Clinical trial NCT02028455: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: CD19+ Acute Leukemia
Keywords: pediatric
young adult
acute lymphoblastic leukemia
CD19
leukemia
Chimeric Antigen Receptor
T cell
Lead sponsor: Seattle Children's Hospital
Sponsor class: OTHER
First posted: 2014-01-07
Enrollment: 167
Sex: ALL
Minimum age (years): 1
Maximum age (years): 26
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event Meeting the Dose-Limiting Toxicity Definition
timeFrame: Initial CAR T cell infusion through 30 days post infusion
measure: Number of Participants With an MRD Negative Complete Remission After Initial CAR T Cell Infusion
timeFrame: Initial CAR T cell infusion through Day 63 post infusion assessment (+/- 14 days)
measure: Number of Participants Who Have a Releasable Cell Product Generated
timeFrame: Up to 28 days per manufacturing attempt
Secondary outcomes:
measure: Persistence of Functional CD19 CAR+ T Cells
timeFrame: Initial CAR T Infusion through Day 63 post infusion assessment (+/- 14 days)
measure: Number of Participants With Recrudescence or Development of Acute GVHD (Graft Versus Host Disease) Symptoms Post CAR T Infusion
timeFrame: Initial CAR T Infusion through Day 63 post infusion assessment (+/- 14 days)
measure: Number of Participants That Received Cetuximab Who Have T Cells Successfully Ablated
timeFrame: 3 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Oakland
country: United States
facility: Children's Hospital Oakland
state: California
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Seattle Children's Hospital
name: Colleen Annesley, MD
role: STUDY_CHAIR
References:
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.
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.
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.
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.
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.