A Study of CAR-T Cells Therapy for Patients With Relapsed and/or Refractory Central Nervous System Hematological Malignancies

Clinical Trial for the Safety and Efficacy of CAR-T Cells Therapy for Patients With the Central Nervous System Involvement of Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia or B-cell Non-Hodgkin's Lymphoma

A Study of CAR-T Cells Therapy for Patients With Relapsed and/or Refractory Central Nervous System Hematological Malignancies

Study Overview

• Status: Recruiting
• Conditions: Non-Hodgkin's Lymphoma; Acute Lymphoblastic Leukemia
• Intervention / Treatment: Procedure: Ommaya Reservoir; Drug: CAR-T cells

Detailed Description

This is a single arm, open-label, single-center study. This study is indicated for relapsed or refractory central nervous system CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia and B-cell non-Hodgkin's lymphoma. The selections of dose levels and the numberof subjects are based on clinical trialsof similar foreign products. Two groups of patients will be enrolled, 36 in eachgroup. Primary objective is to explore the safety, main consideration is dose-related safety.

• Study Type: Interventional
• Enrollment (Anticipated): 72
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Affiliated Hospital，College of Medicine, Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Inclusion criteria only for B-ALL:

  1. Male or female aged 3-70 years;
  2. Histologically confirmed diagnosis of B-ALL per the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Acute Lymphoblastic Leukemia (2016.v1);

  3. Relapsed or refractory CD19+ B-ALL (meeting one of the followingconditions):

     1. CR not achieved after standardized chemotherapy;
     2. CR achieved following the first induction, but CR duration isless than 12 months;
     3. Ineffectively after first or multiple remedial treatments;
     4. 2 or more relapses;
  4. The number of primordial cells (lymphoblast and prolymphocyte)in bone marrow is>5% (by morphology), and/or >1% (by flowcytometry);
  5. Philadelphia-chromosome-negative (Ph-) patients; or Philadelphia-chromosome-positive (Ph+) patients who cannot tolerate TKI treatments or do not respond to 2 TKI treatments;

• Inclusion criteria only for B-NHL:

  1. Male or female aged 18-75 years;
  2. Histologically confirmed diagnosis of DLBCL (NOS), FL, DLBCL transformed from CLL/SLL, PMBCL, and HGBCL per the WHOClassification Criteria for Lymphoma (2016);

  3. Relapsed or refractory B-NHL (meeting one of the followingconditions):

     1. No response or relapse after second-line or abovechemotherapy regimens;
     2. Primary drug resistance;
     3. Relapse after auto-HSCT;
  4. At least one assessable tumor lesion per Lugano 2014 criteria;

• Common inclusion criteria for B-ALL and B-NHL:

  1. Highly suspected or confirmed central nervous system involvement of hematological malignancies;
  2. Total bilirubin ≤ 51 umol/L, ALT and AST ≤ 3 times of upper limit ofnormal, creatinine ≤ 176.8 umol/L;
  3. Echocardiogram shows left ventricular ejection fraction (LVEF) ≥50%;
  4. No active infection in the lungs, blood oxygen saturation in indoorair is ≥ 92%;
  5. Estimated survival time ≥ 3 months;
  6. ECOG performance status 0 to 2;
  7. Patients or their legal guardians volunteer to participate in the study and sign the informed consent.

Exclusion Criteria:

Subjects with any of the following exclusion criteria were not eligible for this trial:

1. History of craniocerebral trauma, conscious disturbance,epilepsy,cerebrovascular ischemia, and cerebrovascular hemorrhagic diseases;
2. Electrocardiogram shows prolonged QT interval, severe heart diseases such as severe arrhythmia in the past;
3. Pregnant (or lactating) women;
4. Patients with severe active infections (excluding simple urinarytractinfectionand bacterial pharyngitis);
5. Active infection of hepatitis B virus or hepatitis C virus;
6. Concurrent therapy with systemic steroids within 2 weeks prior to screening, except for the patients recently or currently receiving inhaled steroids;
7. Previously treated with any CAR-T cell product or other genetically-modified T cell therapies;
8. Creatinine>2.5mg/dl, or ALT / AST > 3 times of normal amounts,orbilirubin>2.0 mg/dl;
9. Other uncontrolled diseases that were not suitable for this trial;
10. Patients with HIV infection;
11. Any situations that the investigator believes may increase the risk ofpatients or interfere with the results of study.

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: Administration of CAR T-cells; Dose escalation follows the standard 3+3 doseescalation design. A total of 3 dose levels are set for subjects.	Procedure: Ommaya Reservoir; Surgical catheter placement into the fourth ventricle of the brain; Drug: CAR-T cells; Each subject receive CAR T-cells by intravenous infusion; Other Names: CAR-T cells injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity (DLT)	Adverse events assessed according to NCI-CTCAE v5.0 criteria	Baseline up to 28 days after CAR T-cells infusion
Incidence of treatment-emergent adverse events (TEAEs)	Incidence of treatment-emergent adverse events [Safety and Tolerability]	Up to 2 years after CAR T-cells infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
B-cell acute lymphocytic leukemia(B-ALL), Overall response rate (ORR)	Assessment of ORR (ORR = CR + CRi) at Month 6, 12, 18 and 24	At Month 1, 3, 6, 12, 18 and 24
B-ALL, Overall survival (OS)	From the first infusion of CAR-T cells to death or the last visit	Up to 2 years after CAR-T cells infusion
B-ALL, Event-free survival (EFS)	From the first infusion of CAR-T cells to the occurrence of any event, including death, relapse orgene relapse, disease progression (any one occurs first), and the last visit	Up to 2 years after CAR-T cells infusion
B cell non-hodgkin's lymphoma (B-NHL), Overall response rate (ORR)	Assessment of ORR (ORR = CR + PR) per Lugano 2014 criteria	At Week 4, 12, and Month 6, 12, 18, 24
B-NHL, disease control rate (DCR)	Assessment of DCR (DCR=CR+PR+SD) per Lugano 2014 criteria	At Week 12 and Month 6, 12, 18, 24
Quality of life	Assessment of Quality of life using Research and Treatment of Cancer QOL Core Questionnaire 30 (EORTC QLQ-30) at Baseline, Month 1, 3, 6, 9 and 12	At Baseline, Month 1, 3, 6, 9 and 12
IADL score	Assessment of IADL score at Baseline, Month 1, 3, 6, 9 and 12	At Baseline, Month 1, 3, 6, 9 and 12
ADL score	Assessment of ADL score at Baseline, Month 1, 3, 6, 9 and 12	At Baseline, Month 1, 3, 6, 9 and 12
HADS score	Assessment of Hospital Anxiety and Depression Scale (HADS) score at Baseline, Month 1, 3, 6, 9 and 12	At Baseline, Month 1, 3, 6, 9 and 12

Collaborators and Investigators

• Sponsor: Zhejiang University

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2020
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): November 1, 2026

Study Registration Dates

• First Submitted: August 20, 2020
• First Submitted That Met QC Criteria: August 25, 2020
• First Posted (Actual): August 31, 2020

Study Record Updates

• Last Update Posted (Actual): October 26, 2020
• Last Update Submitted That Met QC Criteria: October 22, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Acute Lymphoblastic Leukemia; CAR T-cell therapy; Non-Hodgkin's Lymphoma
• 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: CNSL-ZhejiangU

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