A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors
Condition: Sarcoma; Osteosarcoma; Neuroblastoma; Melanoma
MeSH terms: Sarcoma; Neuroblastoma; Osteosarcoma
Study type: Interventional
Phase: Phase 1

Summary: 
      Background

      GD2 is a well-characterized tumor antigen in neuroblastoma, which is also expressed on
      osteosarcomas and some other sarcomas. T cells expressing 1st generation anti-GD2 chimeric
      antigen receptors (CARs) were safe and mediated modest antitumor activity in some patients
      with refractory neuroblastoma.

      A 3rd generation anti-GD2-CAR (GD2-CAR.OX40.28.z.ICD9) has been produced and holds promise
      for increased activity compared to the 1st generation GD2-CAR already studied in clinical
      trials. As an added safety measure, the vector includes a suicide switch comprising a caspase
      dimerization domain (ICD9) that can be activated by a small molecule to induce death of the
      genetically engineered cells if they were induce untoward toxicity.

      Objectives

      Primary:Determine the feasibility of producing anti GD2-CAR cells meeting the established
      release criteria and to assess the safety of administering escalating doses of anti-GD2-CAR
      engineered T cells in children and young adults with GD2+ solid tumors, including
      neuroblastoma, following cyclophosphamide-based lymphodepletion.

      Secondary:

        1. Determine if administration anti-GD2-CAR engineered T cells mediate antitumor effects in
           children and young adults with GD2+ solid tumors;

        2. Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this
           with antitumor effects;

        3. Extend information regarding the prevalence and intensity of GD2 expression in
           non-neuroblastoma, non-osteosarcoma solid tumors in children and young adults;

        4. If unacceptable toxicity occurs that is possibly, probably or likely related to
           anti-GD2-CAR T cells, assess the capacity for AP1903, a dimerizing agent, to mediate
           clearance of the genetically engineered cells and resolve toxicity; and

        5. Assess toxicity of AP1903 if administered to mediate clearance of anti-GD2-CAR T cells.

      Eligibility

      Patients 1-35 years of age, at least 15 kg, with osteosarcoma or a GD2+ solid tumor
      (including neuroblastoma) that has recurred after or not responded to standard therapy and is
      deemed incurable by standard therapy.

      Design

      After apheresis to collect T cells for transduction, patients receive cyclophosphamide
      1800mg/m(2)/d as a lymphodepleting regimen. A phase I cell dose escalation scheme will used
      at 4 dose levels (1 x 10(5) transduced T cells/kg; 1 x 10(6) transduced T cells/kg; 3 x 10(6)
      transduced T cells/kg; and 1 x 10(7) transduced T cells/kg), using a standard 3 plus 3 dose
      escalation design. An expanded group of a total of 12 patients will be treated at the highest
      dose, comprising at least 6 osteosarcoma patients.

      Patients will be monitored for toxicity, antitumor effects and persistence of anti-GD2-CAR T
      cells.

      Patients with a PR, SD may receive a 2nd cycle at the next higher dose level a minimum of 60
      days following completion of the first cycle if eligibility criteria are met.

      A maximum of 36 patients may be treated on this study. Given that there is likelihood that
      some patients with non-osteosarcoma will not meet the criteria for GD2 expression to be
      eligible for enrollment, up to 72 subjects will be screened to enroll a maximum of 36
      patients for treatment. Up to 2-3 patients will be accrued per month, and therefore this
      study may require up to 2-3 years to complete enrollment and treatment.
    

Detailed description: 
      Background

      GD2 is a well-characterized tumor antigen in neuroblastoma, which is also expressed on
      osteosarcomas and some other sarcomas. T cells expressing 1st generation anti-GD2 chimeric
      antigen receptors (CARs) were safe and mediated modest antitumor activity in some patients
      with refractory neuroblastoma.

      A 3rd generation anti-GD2-CAR (GD2-CAR.OX40.28.z.ICD9) has been produced and holds promise
      for increased activity compared to the 1st generation GD2-CAR already studied in clinical
      trials. As an added safety measure, the vector includes a suicide switch comprising a caspase
      dimerization domain (ICD9) that can be activated by a small molecule to induce death of the
      genetically engineered cells if they were induce untoward toxicity.

      Objectives

        -  Primary:Determine the feasibility of producing anti GD2-CAR cells meeting the
           established release criteria and to assess the safety of administering escalating doses
           of anti-GD2-CAR engineered T cells in children and young adults with GD2+ solid tumors,
           including neuroblastoma, following cyclophosphamide-based lymphodepletion.

        -  Seconday: 1) Determine if administration of anti-GD2-CAR engineered T cells mediate
           antitumor effects in children and young adults with GD2+ solid tumors; 2) Measure
           persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with
           antitumor effects; 3) Extend information regarding the prevalence and intensity of GD2
           expression in non-neuroblastoma, non- osteosarcoma solid tumors in children and young
           adults; 4) If unacceptable toxicity occurs that is possibly, probably or likely related
           to anti-GD2-CAR T cells, assess the capacity for AP1903, a dimerizing agent, to mediate
           clearance of the genetically engineered cells and resolve toxicity; and 5) Assess
           toxicity of AP1903 if administered to mediate clearance of anti-GD2-CAR T cells.

      Eligibility

      Patients 1-35 years of age, at least 15 kg, with osteosarcoma or a GD2+ solid tumor
      (including neuroblastoma) that has recurred after or not responded to standard therapy and is
      deemed incurable by standard therapy.

      Design

      After apheresis to collect T cells for transduction, patients receive cyclophosphamide
      1800mg/m(2)/d as a lymphodepleting regimen. A phase I cell dose escalation scheme will used
      at 4 dose levels (1 x 10(5) transduced T cells/kg; 1 x 10(6) transduced T cells/kg; 3 x 10(6)
      transduced T cells/kg; and 1 x 10(7) transduced T cells/kg), using a standard 3 plus 3 dose
      escalation design. An expanded group of a total of 12 patients will be treated at the highest
      dose, comprising at least 6 osteosarcoma patients.

      Patients will be monitored for toxicity, antitumor effects and persistence of anti-GD2-CAR T
      cells.

      Patients with a PR, SD may receive a 2nd cycle at the next higher dose level a minimum of 60
      days following completion of the first cycle if eligibility criteria are met.

      A maximum of 36 patients may be treated on this study. Given that there is likelihood that
      some patients with non-osteosarcoma will not meet the criteria for GD2 expression to be
      eligible for enrollment, up to 72 subjects will be screened to enroll a maximum of 36
      patients for treatment. Up to 2-3 patients will be accrued per month, and therefore this
      study may require up to 2-3 years to complete enrollment and treatment.
    

Intervention name(s): Anti-GD2-CAR engineered T cells; AP1903; Cyclophosphamide
Intervention type(s): Biological; Drug; Drug
Intervention description(s): Administer anti-GD2 CAR T cells 1 x 105 transduced T cells/kg; 1 x 106 transduced T cells/kg; 3 x 106 transduced T cells/kg; and 1 x 107 transduced T cells/kg; If unacceptable toxicity occurs that is possibly, probably or likely related to anti-GD2-CAR T cells, AP1903, a dimerizing agent, may be administered to mediate clearance of the genetically engineered cells and resolve toxicity; 1800mg/m2/d X 2 days as a lymphodepleting regimen
Intervention MeSH terms: Cyclophosphamide
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GD2-Expressing Tumors; Anti-GD2 Chimeric Antigen Receptor; Osteosarcoma; Adoptive Immunotherapy; Sarcomas