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B Acute Lymphoblastic Leukemia With t(v;11q23.3); KMT2A RearrangedPhase 1NCT03579888

CD19-Specific T Cells Post AlloSCT

A Phase 1 study testing Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells, Cyclophosphamide and Fludarabine in people with B Acute Lymphoblastic Leukemia With t(v;11q23.3); KMT2A Rearranged and Recurrent B Acute Lymphoblastic Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This phase I trial investigates the side effects and best dose of CD19 positive (+) specific CAR-T cells in treating patients with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Read more about this study

Who is it for?
Ages 18 to 70 yearsHealthy volunteers can take part
What is being tested?
Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells, Cyclophosphamide and Fludarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
1 siteUnited States
Study dates
26 Jun 2020to 27 May 2021
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • RECIPIENT: Patients with high risk or relapsed disease who are planning to receive, or have received prior allogeneic HSCT from an human leukocyte antigen (HLA)-matched related, or HLA-mismatched related donor; high risk is defined as patients with acute lymphoblastic leukemia who have delayed clearance of minimal residual disease, Philadelphia (Ph)-like, or complex, 11q23 or hypodiploid karyotype
  • RECIPIENT: Available donor who provided hematopoietic stem-cell (HSC)
  • RECIPIENT: Patients with CD19+ lymphoid malignancies that are refractory to or intolerant of standard treatment (as defined below):
  • B-cell Acute Lymphoblastic Leukemia (ALL)
  • Non-Hodgkin lymphoma (NHL) to include diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B cell lymphoma, mantle cell lymphoma, or transformed follicular lymphoma (TFL) as defined by the World Health Organization 2008 criteria
  • Small lymphocytic lymphoma (SLL)
Show all 38Show fewer
  • Chronic lymphocytic leukemia (CLL)
  • NOTE: Refractory disease for acute and chronic leukemia is defined by:
  • Presence of > 5% malignant blasts in bone marrow and/or peripheral blood and/or minimal residual disease by flow cytometry or molecular analysis for fusion proteins and/or positive imaging for extra-medullary disease to most recent therapy
  • NOTE: Refractory disease for lymphoma is defined as:
  • Progressive disease or stable disease lasting =< 6 months, as best response to most recent chemotherapy regimen; or disease progression or recurrence =< 12 months after prior ASCT
  • Prior therapy must have included an anti-CD20 monoclonal antibody-containing regimen and an anthracycline-containing chemotherapy regimen
  • For patients with TFL, prior chemotherapy for follicular lymphoma and subsequent refractory disease after transformation to DLBCL
  • At least one measurable lesion according to revised International Working Group (IWG) Response Criteria
  • RECIPIENT: In patients with prior transplant, treatment will begin no earlier than 3 months post-transplant. Enrollment can occur earlier to allow time for donor cell collection
  • RECIPIENT: Karnofsky performance scale > 60
  • RECIPIENT: Patient able to provide written informed consent
  • RECIPIENT: Patient able to provide written informed consent for the long-term follow-up (LTFU) gene therapy study
  • RECIPIENT: Negative human anti-mouse antibody (HAMA)
  • DONOR: HLA-matched related, HLA-mismatched related, including haploidentical donor, or related donor cleared to donate based on Stem Cell Transplantation and Cellular Therapy (SCTCT) standard-of-care (SOC) guidelines
  • DONOR: Negative beta HCG in female of child-bearing potential defined as:
  • Not post-menopausal for 12 months, or
  • No previous surgical sterilization, or
  • Lactating females
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Patient must have measurable disease at the time of treatment
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Not received anti-thymocyte globulin (ATG), Campath, or other T-cell immunosuppressive antibodies or donor-lymphocyte infusion in the 28 days prior to T-cell infusion
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Serum creatinine < 2 x upper limit of normal (ULN)
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x ULN or =< 5 x ULN if documented liver metastases
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Total bilirubin =< 1.5 mg/dL, except in patients with Gilbert's syndrome in whom total bilirubin must be =< 3.0 mg/dL
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Cardiac ejection fraction >= 40%, and no clinically-significant electrocardiogram (ECG) findings
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No clinically significant pleural effusion, baseline oxygen saturation > 90% on room air
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No evidence of grade >= 2 active graft versus host disease (GVHD) using the Center for International Blood and Marrow Transplant Research (CIBMTR) Acute GVHD Grading System or requiring systemic steroid therapy greater than physiologic dosing at time of starting treatment
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Non-hematologic toxicity grade >= 2 (Common Terminology Criteria for Adverse Events [CTCAE] version 5) related to the lymphodepleting chemotherapy until the toxicity has resolved to grade =< 1 and the patient is afebrile
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No new grade > 2 neurologic, pulmonary, cardiac, gastrointestinal, renal or hepatic (excluding albumin) toxicity
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Serum creatinine < 2 x ULN
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Oxygen saturation > 90% on room air
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Active clinically significant infection within 7-days of study treatment
  • T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Using an investigational agent

Who cannot join

  • RECIPIENT: Positive beta human chorionic gonadotropin (HCG) in female of child-bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization or lactating females
  • RECIPIENT: Patients with allergy to mouse products or cetuximab
  • RECIPIENT: Active central nervous system (CNS) disease in patient with history of CNS malignancy
  • RECIPIENT: Positive serology for human immunodeficiency virus (HIV)
  • RECIPIENT: Active hepatitis B or active hepatitis C
  • RECIPIENT: Has received a T-cell product within 6 weeks prior to planned infusion of genetically modified T cells

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Donor-Derived Very-Rapid Manufactured CD19-Specific T Cells for Lymphoid Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation

This phase I trial investigates the side effects and best dose of CD19 positive (+) specific CAR-T cells in treating patients with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Sometimes researchers change the genetic material in the cells of a patient's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the patient's body. Receiving the T-cell infusion may help to control the disease.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To determine the safety and maximum tolerated dose (MTD) of donor-derived genetically modified, CD19-specific T cells expressing mbIL15 and HER1t using the Rapid Personalized Manufacture (RPM) process (autologous CD19-CD8-CD28-CD3zeta-chimeric antigen receptor [CAR]-mbIL15-HER1t T cells [CD19-mbIL15-CAR-T cells]) administered to patients with CD19+ advanced lymphoid malignancies who have previously received an allogeneic hematopoietic stem cell transplantation (HSCT), including haploidentical HSCT.

SECONDARY OBJECTIVES:

  1. To demonstrate the feasibility of the RPM process. II. To determine the incidence and grading of cytokine release syndrome (CRS) and neurotoxicity.

III. To determine persistence of genetically modified T cells. IV. To determine if cetuximab can control numbers of infused T cells. V. To screen for the development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t).

VI. To determine cytokine profile of the patient with infused T cells. VII. To demonstrate the homing ability of the infused T cells. VIII. To assess disease response after T-cell infusion. IX. To assess progression-free and overall survival. X. To detect emergence of CD19 negative (neg) malignant B cells.

OUTLINE: This is a dose-escalation study of autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells.

CHEMOTHERAPY: Patients receive fludarabine intravenously (IV) over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.

T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.

After completion of study treatment, patients are followed up within 3 days after T-cell infusion and at 1, 2, 3, 4, 6, and 8 weeks, then at 3, 6, and 12 months, then periodically for up to 15 years.

Being tested
Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells, Cyclophosphamide, Fludarabine
Medical subject headings
Burkitt Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Lymphoma, Non-Hodgkin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T CellsBiological

    Also called Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-EGFRt T Cells, CD19-CD8CD28zCAR-specific-mbIL15-HER1t T-lymphocytes

    Given IV

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • FludarabineDrug

    Also called Fluradosa

    Given IV

Study groups in NCT03579888
Study groupRoleWhat they receive
Treatment (fludarabine, cyclophosphamide, CD19 T cell)ExperimentalCHEMOTHERAPY: Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity. T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.
Receives: Biological: Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells; Drug: Cyclophosphamide; Drug: Fludarabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of adverse events

    Graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events will be summarized by frequencies and percentages by dose level.

    Measured: Up to 15 years

  2. Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT)

    The MTD is defined as the highest dose at which no more than 1 of 6 patients experiences a DLT. The study will employ a standard 3+3 design to find the MTD of CD19-specific chimeric antigen receptor (CAR) T cell dose.

    Measured: Up to 30 days post-infusion

Secondary outcomes (11)

  1. Incidence and grading of cytokine release syndrome (CRS)

    Graded according to CTCAE.

    Measured: Up to 12 months

  2. Persistence of genetically modified T cells

    Persistence of genetically modified T cells will be assessed by the frequency of patients with any detectable CAR-T cells.

    Measured: Up to 12 months

  3. Change in numbers of infused T cells

    For patients receiving cetuximab (i.e., those who experience >= grade 3 CRS), the change in infused CAR+ T cells from before cetuximab treatment to the nadir of CAR+ T cells after cetuximab summarized by mean, standard deviation, median, and range and days to achieve nadir.

    Measured: Up to 12 months

  4. Development of host immune responses against transgenes

    The development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t) may be assessed by the percentage of patients with antibody formation against each one of the transgenes.

    Measured: Up to 12 months

  5. Cytokine levels

    Individual patient and aggregate cytokine levels (e.g., IL-15, IL-12, IL-8, etc.) will be summarized by means, standard deviations, medians, and ranges.

    Measured: Up to 12 months

  6. Homing ability of the infused T cells

    Homing will be assessed based on presence of infused T cells within biopsied tissue. The frequency and percentage of patients experiencing homing and those who have CD19- malignant B cells will be presented.

    Measured: Up to 12 months

  7. Disease response

    Percentage of patients experiencing disease response, defined as partial or complete clearance of disease e.g., by positron emission tomography (PET) and/or bone marrow report will be computed along with a corresponding 95% confidence interval. The percentage of patients who had T cells successfully prepared, released, and infused will be reported. Additional statistical analyses will be performed if deemed appropriate.

    Measured: At days 30 and 100

  8. Neurotoxicity

    Graded according to CTCAE.

    Measured: Up to 12 months

  9. Presence of CD19 negative (-) malignant B cells

    Presence of CD19- malignant B cells will be based on flow cytometry staining for CD19 in the context of staining for antigens to detect cancerous B cells. The frequency and percentage of patients experiencing homing and those who have CD19- malignant B cells will be presented.

    Measured: Up to 12 months

  10. Progression-free survival

    Will be estimated using the Kaplan-Meier method and presented along with their 95% confidence intervals. Additional statistical analyses will be performed if deemed appropriate.

    Measured: From the time of T-cell infusion to date of progression of date of death, assessed up to 12 months

  11. Overall survival

    Will be estimated using the Kaplan-Meier method and presented along with their 95% confidence intervals. Additional statistical analyses will be performed if deemed appropriate.

    Measured: From the time of T-cell infusion to date of death, assessed up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Jul 2018
  2. Study start26 Jun 2020
  3. Primary completion27 May 2021
  4. Study completion27 May 2021

Why it stopped: Study halted prematurely

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03579888
Sponsor's protocol ID
2019-1063
Other IDs
NCI-2020-03608, 2019-1063
Status last verified
May 2021
First submitted
25 Jun 2018
Last updated
2 Jun 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

    PubMed 34515338

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells, Cyclophosphamide and Fludarabine in people with B Acute Lymphoblastic Leukemia With t(v;11q23.3); KMT2A Rearranged and Recurrent B Acute Lymphoblastic Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 38 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Study halted prematurely). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of adverse events (time frame: Up to 15 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03579888, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2021.

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