Genetically Modified T-Cell Immunotherapy in Treating Patients with Recurrent or Refractory Neuroblastoma

Status: Active

Description

This phase I trial studies the side effects and best dose of genetically modified T-cells in treating patients with neuroblastoma that has come back or does not respond to treatment. Placing a patient's modified gene into white blood cells may help the body build an immune response to kill tumor cells.

Eligibility Criteria

Inclusion Criteria

  • Patient must have a documentation of prior diagnosis of NB or ganglioneuroblastoma either by histologic verification and/or demonstration of tumor cells in the bone marrow with increased catecholamine levels
  • Patient must have had a diagnosis of high risk NB at initial diagnosis or if non-high risk at time of initial diagnosis must have had evidence of metastatic progression when > 18 months of age * Patient must have measurable or evaluable disease occurring as one of the following: ** Disease progression after initiation of upfront NB therapy defined as: *** New disease site documented on MIBG scintigraphy; or computed tomography (CT)/magnetic resonance imaging (MRI); or any new bone site that is fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) avid (in patient known to have MIBG non-avid tumor) AND has MRI findings consistent with tumor OR has a biopsy showing NB or ganglioneuroblastoma *** Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI AND a minimum absolute increase of 5 mm in longest dimension in existing lesions *** Bone marrow biopsy meeting revised International Neuroblastoma Response Criteria (INRC) criteria for progressive disease ** Refractory disease such that response to upfront therapy (defined as at least 4 cycles of multi-agent induction chemotherapy) is less than partial response ** Persistence of disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by MIBG scan, CT/MRI, or bone marrow aspirate/biopsies); patients in this category are REQUIRED to have histologic confirmation of viable NB from at least one residual site; tumor seen on routine bone marrow morphology is sufficient
  • Patient must have a Lansky performance status score of >= 50; 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
  • Patient must have a life expectancy of >= 8 weeks
  • Patient must, in the opinion of the study principal investigator (PI) or designee, have fully recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment onto this study
  • Must be at least 7 days since last chemotherapy or biologic therapy administered; for patients previously enrolled on this trial who had a usable T cell product generated but removed prior to receiving T cell therapy and are re-enrolling on the trial, the time from chemotherapy agent or biologic agent is not restricted
  • No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment
  • At least 3 half-lives from time of last dose of anti-tumor directed antibody therapy or 30 days, whichever is shorter
  • At least 6 weeks from myeloablative therapy and autologous stem cell transplant (timed from stem cell infusion); patients who received stem cell infusion following non-myelo-ablative therapy are eligible once they meet all other eligibility requirements; patient must NOT have received a prior allogeneic hematopoietic stem cell transplant
  • No prior genetically modified cell therapy that is still detectable or prior virotherapy
  • Must not be receiving external beam radiation therapy at the time of study enrollment; must be at least 12 weeks from prior I131 MIBG therapy
  • Normal serum creatinine based on age/gender as defined by Seattle Children's Hospital (SCH) chemistry lab
  • Normal serum sodium level without need for supplementation
  • Total bilirubin: =< 3 x upper limit of normal (ULN) for age OR conjugated bilirubin =< 2 mg/dl
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): =< 5 x the ULN
  • Shortening fraction > 28% by echocardiogram or an ejection fraction > 50% by multigated acquisition scan (MUGA)
  • Absolute lymphocyte count (ALC) >= 100 cells/ul
  • Documented negative human immunodeficiency virus (HIV) antigen and antibody, hepatitis B surface antigen and hepatitis C antibody within 3 months prior to enrollment; for patients with positive hepatitis C antibody (Ab), negative polymerase chain reaction (PCR) testing must be documented in order to be eligible
  • Not requiring supplemental oxygen or mechanical ventilation; oxygen saturation 90% or higher on room air; no dyspnea at rest
  • Patient does NOT have a history of relevant central nervous system (CNS) pathology or current relevant CNS pathology (non-febrile seizure disorder requiring ongoing anti-epileptic medications, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
  • Patient is NOT pregnant or breast-feeding; fertile patient MUST agree 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 (both): *** 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 patient 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
  • Patient is able to tolerate apheresis procedure including placement of temporary apheresis catheter if necessary or has prior apheresis product of 50 x 10^6 mononuclear (MNC) cells available for use
  • Patient does NOT have an active malignancy other than NB
  • Patient does NOT have known intracranial metastatic neuroblastoma; skull based disease with soft tissue extension is allowed
  • Patient 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
  • Patient does NOT have any concurrent medical condition that, in the opinion of the protocol 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
  • Patient is NOT receiving any other anti-cancer agents or radiotherapy at the time of study entry
  • Patient and/or parents or authorized legal representative have signed a written informed consent/assent per institutional guidelines
  • 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
  • ELIGIBILITY CRITERIA AT THE TIME OF APHERESIS: Patients must NOT have an active severe infection defined as: * A positive blood culture within 48 hours of blood draw OR * A fever above 38.2 C AND clinical signs of infection within 48 hours of blood draw
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Research participant without clinically significant encephalopathy/new focal neurologic deficits
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Research participant is not receiving systemically administered steroid therapy; glucocorticosteroid physiologic replacement therapy for management of adrenal insufficiency is allowed
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Patient has not received immunotherapy (for example- murine, chimeric or humanized monoclonal antibodies), T cell growth factors (such as IL-2, IL-7 or IL-15), interferons, vaccines, and other cellular products), pentoxifylline within the 7 days prior to the infusion of the T cell product
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air and no dyspnea at rest
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Absolute lymphocyte count < 500/ul or patient has received lymphodepleting chemotherapy administered at least 24 hours prior to T cell infusion
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a normal serum creatinine based on age/gender
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Normal serum sodium levels without need for supplementation
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Total bilirubin: =< 3 x ULN for age OR conjugated bilirubin =< 2 mg/dL
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: ALT (SGPT): =< 5 x ULN
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: Patients must NOT have an active severe infection defined as: * A positive blood culture within 48 hours of scheduled T cell infusion * A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell infusion
  • ELIGIBILITY CRITERIA FOR T-CELL PRODUCT INFUSION: If a patient has received anthracycline chemotherapy after enrollment, they must have demonstrated adequate cardiac function at any time following latest administration of an anthracycline chemotherapy (does NOT need to be within 48 hours of T cell infusion) defined as shortening fraction > 28% by echocardiogram or an ejection fraction > 50% by MUGA
  • RETREATMENT WITH MODIFIED T CELLS: Subject has tolerated prior dose of modified T cell infusion without experiencing a dose limiting toxicity
  • RETREATMENT WITH MODIFIED T CELLS: Subject has modified T cell product available for release
  • RETREATMENT WITH MODIFIED T CELLS: Subject has < 5% detectable modified T cells in peripheral blood (can be done any time prior)
  • RETREATMENT WITH MODIFIED T CELLS: Subject has evidence of persistent NB
  • RETREATMENT WITH MODIFIED T CELLS: Research participant without clinically significant encephalopathy/ new focal neurologic deficits
  • RETREATMENT WITH MODIFIED T CELLS: Oxygen saturation 90% or higher on room air
  • RETREATMENT WITH MODIFIED T CELLS: Normal serum creatinine based on age/gender
  • RETREATMENT WITH MODIFIED T CELLS: Normal serum sodium level without need for supplementation
  • RETREATMENT WITH MODIFIED T CELLS: Total bilirubin: =< 3 x ULN for age OR conjugated bilirubin =< 2 mg/dL
  • RETREATMENT WITH MODIFIED T CELLS: ALT (SGPT): =< 5 x ULN

Exclusion Criteria

  • RETREATMENT WITH MODIFIED T CELLS: Patient requiring supplemental oxygen or mechanical ventilation
  • RETREATMENT WITH MODIFIED T CELLS: Patient has an active severe infection defined as: * A positive blood culture within 48 hours of scheduled T cell infusion * A fever above 38.2 C AND clinical signs of infection within 48 hours of T cell infusion

Locations & Contacts

Washington

Seattle
Seattle Children's Hospital
Status: Active
Contact: Julie Ruggieri Park
Phone: 206-987-2106
Email: Julie.park@seattlechildrens.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the safety and toxicity of cellular immunotherapy utilizing ex-vivo expanded autologous T cell lines formulated as a 1:1 mixture of CD4+ and CD8+ T cells genetically modified to express a CD171-specific second generation or CD171-specific third generation chimeric antigen receptor (CAR) and EGFRt following a lymphodepleting regimen in children with recurrent/refractory neuroblastoma (NB).

II. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs).

III. To describe the full toxicity profile for second and third generation CD171-specific CAR+ EGFRt+ T cell products.

IV. To assess the feasibility of generating CAR T cell products from patients undergoing treatment for recurrent or refractory NB.

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 adoptively transferred T cells in the bone marrow.

III. To evaluate for presence of adoptively transferred T cells in tumor tissue or normal tissue in case of clinically indicated biopsy or resection.

IV. To quantitate anti-NB responses by measuring changes in tumor burden by 123 iodine-metaiodobenzylguanidine (I-MIBG)-scintigraphy, anatomic imaging of the involved region and clearance of tumor cells from the marrow.

V. To screen for the development of CAR and/or EGFRt immune responses in study subjects whose persistence data suggest rejection.

VI. To assess the efficacy of infusional cetuximab in ablating transferred T cells and ameliorating acute toxicities in treated patients.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 arms.

ARM A (2nd generation T cells): After completing a lymphodepleting regimen at least 24 hours prior to T cell infusion, patients receive 2nd generation autologous CD171-specific CAR-CD28 zeta-4-1-BB-EGFRt-expressing T lymphocytes intravenously (IV) over 20 minutes on day 0. Patients who have not developed a DLT following T cell infusion but have lost persistence of T cells may be eligible to receive additional infusion of T cells in the absence of unacceptable toxicity.

ARM B (3rd generation T cells): After completing a lymphodepleting regimen at least 24 hours prior to T cell infusion, patients receive 3rd generation autologous CD171-specific CAR-CD28 zeta-4-1-BB-EGFRt-expressing T lymphocytes IV over 20 minutes on day 0. Patients who have not developed a DLT following T cell infusion but have lost persistence of T cells may be eligible to receive additional infusion of T cells in the absence of unacceptable toxicity.

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

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Seattle Children's Hospital

Principal Investigator
Julie Ruggieri Park

Trial IDs

Primary ID ENCIT-01
Secondary IDs NCI-2017-01464
Clinicaltrials.gov ID NCT02311621