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T Cell Receptor Gene Therapy in Treating Younger Patients with Solid Tumors

Trial Status: Complete

This pilot phase I trial studies the side effects and best dose of T cell receptor gene therapy in treating younger patients with solid tumors. Placing a gene that has been created in the laboratory into white blood osteosarcoma, rhabdomyosarcoma, neuroblastoma or melanoma cells may help the body build an immune response to kill tumor cells.

Inclusion Criteria

  • Osteosarcoma, neuroblastoma and melanoma that have been treated with standard frontline therapy and are judged to be incurable with standard therapy, based upon the fact that they are unresectable, metastatic, progressive/persistent or recurrent; evaluable disease must be present * For all histologies except osteosarcoma and neuroblastoma, pathologic review of frozen tissue must document GD2+ expression; positive expression is defined as at least 2+ expression (0-4+ scale) in > 50% of the tumor cells using anti-GD2 monoclonal antibody (mAb) 14G2a; if adequate archived frozen tissue is available, this may be utilized, or if not, patients may undergo biopsy following enrollment to obtain tissue to assess GD2 expression, with the following restrictions * Patients with histologies other than osteosarcoma or neuroblastoma must have adequate accessible tumor for biopsy (at least 1 cm diameter) * Procedures employed to acquire biopsies for tumor lysates will be limited to percutaneous needle or core biopsies, thoracoscopic excision or open biopsies of readily accessible lesions; pulmonary lesions may be biopsied but extensive surgery such as thoracotomy or laparotomy should not be employed * Patients who will require biopsy should not be enrolled if in the opinion of the principal investigator, the tumor site places the patient at substantial risk from the biopsy procedure
  • Weight >= 15 kg
  • Prior therapy: * The patient’s malignancy must have relapsed after or failed to respond to frontline curative therapy and/or there must not be any curative treatment options available at the time of study entry * There is no limit to the number of prior treatment regimens; however, patients must have fully recovered from the acute toxic effects of prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment; any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less * Myelosuppressive chemotherapy: patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea) * Hematopoietic growth factors: at least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim * At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinase inhibitor or a metronomic non-myelosuppressive regimen * Monoclonal antibodies: at least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody * Radiotherapy: 3 weeks must have elapsed since external beam radiation therapy (XRT)
  • Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2, or for children =< 10 years of age, Lansky >= 60
  • Left ventricular ejection fraction >= 40% or fractional shortening >= 28%
  • Serum total bilirubin < 2 mg/dl; patients with Gilbert’s syndrome are excluded from the requirement of a normal bilirubin and patients will not be excluded if liver enzyme elevation is due to tumor involvement; NOTE: adult values will be used for calculating hepatic toxicity and determining eligibility, as is standard on Pediatric Oncology Branch (POB) phase I trials
  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal; NOTE: adult values will be used for calculating hepatic toxicity and determining eligibility, as is standard on POB phase I trials
  • Age-adjusted normal serum creatinine according to the following table or a creatinine clearance >= 60 ml/min/1.73 m^2: * Age =< 5 years: maximum serum creatinine 0.8 mg/dL * Age > 5 =< 10 years: maximum serum creatinine 1.0 mg/dL * Age > 10 =< 15 years: maximum serum creatinine 1.2 mg/dL * Age > 15 years: maximum serum creatinine 1.5 mg/dL
  • Absolute neutrophil count (ANC) must be > 750/mm^3 (not achieved by transfusion)
  • Platelet count must be >= 50,000/mm^3 (not achieved by transfusion)
  • For patients < 18 years of age, their legal guardian must give informed consent; pediatric patients will be included in age-appropriate discussion in order to obtain verbal assent
  • Durable power of attorney form offered (patients >= 18 years of age only)
  • Female and male patients (and when relevant their partners) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential
  • Both men and women of all races and ethnic groups are eligible for this trial
  • Neuropathic pain =< grade 1
  • ECOG 0, 1 or 2, or for children =< 10 years of age, Lansky >= 60
  • Patient may have no active uncontrollable systemic infection
  • No requirement for supplemental oxygen therapy
  • Response to first infusions: * Subjects who had a PR, or SD with clinical benefit may elect to receive a second infusion of cells; subjects that initially had a CR may only receive a second dose if evaluable disease recurs; clinical benefit is indicated by an improvement in the subject’s health status (eg, improved performance status or quality of life, decreased pain, etc.)
  • At least 60 days must have passed since the first cell infusion and the subject must not have experienced a dose limiting toxicity (DLT) in this time
  • Patients will NOT receive a second infusion of GD-2 CAR T cells if >= 5 % of the circulating T cells are GD2-CAR positive by flow cytometry
  • Subjects who experienced grade 3 or 4 toxicity regardless of causality to the cell infusion must have had a reduction to a grade 1 or less or returned to baseline levels
  • Subjects must meet all the initial eligibility criteria except for the requirement regarding previous anti-GD2-CAR therapy
  • An adequate number of cryopreserved GD2-CAR cells must be available, or an adequate number of cryopreserved PBMC from the original apheresis must be available to generate a second dose of GD2-CAR T cells; post-GD2 CAR apheresis will not be used to harvest peripheral blood mononuclear cell (PBMC) cells for the transduction for the second infusion
  • The cell dose (based on CAR transduced cells) for the second infusion shall not be greater than the current dose level completed or the MTD if this has been determined and not less than the first dose level of this study (1 x 10^5/kg)

Exclusion Criteria

  • Clinically significant systemic illness (e.g., serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the principal investigator (PI) would compromise the patient’s ability to tolerate protocol therapy or significantly increase the risk of complications; peripheral nerve symptoms from prior therapies or from tumor compression > grade 1
  • Extradural masses that have not invaded the brain parenchyma or parameningeal tumors without evidence for leptomeningeal spread will not render the patient ineligible; patients with previous central nervous system (CNS) tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible; patients who are clinically stable as evidenced by no requirements for corticosteroids, no evolving neurologic deficits and no progression of residual brain abnormalities without specific therapy, are eligible one week post radiation or radiosurgery; patients with asymptomatic sub-centemeric CNS lesions will be eligible if no immediate radiation or surgery indicated
  • Previous treatment with genetically engineered GD2-CAR T cells; previous vaccine therapy, anti-GD2 mAb therapy or therapy with other genetically engineered T cells is not an exclusion criteria
  • Lactating or pregnant females
  • Active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  • Patients who require systemic corticosteroid or other immunosuppressive therapy; immunosuppressive therapy must be stopped at least 14 days prior to cell infusion


National Cancer Institute Pediatric Oncology Branch
Contact: Rosandra Natasha Reich Kaplan
Phone: 240-760-6198
National Institutes of Health Clinical Center
Contact: Rosandra Natasha Reich Kaplan
Phone: 240-760-6198


I. Determine the feasibility of producing anti-gangliosides (GD)2-chimeric antigen receptor (CAR) cells meeting the established release criteria and to assess the safety of administering escalating doses of autologous anti-GD2-CAR (anti-GD2.28.z.OX40.ICD9) engineered T cells (iC9-GD2-cluster of differentiation [CD]28-OX40-expressing T lymphocytes) in children and young adults with osteosarcoma and GD2+ solid tumors (including neuroblastoma) following cyclophosphamide based lymphodepletion.


I. Determine if anti-GD2-CAR engineered T cells mediate antitumor effects in children and young adults with GD2+ solid tumors (including neuroblastoma).

II. Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with antitumor effects.

III. Extend information regarding the prevalence and intensity of GD2 expression in non-neuroblastoma, non-osteosarcoma solid tumors in children and young adults.

IV. If unacceptable toxicity occurs that is possibly, probably or likely related to anti-GD2-CAR T cells, assess the capacity for AP1903 (rimiducid), a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity.

V. Assess toxicity of AP1903 if administered to mediate clearance of anti-GD2-CAR T cells.

VI. To assess cognitive functioning pre- and post-infusion to examine the cognitive effects of the anti-GD2 CAR T cell administration.


I. To assess cognitive functioning in participants who return to the National Institutes of Health (NIH) for follow-up evaluations at 3 months post-infusion to explore the later cognitive effects of the anti-GD2 CAR T cell administration.

II. To explore the relationships between cognitive test scores and serum cytokine levels (e.g., interferon [IFN]-gamma, interleukin [IL]-2, IL-7, and tumor necrosis factor alpha [TNFa]).

OUTLINE: This is a dose-escalation study of iC9-GD2-CD28-OX40-expressing T lymphocytes.

LYMPHODEPLETING CHEMOTHERAPY AND CELL INFUSION: Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -3 and -2 and iC9-GD2-CD28-OX40-expressing T lymphocytes IV over 15-30 minutes on day 0. Patients also receive filgrastim subcutaneously (SC) on day 4 and continue until blood counts recover. Patients who had a partial response (PR) or stable disease (SD) with clinical benefit or initially had a complete response (CR) with evaluable disease may receive a second infusion of iC9-GD2-CD28-OX40-expressing T lymphocytes at least 60 days from first infusion.

After completion of study treatment, patients are followed up at day 28 and 42, monthly for 6 months, every 3 months for 1 year, every 6 months for 1 year, and then annually for 13 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Rosandra Natasha Reich Kaplan

  • Primary ID 14-C-0059
  • Secondary IDs NCI-2014-02506, P131369
  • ID NCT02107963