CD19-CAR T-cell Immunotherapy in Treating Patients with CD19-Positive Leukemia

Status: Active

Description

This phase I / II clinical trial studies the side effects of CD19-CAR T-cell immunotherapy and how well it works in treating patients with CD19-positive leukemia. Biological therapies, such as CD19-CAR T-cell immunotherapy, use substances made from living organisms that may attack specific tumor cells and stop them from growing or kill them.

Eligibility Criteria

Inclusion Criteria

  • Must be >= 10 kg
  • CD19+ leukemia
  • PHASE I: If post allogeneic HCT: Confirmed CD19+ leukemia recurrence defined as >= 0.01% disease by Seattle Children’s Hospital (SCH) or University of Washington (UW) Pathology Department following allogeneic HCT
  • PHASE I: If relapse/refractory status with no prior history of allogeneic HCT (one of the following) * 2nd or greater marrow relapse, with or without extramedullary disease * 1st marrow relapse at end of 1st month of re-induction with marrow having * >= 0.01% blast by morphology and/or MPF, with or without extramedullary disease * Primary refractory as defined as having M2 or M3 marrow after 2 or more separate induction regimens * Subject has indication for HCT but has been deemed ineligible
  • PHASE I: Patients with central nervous system (CNS) involvement are eligible provided that they are asymptomatic and in the opinion of the study principal investigator (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
  • PHASE II: Confirmed CD19+ leukemia recurrence defined as >= 0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT OR
  • PHASE II: 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
  • PHASE II: CD19+ non-Hodgkin lymphoma (NHL) refractory or relapsed with no known curative therapies available
  • PHASE II: 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 AND
  • PHASE II: For those subjects with marrow involvement, the first 15 subjects enrolled after the 03.28.2017 amendment must have detectable disease at the time of enrollment
  • Patients must be free from active graft versus host disease (GVHD) and off immunosuppressive GVHD therapy for 4 weeks prior to enrollment
  • Patients must have a Lansky performance status score of >= 50 or a Karnofsky score of >= 50 for patients >= 16 years of age; Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must have a life expectancy of > 8 weeks
  • All patients must, in the opinion of the study PI, have sufficiently recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
  • Must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy which can be administered at any given time pre study or upon enrollment nor does it include maintenance chemotherapy for the subset of patients who relapse during maintenance); for patients who were previously enrolled on the trial but were removed prior to receiving T cell therapy and are re-enrolling on the trial and already have a useable T cell product generated during previous enrollment, the duration and chemotherapy agents used is not restricted
  • No antibodies within 3 half-lives prior to study enrollment (applicable to phase 1 only)
  • 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; patients who are otherwise eligible but have detectable circulating CAR T cells of < 5% will be eligible, but will be evaluated as a separate strata from CAR-naive patients in the phase 2 portion of the study
  • PHASE I: For the post allo-HCT cohort, chimerism analysis must demonstrate > 95% either donor or recipient in peripheral blood CD3 cells, must be done within 1 month of enrollment (no mixed chimerism are eligible)
  • Adequate renal function defined as: a serum creatinine that is =< maximum based on age/gender Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 Age: 2 years < 6 years; maximum serum creatinine (mg/dL): 0.8 Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1.0 Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 Age: 13 to < 16 years; maximum serum creatinine (mg/dL):1.5 (male) 1.4 (female) Age: > 16 years; maximum serum creatinine (mg/dL): 1.7 (male) 1.4 (female)
  • Total bilirubin: =< 3 X upper limit of normal (ULN) for age OR conjugated bilirubin =< 2 mg/dl
  • Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 5 X the upper limit of normal (ULN)
  • Shortening fraction > 28% by echocardiogram or Ejection Fraction of > 50 % by multigated acquisition (MUGA)
  • Absolute lymphocyte count (ALC) >= 100 cells/ul
  • Documented negative human immunodeficiency infection virus (HIV) antigen and antibody, hepatitis B surface antigen, and hepatitis C antibody within 3 months prior to enrollment; for patient with positive hepatitis C antibody (Ab), negative polymerase chain reaction (PCR) testing must be documented in order to be eligible
  • Adequate respiratory function defined as not requiring supplemental oxygen or mechanical ventilation; oxygen saturation 90% or higher on room air
  • 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)
  • Patients who are pregnant or breast-feeding are not eligible for this study; fertile patients may not participate unless they have agreed to use contraception during and for 12 months after T cell infusion; highly effective contraception is defined as either: * Total abstinence: When this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Sterilization: Patient has had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); [for female study patients, the vasectomized male partner should be the sole partner for that patient] * Use a combination of the following: ** Hormonal contraception (oral or injected) or placement of an intrauterine device (IUD) or an intrauterine system (IUS) ** Barrier method of contraception: condom or occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository Note: Women are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential; male patients must use highly effective (double barrier) methods of contraception (e.g., spermicidal gel plus condom); a condom is required to be used also by vasectomized men in order to prevent delivery of the study treatment via seminal fluid
  • 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 celsius (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
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has tolerated prior dose of modified T cell infusion without experiencing a dose limiting toxicity OR if patient did have a dose limiting toxicity (DLT), they have fully recovered back to baseline
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has modified T cell product available for release
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has < 5 % detectable modified T cells in peripheral blood (can be done at any time prior)
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Subject has evidence of persistence of leukemic cells OR has CD19+ B cell recovery detected within 1 year of initial T cell infusion
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Research participant without clinically significant encephalopathy/new focal neurologic deficits
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Oxygen saturation 90% or higher on room air
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Adequate renal function defined as: a serum creatinine that is =< maximum based on age/gender Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 Age: 2 years < 6 years; maximum serum creatinine (mg/dL): 0.8 Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1.0 Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 Age: 13 to < 16 years; maximum serum creatinine (mg/dL):1.5 (male) 1.4 (female) Age: > 16 years; maximum serum creatinine (mg/dL): 1.7 (male) 1.4 (female)
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: Total bilirubin: =< 3 x ULN for age OR conjugated bilirubin =< 2 mg/dL
  • RETREATMENT WITH MODIFIED T-CELLS INCLUSION CRITERIA: ALT (SGPT): =< 5 x ULN

Exclusion Criteria

  • RETREATMENT WITH MODIFIED T-CELLS EXCLUSION CRITERIA: Research participant with current evidence of GVHD
  • RETREATMENT WITH MODIFIED T-CELLS EXCLUSION CRITERIA: Patient requiring supplemental oxygen or mechanical ventilation
  • RETREATMENT WITH MODIFIED T-CELLS EXCLUSION CRITERIA: Patients has an active severe infection defined as: * A positive blood culture within 48 hours of scheduled T cell infusion OR * A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell infusion

Locations & Contacts

California

Los Angeles
Children's Hospital Los Angeles
Status: Active
Contact: Michael Allen Pulsipher
Phone: 323-361-2121
Email: mpulsipher@chla.usc.edu

Washington

Seattle
Seattle Children's Hospital
Status: Active
Contact: Rebecca Alice Emmons Gardner
Phone: 206-987-2106
Email: rebecca.gardner@seattlechildrens.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the safety and toxicity of cellular immunotherapy utilizing ex-vivo expanded patient-derived CD4+/CD8+ T cells genetically modified to express a CD19-specific scFvIgG4hinge: CD28tm/4-1BB zeta chimeric antigen receptor (CAR) and EGFRt in children and young adults who relapse with CD19+ leukemia.

II. To describe the full toxicity profile.

III. To assess the feasibility of manufacturing and releasing T cell products from pediatric and young adult patients who relapse with CD19+ leukemia after both before and after allo-hematopoietic cell transplant (HCT).

IV. To estimate the efficacy, defined as a complete remission (CR), minimal residual disease (MRD) negative response to ex-vivo expanded patient-derived CD4+/CD8+ T cells genetically modified to express a CD19-specific scFvIgG4hinge: CD28tm/4-1BB zeta CAR and EGFRt in patients with relapsed or refractory CD19+ leukemia.

V. To estimate the rate of persistence of functional CAR+ T cells past day +63.

SECONDARY OBJECTIVES:

I. To determine the duration and magnitude of in vivo persistence of adoptively transferred T cells in the peripheral blood.

II. To assess the accumulation of transferred T-cells in the bone marrow and cerebral spinal fluid (CSF).

III. To quantitate anti-leukemic responses by measuring changes in leukemia burden using multi-parameter flow cytometry (MPF), IgH deep sequencing and/or induction of CD19+ B-cell aplasia.

IV. To determine the incidence of recrudescence or development of acute graft-versus-host-disease (GVHD) in treated patients and its association with the engraftment of transferred T cells for the post-allogenic HCT cohort.

V. To assess the efficacy of infusional cetuximab in ablating transferred T cells and ameliorating acute toxicities and/or facilitating B cell recovery in treated patients.

VI. To separately determine response rates and toxicity rates in the CR, MRD+ group and the refractory group.

VII. To explore relationships of CD19 antigen load/disease burden and conditioning regimen on persistence of CAR+ T cells.

OUTLINE:

Patients undergo apheresis over 6 hours. Patients then receive CD19-CAR T-cell immunotherapy intravenously (IV) over 20 minutes on day 0.

After completion of study treatment, patients are followed up every 6 months for 5 years and then every 12 months for up to 10 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Seattle Children's Hospital

Principal Investigator
Rebecca Alice Emmons Gardner

Trial IDs

Primary ID PLAT-02
Secondary IDs NCI-2017-01468
Clinicaltrials.gov ID NCT02028455