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

• Sponsor: Seattle Children's Hospital
• Information provided by (Responsible Party): Rebecca Gardner, Seattle Children's Hospital

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.

Condition or disease	Intervention/treatment	Phase
CD19+ Acute Leukemia	Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt	Phase 1; Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	February 11, 2014
Estimated Primary Completion Date :	September 2019
Estimated Study Completion Date :	September 2034

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; This cohort will determine the maximum tolerated dose of the Patient Derived CD19 specific CAR T cells also expressing an EGFRt and is restricted to patients with a prior history of allo-HCT	Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt; Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt
Experimental: Cohort 2A; This cohort is for patient who have a history of allo-HCT with recurrence of disease post HCT and they will receive the MTD of Patient Derived CD19 specific CAR T cells also expressing an EGFRt determined in cohort 1.	Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt; Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt
Experimental: Cohort 2B; This cohort is restricted to patients wtih no prior history of allo-HCT and they will receive the MTD of Patient Derived CD19 specific CAR T cells also expressing an EGFRt determined in cohort 1	Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt; Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events [ Time Frame: 30 days ]
   The safety of the T cell infusion will be described and the maximum tolerated dose determined
2. Number of participants with an MRD negative complete remission after T cells infusion [ Time Frame: 63 days ]
   The efficacy fo the T cell infusion will be estimated based on the number of participants who have an MRD negative bone marrow aspirate following the T cell infusion
3. Number of Participants who have a Releasable Cell Product Generated [ Time Frame: 28 days ]
   The feasibility of manufacturing and releasing T cell products from pediatric and young adult patients who relapse with CD19+ leukemia both before and after allo-HCT will be measured.

Secondary Outcome Measures :

1. Persistence of functional CD19 CAR+ T cells [ Time Frame: 63 days ]
   Participants will be followed for 63 days to determine if the transferred T cells remain detectable in the blood, bone marrow and CSF
2. Number of participants with recrudescence or development of acute GVHD [ Time Frame: 63 days ]
3. Number of participants who have T cells ablated with cetuximab [ Time Frame: 3 years ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 26 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

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

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.

Contacts and Locations

Contacts

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Contact: Rebecca Gardner, MD	206-987-2106	CBDCIntake@seattlechildrens.org

Locations

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United States, California
Children's Hospital Los Angeles	Recruiting
Los Angeles, California, United States, 90027
Contact: Michael C Pulsipher, MD 323-361-2121 mpulsipher@chla.usc.edu
Contact: Tina Zhang 323-361-8658 tzhang@chla.usc.edu
Principal Investigator: Michael C Pulsipher, MD
Children's Hospital Oakland	Recruiting
Oakland, California, United States, 94609
Contact: Anurag Agrawal, MD 510-428-3539 aagrawal@mail.cho.org
Contact: Marci Moriarty, RN 510-428-3885 mmoriarty@mail.cho.org
Principal Investigator: Anurag Agrawal, MD
United States, Washington
Seattle Children's Hospital	Recruiting
Seattle, Washington, United States, 98105
Contact: Rebecca Gardner, MD 206-987-2106 CBDCIntake@seattlechildrens.org
Principal Investigator: Rebecca Gardner, MD

Sponsors and Collaborators

Seattle Children's Hospital

Investigators

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Study Chair:	Rebecca Gardner, MD	Seattle Children's Hospital
Principal Investigator:	Michael Pulsipher, MD	Children's Hospital Los Angeles
Principal Investigator:	Anurag Agrawal, MD	Children's Hospital & Research Center Oakland

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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Responsible Party:	Rebecca Gardner, Associate Medical Director, Immunotherapy Coordinating Center, Seattle Children's Hospital
ClinicalTrials.gov Identifier:	NCT02028455 History of Changes
Other Study ID Numbers:	PLAT-02
First Posted:	January 7, 2014
Last Update Posted:	January 23, 2019
Last Verified:	January 2019

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

Keywords provided by Rebecca Gardner, Seattle Children's Hospital:

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

Additional relevant MeSH terms:

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Leukemia; Neoplasms by Histologic Type; Neoplasms