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A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

Primary Purpose

CD19+ Acute Leukemia

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Patient Derived CD19 specific CAR T cells also expressing an EGFRt

About this trial

This is an interventional treatment trial for CD19+ Acute Leukemia focused on measuring pediatric, young adult, acute lymphoblastic leukemia, CD19, leukemia, Chimeric Antigen Receptor, T cell

Eligibility Criteria

1 Year - 26 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must be ≥12 months of age and <27 years of age at the time of study enrollment.

Must be ≥10kg

Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT. [N.B. Study closed to enrollment of leukemia subjects]

No prior history of allogeneic HCT (one of the following)

2nd or greater relapse, with or without extramedullary disease (isolated extramedullary disease is eligible)
1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast disease, with or without extramedullary disease
Primary Refractory as defined as having M2 or M3 marrow after induction
Subject has indication for HCT but has been deemed ineligible

CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative therapies available [N.B. Study remains open to enrollment of lymphoma subjects]

Patients with CNS involvement are eligible provided that they are asymptomatic and in the opinion of the study PI have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion. Patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization.

Patients must have a Lansky performance status score of ≥50 or a Karnofsky score of ≥ 50 for patients ≥16 years of age.

Life Expectancy of >8 weeks

Patients must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks prior to enrollment.

Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy

It must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy or maintenance chemotherapy)

No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment.

No prior genetically modified cell therapy that is still detectable or virotherapy allowed.

Normal serum creatinine based on age/gender
Total bilirubin </3x ULN OR conjugated bilirubin </2mg/dl
ALT </5X ULN
SF of >28% by ECHO or EF >50% by MUGA
ALC of >/= 100 cells/ul
Pulse ox >/= 90% on room air

Patient must have documented negative HIV antigen and antibody, Hepatitis B surface antigen, and Hepatitis C antibody within 3 months prior to enrollment. For patient with positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible.

Patients must NOT have active clinically significant CNS dysfunction (including but not limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)

Must agree to highly effective contraception during and for 12 months after T cell infusion.

Patients must be able to tolerate apheresis procedure, including placement of temporary apheresis line if required.

Patients must NOT have an active malignancy other than CD19+ leukemia.

Patients must NOT have an active severe infection defined as:

A positive blood culture within 48 hours of study enrollment
A fever above 38.2 C AND clinical signs of infection within 48 hours of study enrollment

Patients must NOT have any concurrent medical condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy. Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial.

Research participant or parent/legal guardian must agree to participate in long-term follow-up for up to 15 years, if they are enrolled in the study and receive T-cell infusion.

Sites / Locations

Children's Hospital Los Angeles
Children's Hospital Oakland
Seattle Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Arm Label

Phase 1 - Cohort 1A

Phase 1 - Cohort 1B

Phase 1 - Cohort 1C

Phase 1 - Cohort 1D

Phase 1 - Cohort 1F1

Phase 1 - Cohort 1F2

Phase 2

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^5 CAR T cells/kg

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^6 CAR T cells/kg

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^6 CAR T cells/kg

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^7 CAR T cells/kg

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^5 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^6 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide

The phase 2 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1 x 10^6 CAR T cells/kg following lymphodepletion if indicated.

Outcomes

Primary Outcome Measures

Number of Participants Who Experienced an Adverse Event Meeting the Dose-Limiting Toxicity Definition

The safety of the T cell infusion at the maximum tolerated dose determined in Phase 1, and further characterized in Phase 2, will be described

Number of Participants With an MRD Negative Complete Remission After Initial CAR T Cell Infusion

The efficacy of the T cell infusion will be estimated based on the number of participants who have an MRD negative bone marrow aspirate following the initial T cell infusion

Number of Participants Who Have a Releasable Cell Product Generated

The feasibility of manufacturing and releasing T cell products from pediatric and young adult patients with CD19+ relapsed or refractory leukemia

Secondary Outcome Measures

Persistence of Functional CD19 CAR+ T Cells

Participants will be followed for 63 days to determine if the transferred T cells remain detectable in the blood and bone marrow

Number of Participants With Recrudescence or Development of Acute GVHD (Graft Versus Host Disease) Symptoms Post CAR T Infusion

Number of Participants That Received Cetuximab Who Have T Cells Successfully Ablated

The efficacy of cetuximab to ablate the T cells will be measured by loss of detection of T cells and any associated toxicities as well as facilitating B cell recovery.

Full Information

NCT ID

NCT02028455

First Posted

January 3, 2014

Last Updated

June 27, 2023

Sponsor

Seattle Children's Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02028455

Brief Title

A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

Official Title

Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02: A Phase 1/2 Feasibility and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

February 11, 2014 (Actual)

Primary Completion Date

August 10, 2021 (Actual)

Study Completion Date

July 2036 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Seattle Children's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.

Detailed Description

Upon meeting the eligibility requirements and enrolling on study, subjects will undergo apheresis to obtain the T cells for the generation of the CD19 CAR+ T cells. In patients with a prior history of allogeneic HCT, the T cells obtained are of donor origin. The T cells are isolated from the apheresis product, the CD4 and CD8 T cells are then selected and grown separately, transduced with a lentivirus to express the CD19 CAR as well as a truncated EGFR that has no signaling capacity (noted EGFRt) and expanded in culture over a three week period. During the process of cell generation, subjects will continue to be cared for by their primary oncologist and may undergo additional treatment directed at the leukemia during this time. After the CAR+ T cells have been generated, the subject undergoes a disease assessment and determination if lymphodepletion is necessary. A variety of lymphodepletion strategies are acceptable and determined on a case by case basis. At least 48 hours after the completion of lymphodepletion, the subject will receive and infusion of CAR+ T cells at an approximate 1:1 ratio of CD4 to CD8 CAR+ T cells. Following treatment with the CAR+ T cells, subjects will be followed intensely for 2 months with serial blood testing and re-evaluation of disease status with bone marrow aspirates. After 2 months, the subjects clinical care will be resumed by their primary oncologist, and it is possible that they would receive additional chemotherapy or HCT. Some subjects will receive cetuximab for ablation of the genetically modified T cells. Criteria to receive cetuximab include acute toxicities that are life threatening, as well as an ongoing remission with continued B cell aplasia. Upon completion of the study, subjects will be followed bi-annually for 5 years, and then annually for 10 additional years with either a medical history, physical exam and blood tests or a phone call/questionnaire. This follow up will help to determine if the subject develops any long-term health problems related to the CAR+ T cells including a new cancer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CD19+ Acute Leukemia

Keywords

pediatric, young adult, acute lymphoblastic leukemia, CD19, leukemia, Chimeric Antigen Receptor, T cell

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

167 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase 1 - Cohort 1A

Arm Type

Experimental

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^5 CAR T cells/kg

Arm Title

Phase 1 - Cohort 1B

Arm Type

Experimental

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^6 CAR T cells/kg

Arm Title

Phase 1 - Cohort 1C

Arm Type

Experimental

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^6 CAR T cells/kg

Arm Title

Phase 1 - Cohort 1D

Arm Type

Experimental

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^7 CAR T cells/kg

Arm Title

Phase 1 - Cohort 1F1

Arm Type

Experimental

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^5 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide

Arm Title

Phase 1 - Cohort 1F2

Arm Type

Experimental

Arm Description

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^6 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide

Arm Title

Phase 2

Arm Type

Experimental

Arm Description

The phase 2 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1 x 10^6 CAR T cells/kg following lymphodepletion if indicated.

Intervention Type

Biological

Intervention Name(s)

Patient Derived CD19 specific CAR T cells also expressing an EGFRt

Intervention Description

Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt

Primary Outcome Measure Information:

Title

Number of Participants Who Experienced an Adverse Event Meeting the Dose-Limiting Toxicity Definition

Description

The safety of the T cell infusion at the maximum tolerated dose determined in Phase 1, and further characterized in Phase 2, will be described

Time Frame

Initial CAR T cell infusion through 30 days post infusion

Title

Number of Participants With an MRD Negative Complete Remission After Initial CAR T Cell Infusion

Description

The efficacy of the T cell infusion will be estimated based on the number of participants who have an MRD negative bone marrow aspirate following the initial T cell infusion

Time Frame

Initial CAR T cell infusion through Day 63 post infusion assessment (+/- 14 days)

Title

Number of Participants Who Have a Releasable Cell Product Generated

Description

The feasibility of manufacturing and releasing T cell products from pediatric and young adult patients with CD19+ relapsed or refractory leukemia

Time Frame

Up to 28 days per manufacturing attempt

Secondary Outcome Measure Information:

Title

Persistence of Functional CD19 CAR+ T Cells

Description

Participants will be followed for 63 days to determine if the transferred T cells remain detectable in the blood and bone marrow

Time Frame

Initial CAR T Infusion through Day 63 post infusion assessment (+/- 14 days)

Title

Number of Participants With Recrudescence or Development of Acute GVHD (Graft Versus Host Disease) Symptoms Post CAR T Infusion

Time Frame

Initial CAR T Infusion through Day 63 post infusion assessment (+/- 14 days)

Title

Number of Participants That Received Cetuximab Who Have T Cells Successfully Ablated

Description

The efficacy of cetuximab to ablate the T cells will be measured by loss of detection of T cells and any associated toxicities as well as facilitating B cell recovery.

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

26 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must be ≥12 months of age and <27 years of age at the time of study enrollment. Must be ≥10kg Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT. [N.B. Study closed to enrollment of leukemia subjects] OR No prior history of allogeneic HCT (one of the following) 2nd or greater relapse, with or without extramedullary disease (isolated extramedullary disease is eligible) 1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast disease, with or without extramedullary disease Primary Refractory as defined as having M2 or M3 marrow after induction Subject has indication for HCT but has been deemed ineligible OR CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative therapies available [N.B. Study remains open to enrollment of lymphoma subjects] Patients with CNS involvement are eligible provided that they are asymptomatic and in the opinion of the study PI have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion. Patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization. Patients must have a Lansky performance status score of ≥50 or a Karnofsky score of ≥ 50 for patients ≥16 years of age. Life Expectancy of >8 weeks Patients must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks prior to enrollment. Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy It must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy or maintenance chemotherapy) No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment. No prior genetically modified cell therapy that is still detectable or virotherapy allowed. Normal serum creatinine based on age/gender Total bilirubin </3x ULN OR conjugated bilirubin </2mg/dl ALT </5X ULN SF of >28% by ECHO or EF >50% by MUGA ALC of >/= 100 cells/ul Pulse ox >/= 90% on room air Patient must have documented negative HIV antigen and antibody, Hepatitis B surface antigen, and Hepatitis C antibody within 3 months prior to enrollment. For patient with positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible. Patients must NOT have active clinically significant CNS dysfunction (including but not limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) Must agree to highly effective contraception during and for 12 months after T cell infusion. Patients must be able to tolerate apheresis procedure, including placement of temporary apheresis line if required. Patients must NOT have an active malignancy other than CD19+ leukemia. Patients must NOT have an active severe infection defined as: A positive blood culture within 48 hours of study enrollment A fever above 38.2 C AND clinical signs of infection within 48 hours of study enrollment Patients must NOT have any concurrent medical condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy. Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial. Research participant or parent/legal guardian must agree to participate in long-term follow-up for up to 15 years, if they are enrolled in the study and receive T-cell infusion.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Colleen Annesley, MD

Organizational Affiliation

Seattle Children's Hospital

Official's Role

Study Chair

Facility Information:

Facility Name

Children's Hospital Los Angeles

City

Los Angeles

State/Province

California

ZIP/Postal Code

90027

Country

United States

Facility Name

Children's Hospital Oakland

City

Oakland

State/Province

California

ZIP/Postal Code

94609

Country

United States

Facility Name

Seattle Children's Hospital

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

35580141

Citation

Ceppi F, Wilson AL, Annesley C, Kimmerly GR, Summers C, Brand A, Seidel K, Wu QV, Beebe A, Brown C, Mgebroff S, Lindgren C, Rawlings-Rhea SD, Huang W, Pulsipher MA, Wayne AS, Park JR, Jensen MC, Gardner RA. Modified Manufacturing Process Modulates CD19CAR T-cell Engraftment Fitness and Leukemia-Free Survival in Pediatric and Young Adult Subjects. Cancer Immunol Res. 2022 Jul 1;10(7):856-870. doi: 10.1158/2326-6066.CIR-21-0501.

Results Reference

derived

PubMed Identifier

34515338

Citation

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.

Results Reference

derived

PubMed Identifier

30860496

Citation

Finney OC, Brakke HM, Rawlings-Rhea S, Hicks R, Doolittle D, Lopez M, Futrell RB, Orentas RJ, Li D, Gardner RA, Jensen MC. CD19 CAR T cell product and disease attributes predict leukemia remission durability. J Clin Invest. 2019 Mar 12;129(5):2123-2132. doi: 10.1172/JCI125423. Print 2019 May 1.

Results Reference

derived

PubMed Identifier

28408462

Citation

Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, Bleakley M, Brown C, Mgebroff S, Kelly-Spratt KS, Hoglund V, Lindgren C, Oron AP, Li D, Riddell SR, Park JR, Jensen MC. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017 Jun 22;129(25):3322-3331. doi: 10.1182/blood-2017-02-769208. Epub 2017 Apr 13.

Results Reference

derived

PubMed Identifier

26907630

Citation

Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, Smithers H, Jensen MC, Riddell SR, Maloney DG, Turtle CJ. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016 May 19;127(20):2406-10. doi: 10.1182/blood-2015-08-665547. Epub 2016 Feb 23.

Results Reference

derived

Learn more about this trial

A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

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