NK White Blood Cells and Interleukin in Children and Young Adults With Advanced Solid Tumors
Condition: Solid Tumors; Brain Tumors; Sarcoma; Pediatric Cancers; Neuroblastoma
MeSH terms: Neoplasms; Neuroblastoma
Study type: Interventional
Phase: Phase 1

Summary: 
      BACKGROUND:

        -  Despite progress, some children and young adults with solid tumors still experience poor
           survival.

        -  Activated NK cells potently kill autologous pediatric solid tumors, and clinical grade
           procedures are available to generate large numbers of activated NK cells for adoptive
           cell therapy.

      OBJECTIVES:

        -  Primary objectives are: 1) to assess the feasibility of harvesting and expanding
           activated NK cells to meet escalating dose goals in Cohort A, 2) to assess the toxicity
           of infusing escalating doses of activated NK cells following lymphodepleting
           chemotherapy without rhIL15 (cohort A), and 3) to assess the toxicity of infusing NK
           activated cells with escalating doses of rhIL15 (cohort B) in pediatric patients with
           refractory malignant solid tumors.

        -  Secondary objectives are: 1) to identify biologically active doses of activated
           autologous NK cells plus or minus rhIL15 by monitoring changes in NK cell number,
           phenotype and function, 2) to assess pharmacokinetics and immunogenicity of rhIL15 in a
           pediatric population, and 3) assess antitumor effects and changes in FDG-PET following
           administration of activated NK cells to lymphopenic hosts plus or minus rhIL15. 4) to
           evaluate saftey and efficacy of subsequent cycles of autologous NK cell infusions in
           patients in cohort A who received benefit from the first NK cell infusion.

      ELIGIBILITY:

        -  Patients in Cohort A: 2-29 years with with refractory pediatric malignant solid tumors,
           Patients in Cohort B: 2-25 years with refractory pediatric malignant solid tumors.

        -  Adequate performance status and organ function, recovered from toxic effects of prior
           therapy, no requirement for systemic corticosteroids and no history of allogeneic stem
           cell transplantation.

      DESIGN:

        -  All patients receive pre-NK lymphodepleting chemotherapy with cyclophosphamide.

        -  Cohort A receives escalating doses of activated autologous NK cells to identify
           feasibility of generating cells and tolerability, and potentially identify an MTD.

        -  A1: 1x10(6) NK cells/kg

        -  A2: 1 x 10(7) NK cells/kg

        -  A3: 1 x 10(8) NK cells/kg

        -  If feasibility and acceptable toxicity is demonstrated for all doses in Cohort A,
           patients enrolled on cohort B will receive activated autologous NK cells plus escalating
           doses of rhIL15 using the following schema:

        -  B1: 1 x 10(7) NK cells/kg + rhIL15 0.25 mcg/kg/d IV x 10

        -  B2: 1 x 10(7) NK cells/kg + rhIL15 0.5 mcg/kg/d IV x 10

        -  B3: 1 x 10(7) NK cells/kg + rhIL15 1 mcg/kg/d IV x 10

        -  B4: 1 x 10(7) NK cells/kg + rhIL15 2 mcg/kg/d IV x 10

        -  Three patients will be enrolled at each dose level, with the dose level expanded to 6 if
           dose-limiting toxicity occurs. An expanded group of 12 patients will be treated at the
           highest tolerable dose level. DLT toxicity monitoring will continue for 21 days after
           the NK infusion, or 14 days after the last rhIL15 dose in Cohort B (whichever is later).
    

Detailed description: 
      BACKGROUND:

        -  Despite progress, some children and young adults with solid tumors still experience poor
           survival.

        -  Activated NK cells potently kill autologous pediatric solid tumors, and clinical grade
           procedures are available to generate large numbers of activated NK cells for adoptive
           cell therapy.

      OBJECTIVES:

        -  Primary objectives are: 1) to assess the feasibility of harvesting and expanding
           activated NK cells to meet escalating dose goals in Cohort A, 2) to assess the toxicity
           of infusing escalating doses of activated NK cells following lymphodepleting
           chemotherapy without rhIL15 (cohort A), and 3) to assess the toxicity of infusing NK
           activated cells with escalating doses of rhIL15 (cohort B) in pediatric patients with
           refractory malignant solid tumors.

        -  Secondary objectives are: 1) to identify biologically active doses of activated
           autologous NK cells plus or minus rhIL15 by monitoring changes in NK cell number,
           phenotype and function, 2) to assess pharmacokinetics and immunogenicity of rhIL15 in a
           pediatric population, and 3) assess antitumor effects and changes in FDG-PET following
           administration of activated NK cells to lymphopenic hosts plus or minus rhIL15. 4) to
           evaluate saftey and efficacy of subsequent cycles of autologous NK cell infusions in
           patients in cohort A who received benefit from the first NK cell infusion.

      ELIGIBILITY:

        -  Patients in Cohort A: 2-29 years with with refractory pediatric malignant solid tumors,
           Patients in Cohort B: 2-25 years with refractory pediatric malignant solid tumors.

        -  Adequate performance status and organ function, recovered from toxic effects of prior
           therapy, no requirement for systemic corticosteroids and no history of allogeneic stem
           cell transplantation.

      DESIGN:

        -  All patients receive pre-NK lymphodepleting chemotherapy with cyclophosphamide.

        -  Cohort A receives escalating doses of activated autologous NK cells to identify
           feasibility of generating cells and tolerability, and potentially identify an MTD.

        -  A1: 1x10(6) NK cells/kg

        -  A2: 1 x 10(7) NK cells/kg

        -  A3: 1 x 10(8) NK cells/kg

        -  If feasibility and acceptable toxicity is demonstrated for all doses in Cohort A,
           patients enrolled on cohort B will receive activated autologous NK cells plus escalating
           doses of rhIL15 using the following schema:

        -  B1: 1 x 10(7) NK cells/kg + rhIL15 0.25 mcg/kg/d IV x 10

        -  B2: 1 x 10(7) NK cells/kg + rhIL15 0.5 mcg/kg/d IV x 10

        -  B3: 1 x 10(7) NK cells/kg + rhIL15 1 mcg/kg/d IV x 10

        -  B4: 1 x 10(7) NK cells/kg + rhIL15 2 mcg/kg/d IV x 10

        -  Three patients will be enrolled at each dose level, with the dose level expanded to 6 if
           dose-limiting toxicity occurs. An expanded group of 12 patients will be treated at the
           highest tolerable dose level. DLT toxicity monitoring will continue for 21 days after
           the NK infusion, or 14 days after the last rhIL15 dose in Cohort B (whichever is later).
    

Intervention name(s): Recombinant human interleukin-15 (rhIL-15); NK Cell Infusion
Intervention type(s): Biological; Biological
Intervention description(s): Continuous infusion rhIL15 IV; Infuse expanded NK cells at Day 0 after 2 days of Cyclophosphamide lymphodepletion
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: NK Cells; Cytokine; Lymphodepleting Chemotherapy; Immunotherapy; Pediatric