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A Trial of "Armored" CAR T Cells Targeting CD19 For Patients With Relapsed CD19+ Hematologic Malignancies

Primary Purpose

Chronic Lymphocytic Leukemia (CLL), Relapsed, Refractory

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
EGFRt/19-28z/4-1BBL CAR T cells
Sponsored by
Memorial Sloan Kettering Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia (CLL) focused on measuring CAR T Cells Targeting CD19, EGFRt/19-28z/4-1BBL, 16-1570

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have CD19+ B cell malignancy with relapsed or refractory disease, defined as below:

Patients with CLL:

  • Refractory to or relapsed after at least 2 prior chemo or chemoimmunotherapy (e.g. FCR, BR) requiring further treatment
  • Refactory to or relapsed after at least 1 prior biologic agent (e.g. Ibrutinib, idelalisib, venetoclax, except a single agent anti-CD20 monoclonal antibody) requiring further treatment

Patients with iNHL (FZ, MZL, WM):

  • Refractory or relapsed after at least 2 lines of chemoimmunotherapy (including at least one course of anti-CD20 antibody)
  • Refractory or relapsed after at least 1 prior biologic agent (e.g. lenalidomide, ibrutinib, idelalisib)
  • Patients must have measurable disease (for WM patients, measureable disease is demonstrable monoclonal paraprotein and bone marrow involvement)

Patients with DLBCL, Transformed B cell lymphoma, or High grade B cell lymphoma:

  • Refractory to or relapsed after 1 or more prior chemoimmunotherapies with at least one containing an anthracycline and CD20 directed therapy
  • Transplant ineligible
  • Biopsy proven relapsed disease

Patients with ALL, CML in lymphoid blast crisis or Burkitt's lymphoma:

  • Refractory to at least 1 prior induction chemotherapy
  • Relapsed after at least 1 prior multiagent systemic chemotherapy that included induction and consolidation

  • Patients with Philadelphia chromosome-positive ALL must have failed a second generation tyrosine kinase inhibitor

    • Age ≥ 18 years of age
    • Creatinine ≤2.0 mg/100 ml, direct bilirubin ≤2.0 mg/100 ml, AST and ALT ≤3.0x upper limit of normal (ULN)
    • Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse oximetry

Exclusion Criteria:

  • Karnofsky performance status <70
  • Pregnant or lactating women. Women and men of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished
  • Impaired cardiac function (LVEF <40%) as assessed by ECHO or MUGA scan
  • Patients with active known autoimmune disease are ineligible

  • Patients with following cardiac conditions will be excluded:

    • New York Heart Association (NYHA) stage III or IV congestive heart failure
    • Myocardial infarction </= 6 months prior to enrollment
    • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration <6 months prior to enrollment
    • History of severe non-ischemic cardiomyopathy with EF </=20%
  • Patients with HIV or active hepatitis B or hepatitis C infection are ineligible
  • Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible
  • Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of skin
  • Patients with history or presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible
  • Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study

Sites / Locations

  • Memorial Sloan Kettering Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

EGFRt/19-28z/4-1BBL CAR T cells

Arm Description

Following enrollment, patients will undergo leukapheresis of peripheral blood for further T cell enrichment, activation and genetic modification using a retroviral vector encoding a CD19targeted CAR, the co-stimulatory ligand 4-1BBL and the EGFRt safety system (EGFRt/19-28z/4-1BBL). These T cells will be expanded and after the appropriate number of cells is generated, the modified T cells may be infused fresh or frozen for later use according to standard operation procedures. Modified T cell infusions will be administered 2-7 days following completion of the treating investigator's choice of conditioning chemotherapy. Serial sampling of blood and bone marrow will be performed following treatment to assess toxicity, therapeutic effects, and survival of the genetically modified T cells.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD)
Cohorts of 3-6 patients each will be treated with escalating doses of modified T cell. At least 3 patients will be treated at each dose level with an accrual of no more than 2 patients per month within each dose level. At least two weeks will elapse from the first patient's T cell infusions before the second patient is treated (on dose level 1) to allow for toxicity and safely assessment. All patients treated at the preceding dose level will be observed a minimum of 4 weeks before dose escalation occurs.

Secondary Outcome Measures

Full Information

First Posted
March 15, 2017
Last Updated
September 26, 2023
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Juno Therapeutics, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03085173
Brief Title
A Trial of "Armored" CAR T Cells Targeting CD19 For Patients With Relapsed CD19+ Hematologic Malignancies
Official Title
A Phase I Trial of CD19-Targeted EGFRt/19-28z/4-1BBL "Armored" Chimeric Antigen Receptor (CAR) Modified T Cells in Patients With Relapsed or Refractory CD19+ Hematologic Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 15, 2017 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Juno Therapeutics, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
The purpose of this phase I study is to test the safety of different dose levels of specially prepared cells collected from the patient called "modified T cells". The investigators want to find a safe dose of modified T cells for patients with this type of cancer that has progressed after standard therapy. The investigators also want to find out what effects these modified T cells have on the patient and the cancer. For patients who were treated, had progression of disease and were removed from study, duplicate enrollment is permitted if it is determined the patients could receive a benefit. If the patients meet all eligibility criteria, they can be enrolled onto study a second time as a new accrual, and receive treatment in a higher dose level cohort.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia (CLL), Relapsed, Refractory
Keywords
CAR T Cells Targeting CD19, EGFRt/19-28z/4-1BBL, 16-1570

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
A Phase I Trial of CD19-Targeted EGFRt/19-28z/4-1BBL "Armored" Chimeric Antigen Receptor (CAR) Modified T Cells in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
EGFRt/19-28z/4-1BBL CAR T cells
Arm Type
Experimental
Arm Description
Following enrollment, patients will undergo leukapheresis of peripheral blood for further T cell enrichment, activation and genetic modification using a retroviral vector encoding a CD19targeted CAR, the co-stimulatory ligand 4-1BBL and the EGFRt safety system (EGFRt/19-28z/4-1BBL). These T cells will be expanded and after the appropriate number of cells is generated, the modified T cells may be infused fresh or frozen for later use according to standard operation procedures. Modified T cell infusions will be administered 2-7 days following completion of the treating investigator's choice of conditioning chemotherapy. Serial sampling of blood and bone marrow will be performed following treatment to assess toxicity, therapeutic effects, and survival of the genetically modified T cells.
Intervention Type
Biological
Intervention Name(s)
EGFRt/19-28z/4-1BBL CAR T cells
Intervention Description
Cohorts of 3-6 patients will be infused with escalating doses of EGFRt/19-28z/4-1BBL CAR T cells to establish the maximum tolerated dose (MTD). There are 4 planned dose levels: 1 x 10^5, 3 x 10^5, 1 x 10^6, and 3 x 10^6 CAR T cells/kg.
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD)
Description
Cohorts of 3-6 patients each will be treated with escalating doses of modified T cell. At least 3 patients will be treated at each dose level with an accrual of no more than 2 patients per month within each dose level. At least two weeks will elapse from the first patient's T cell infusions before the second patient is treated (on dose level 1) to allow for toxicity and safely assessment. All patients treated at the preceding dose level will be observed a minimum of 4 weeks before dose escalation occurs.
Time Frame
occurring within 30 days from the last infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have CD19+ B cell malignancy with relapsed or refractory disease, defined as below: Patients with CLL: Refractory to or relapsed after at least 2 prior chemo or chemoimmunotherapy (e.g. FCR, BR) requiring further treatment Refactory to or relapsed after at least 1 prior biologic agent (e.g. Ibrutinib, idelalisib, venetoclax, except a single agent anti-CD20 monoclonal antibody) requiring further treatment Patients with iNHL (FZ, MZL, WM): Refractory or relapsed after at least 2 lines of chemoimmunotherapy (including at least one course of anti-CD20 antibody) Refractory or relapsed after at least 1 prior biologic agent (e.g. lenalidomide, ibrutinib, idelalisib) Patients must have measurable disease (for WM patients, measureable disease is demonstrable monoclonal paraprotein and bone marrow involvement) Patients with DLBCL, Transformed B cell lymphoma, or High grade B cell lymphoma: Refractory to or relapsed after 1 or more prior chemoimmunotherapies with at least one containing an anthracycline and CD20 directed therapy Transplant ineligible Biopsy proven relapsed disease Patients with ALL, CML in lymphoid blast crisis or Burkitt's lymphoma: Refractory to at least 1 prior induction chemotherapy Relapsed after at least 1 prior multiagent systemic chemotherapy that included induction and consolidation Patients with Philadelphia chromosome-positive ALL must have failed a second generation tyrosine kinase inhibitor Age ≥ 18 years of age Creatinine ≤2.0 mg/100 ml, direct bilirubin ≤2.0 mg/100 ml, AST and ALT ≤3.0x upper limit of normal (ULN) Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse oximetry Exclusion Criteria: Karnofsky performance status <70 Pregnant or lactating women. Women and men of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished Impaired cardiac function (LVEF <40%) as assessed by ECHO or MUGA scan Patients with active known autoimmune disease are ineligible Patients with following cardiac conditions will be excluded: New York Heart Association (NYHA) stage III or IV congestive heart failure Myocardial infarction </= 6 months prior to enrollment History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration <6 months prior to enrollment History of severe non-ischemic cardiomyopathy with EF </=20% Patients with HIV or active hepatitis B or hepatitis C infection are ineligible Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of skin Patients with history or presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jae Park, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mskcc.org/mskcc/html/44.cfm
Description
Memorial Sloan Kettering Cancer Center

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A Trial of "Armored" CAR T Cells Targeting CD19 For Patients With Relapsed CD19+ Hematologic Malignancies

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