huCART19-IL18 in CD19+ Cancers

June 20, 2023 updated by: University of Pennsylvania

Phase I Trial of huCART19-IL18 Cells in Patients With Relapsed or Refractory CD19+ Cancers

The purpose of this study is to find the maximum dose of huCART19-IL18 cells that is safe for use in humans with CD19+ cancers.

Study Overview

Detailed Description

This is a Phase I dose finding study to determine the maximum tolerated dose (MTD) and assess the safety, tolerability, manufacturing feasibility, pharmacokinetics, and preliminary efficacy of huCART19-IL18 cells in patients with CD19+ cancers. Up to 7 total dose levels will be evaluated using the Bayesian Optimal Interval (BOIN) design with accelerated titration in order to determine the maximum tolerated dose (MTD) of huCART19-IL18 cells within each of the following disease-specific cohorts:

  • Cohort A: Non-Hodgkin Lymphoma (NHL)
  • Cohort B: Chronic Lymphocytic Leukemia (CLL)
  • Cohort C: Acute Lymphoblastic Leukemia (ALL)

Study Type

Interventional

Enrollment (Estimated)

72

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. 1. Signed informed consent form
  2. Documentation of CD19 expression on malignant cells a. Cohort A (NHL): Within 6 months of physician-investigator confirmation of eligibility as long as there has been no intervening CD19 directed therapy since expression confirmed. Results outside of this window may be used, if there is no accessible tumor site and the subject did not receive intervening CD19 directed therapy since CD19 expression was confirmed.

    b. Cohorts B (CLL) and C (ALL): At time of most recent relapse

  3. Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:

    1. Have no active GVHD and require no immunosuppression
    2. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility
  4. Adequate organ function defined as:

    1. Creatinine ≤ 1.6 mg/dl
    2. ALT/AST ≤ 3x upper limit of normal range
    3. Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl)
    4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
    5. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
  5. Evidence of active disease within 12 weeks of physician-investigator confirmation of eligibility. .
  6. Male or female age ≥ 18 years.
  7. ECOG Performance Status that is either 0 or 1.
  8. Subjects of reproductive potential must agree to use acceptable birth control methods.
  9. Disease-specific criteria:

    a. Cohort A (NHL): i. Patients with any of the following diagnoses: Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS), germinal center or activated B-cell types; Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e. "Double or Triple Hit"); High-grade B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma.

1. Patients must have either relapsed after, or be ineligible for, prior CAR T cell therapy, and meet one of the following criteria:

  1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy and are ineligible for autologous stem cell transplant; OR
  2. Relapsed/refractory disease after autologous SCT; OR
  3. Relapsed/refractory disease after allogeneic SCT. ii. Follicular lymphoma

    1. Patients must have either relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
    2. Received at least 2 prior lines of appropriate therapy (not including single agent monoclonal antibody therapy) and progressed within 2 years after second or higher line of therapy.

iii. Mantle cell lymphoma

  1. Patients must have either failed standard of care CAR T cell therapy (e.g. Tecartus™, etc) or other investigational CAR T cell product, OR be ineligible for standard of care Tecartus™; and
  2. Patients must also meet one of the following criteria:

    1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a BTK inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy; OR
    2. Relapsed/refractory disease after prior autologous SCT; OR
    3. Relapsed/refractory disease after prior allogeneic SCT. iv. Large cell transformation of CLL (Richter's Transformation)

1. Patients must be primary refractory or received at least 1 prior line of treatment.

b. Cohort B (CLL): i. Patients with relapsed/refractory disease after at least 2 prior lines of appropriate therapy; AND ii. Patients must have previously received, or be intolerant to an approved BTK inhibitor and venetoclax, unless a BTK inhibitor or venetoclax is contraindicated.

c. Cohort C (ALL): i. Patients with b-cell acute lymphoblastic leukemia. Note: Chronic myeloid leukemia (CML) lymphoid blast crisis is considered a sub-type of relapsed B-ALL, thus will be encompassed in our definition of B-ALL throughout; AND ii. Patients with 2nd or greater relapse or refractory disease as defined by one of the following criteria:

  1. Recurrent disease in the blood or bone marrow identified morphologically, by IHC or flow; OR
  2. Isolated CNS disease. Note: Patients with prior/current history of CNS3 disease will only be eligible for treatment if the CNS disease is responsive to therapy; OR
  3. Recurrent extramedullary disease at other (non-CNS) sites if disease response can be assessed radiographically. Note: Patients with recurrent extramedullary disease do not need to have detectable blood or bone marrow involvement; OR
  4. Any relapse after allogeneic SCT; OR
  5. Patients with refractory disease as defined by one of the following:

    1. Failure to achieve remission (<5% bone marrow blasts or ongoing extramedullary or CNS disease) after 2 cycles of induction chemotherapy; OR
    2. Patients that achieve remission but remain MRD+ after ≥2 cycles of induction chemotherapy.

Exclusion Criteria:

  1. Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
  2. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
  3. Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
  4. Active acute or chronic GVHD requiring systemic therapy.
  5. Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
  6. RETIRED WITH PROTOCOL AMENDMENT V7
  7. Receipt of prior huCART19 therapy.
  8. CNS disease as defined by disease-cohort as follows:

    1. Cohorts A + B: Active CNS disease. Note: Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
    2. Cohort C: CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
  9. Pregnant or nursing (lactating) women.
  10. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to their cancer or previous cancer treatment.
  11. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: NHL Dose Level 1a (DL1a)
3x10^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: NHL Dose Level -1 (DL-1)
7x10^5 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 1a.
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: NHL Dose Level 1b (DL1b)
3x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: NHL Dose Level 2 (DL2)
7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: NHL Dose Level 3 (DL3)
3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: NHL Dose Level 4 (DL4)
7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: NHL Dose Level 5 (DL5)
3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: CLL Dose Level 1b (DL1b)
3x10^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: CLL Dose Level 2 (DL2)
7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: CLL Dose Level 3 (DL3)
3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: CLL Dose Level 4 (DL4)
7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: CLL Dose Level 5 (DL5)
3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: ALL Dose Level 1b (DL1b)
3x10^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: ALL Dose Level 2 (DL2)
7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: ALL Dose Level 3 (DL3)
3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: ALL Dose Level 4 (DL4)
7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: ALL Dose Level 5 (DL5)
3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0.
Time Frame: 12 months
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression free survival (PFS)
Time Frame: 12 months
12 months
Overall Survival (OS)
Time Frame: 12 months
12 months
Percentage of manufacturing products that meet release criteria.
Time Frame: 3 months
3 months
Duration of Response (DOR)
Time Frame: 12 months
12 months
Characterize low level disease and B cell assessment in response to huCART19-IL18 cells
Time Frame: 12 months
Polychromatic flow cytometry-based assessment of leukemia and B cells, extent and duration of leukemic response
12 months
Characterize low level disease and B cell assessment in response to huCART19-IL18 cells
Time Frame: 12 months
Presence or absence of malignant B cells by Next-Generation Immunoglobulin heavy chain Sequencing (NGIS)
12 months
Occurrence of dose-limiting toxicities (DLTs).
Time Frame: 3 months
3 months
Determination of Maximum Tolerated Dose (MTD)
Time Frame: 3 months
3 months
Overall Response Rate (ORR).
Time Frame: 3 months
Cohort A (NHL) and Cohort B (CLL)
3 months
Overall Remission Rate (ORR).
Time Frame: 1 months
Cohort C (ALL)
1 months
Best Overall Response (BOR)
Time Frame: 3 months
Cohort A (NHL) and Cohort B (CLL)
3 months
Best Overall Response (BOR)
Time Frame: 6 months
6 months
Event Free Survival (EFS)
Time Frame: 12 months
Cohort C (ALL)
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Jakub Svoboda, MD, University of Pennsylvania

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 6, 2021

Primary Completion (Estimated)

May 1, 2036

Study Completion (Estimated)

May 1, 2036

Study Registration Dates

First Submitted

December 11, 2020

First Submitted That Met QC Criteria

December 21, 2020

First Posted (Actual)

December 24, 2020

Study Record Updates

Last Update Posted (Actual)

June 22, 2023

Last Update Submitted That Met QC Criteria

June 20, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

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

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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