipated): November 1, 2026

Study Registration Dates

• First Submitted: June 13, 2021
• First Submitted That Met QC Criteria: September 7, 2021
• First Posted (Actual): September 14, 2021

Study Record Updates

• Last Update Posted (Actual): September 14, 2021
• Last Update Submitted That Met QC Criteria: September 7, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: T-ALL; CAR-T cell therapy; CAR T-cell therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Brain Diseases; Leukemia, Lymphoid; Acute Disease
• Other Study ID Numbers: 2020/01325

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No