A Pilot Study of Immunotherapy Including Haploidentical NK Cell Infusion Following CD133+ Positively-Selected Autologous Hematopoietic Stem Cells in Children With High Risk Solid Tumors or Lymphomas

Study Overview
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Brief Summary
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This is a pilot clinical trial investigating the addition of haploidentical natural killer cell infusion to autologous stem cell transplantation. This intervention will be evaluated in children with high-risk solid tumors for whom autologous transplantation is indicated. Natural killer cells from a haploidentical family member will be given after high dose chemotherapy and positively selected autologous stem cells. In patients with neuroblastoma, the anti-GD2 antibody hu14.18K322A will also be given. The effect on normal hematopoietic cell recovery will be evaluated and survival of children treated with this approach will be determined. The investigators expect to enroll 36 participants. Haploidentical family members (donors) will also be recruited to provide natural killer cells.

Detailed Description
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Primary Objective: To evaluate day +35 ANC engraftment in autologous stem cell transplantation for high risk pediatric malignancies after stem cell selection and immunotherapy. Secondary Objectives To estimate incidence of relapse, disease-free survival and overall survival. To characterize lymphocyte and hematopoietic reconstitution in these patients. To describe the characteristics of the stem cell and natural killer cell grafts. To estimate the overall survival of patients treated without stem cell manipulation or NK cell infusion due to off therapy criteria

Official Title
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A Pilot Study of Immunotherapy Including Haploidentical NK Cell Infusion Following CD133+ Positively-Selected Autologous Hematopoietic Stem Cells in Children With High Risk Solid Tumors or Lymphomas

Conditions
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Neuroblastoma, Lymphoma, High-risk Tumor

Intervention / Treatment
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* Biological: CD133+ selected autologous stem cell infusion
* Biological: IL-2
* Biological: hu14.18K322A
* Drug: Busulfan
* Drug: Melphalan
* Biological: GM-CSF
* Drug: Bendamustine
* Drug: Etoposide
* Drug: Cytarabine
* Drug: Carboplatin
* Device: Haploidentical natural killer cell infusion
* Biological: G-CSF
* Drug: Etoposide phosphate
* Device: CliniMACS


Participation Criteria
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Eligibility Criteria
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The transplant recipient will be evaluated for eligibility at two time points during study participation. The first phase will be when the autologous stem cell product is collected. The recipient will later need to meet specific eligibility criterion at the time of the autologous stem cell infusion. The two phases and the respective criteria are described below. Inclusion criteria for autologous stem cell collection (Phase 1 - transplant recipient): Less than or equal to 21 years of age. Malignancy at high risk of treatment failure for which autologous hematopoietic stem cell transplantation is considered within standard practice. Group A: High-risk neuroblastoma Group B: Recurrent or refractory Hodgkin lymphoma; recurrent or refractory non-Hodgkin lymphoma Group C: High-risk, recurrent or metastatic sarcoma; recurrent or advanced stage Wilms tumor; desmoplastic small round cell tumor; metastatic or recurrent retinoblastoma, high-risk germ cell tumors, and high-risk brain tumors Sarcoma or Wilms tumor diagnosis (Group C) will require evaluation by physician in the St. Jude Solid Tumor Division, other than the referring physician, attesting that autologous SCT provides the prospect of direct benefit for the participant. Has a potentially suitable human leukocyte antigen (HLA) haploidentical donor available. Research participant or legal guardian/representative must be willing to give written informed consent Does not have any active or prior malignant or pre-malignant condition of the bone marrow, excluding metastasis of the primary malignancy. Has no known allergy to murine products or positive human anti-mouse antibody (HAMA). (Female only) Negative serum or urine pregnancy test (to be conducted within 7 days prior to enrollment). (Female only) Not breastfeeding. Inclusion criteria to proceed with autologous stem cell transplantation (Phase 2 - transplant recipient): Has a confirmed suitable HLA haploidentical donor available. Previously collected autologous stem cell product met the minimum collection target and minimum infusion target as described in the protocol. At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation therapy. Has recovered from all acute NCI Common Toxicity Criteria grade II-IV non-hematologic toxicities from prior therapy per the judgment of the PI. Shortening fraction greater than or equal to 25%. Creatinine clearance or glomerular filtration rate greater than or equal to 50 mL/min/1.73 m^2. Pulse oximetry greater than or equal to 92% on room air. Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to 3 times the upper limit of the institution-established normal range. Direct bilirubin less than or equal to 3.0 mg/dL. Karnofsky or Lansky performance score of greater than or equal to 50. Has not received a prior hematopoietic stem cell transplant within 3 months. Has no known allergy to murine products or positive human anti-mouse antibody (HAMA) (Female only) Is not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to admission for transplant). (Female only) Is not breastfeeding. Does not meet donation eligibility requirements as outlined by 21 CFR 1271 and agency guidance. Inclusion criteria for haploidentical NK cell donor: At least 18 years of age. Partially HLA matched family member. Human immunodeficiency virus (HIV) negative. (Female only) Is not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment). (Female only) Is not breastfeeding.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Neuroblastoma<br>All participants first receive standard of care high-dose chemotherapy specific to their tumor type. Group A participants receive busulfan, melphalan, CD133+ selected autologous stem cell infusion, hu14.18K322A, IL-2, haploidentical natural killer cell infusion, G-CSF, and GM-CSF. Cells for infusion are prepared using the CliniMACS System. | Biological: CD133+ selected autologous stem cell infusion<br>* Hematopoietic stem cells will be collected from children with high-risk solid tumors. After collection, they will be immuno-magnetically selected using CD133 as a marker in efforts to reduce tumor cell contamination in the stem cell graft. After high dose chemotherapy, those selected stem cells will be infused, followed shortly thereafter by an infusion of haploidentical natural killer cells.<br>* Other names: Natural killer (NK) cell infusion;Biological: IL-2<br>* Following infusion of haploidentical natural killer cells, interleukin-2 (IL-2) subcutaneously (SQ) will be given to support the in vivo survival of donor NK cells.<br>* Other names: Proleukin(R);Biological: hu14.18K322A<br>* Participants with neuroblastoma (Group A) will receive hu14.18K322A intravenously (IV).<br>* Other names: Hu14.18K322MAB;Drug: Busulfan<br>* Given IV - Group A only.<br>* Other names: Myleran(R);Drug: Melphalan<br>* Given IV - All groups.<br>* Other names: L-sarcolysin;Biological: GM-CSF<br>* Given SQ - All groups.<br>* Other names: Leukine(R);Device: Haploidentical natural killer cell infusion<br>* NK cell product will be collected from donors using leukapheresis procedures. The autologous hematopoietic stem cell graft product will be positively selected using the investigational CliniMACS device and CD133 Microbead reagent. Following standard laboratory procedures, the NK cell product will be enumerated and assessed for viable cell content. NK cells will be infused by slow IV push over 3 to 15 minutes immediately after processing, evaluation and release testing.<br>* Other names: NK cell infusion;Biological: G-CSF<br>* Given SQ - All Groups.<br>* Other names: Neupogen(R);Device: CliniMACS<br>* The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.<br>* Other names: Cell Selection System;|
| Experimental: Group B: Lymphoma<br>All participants first receive standard of care high-dose chemotherapy specific to their tumor type. Group B participants receive bendamustine, etoposide (or etoposide phosphate), cytarabine, melphalan, CD133+ selected autologous stem cell infusion, IL-2, haploidentical natural killer cell infusion, G-CSF, and GM-CSF. Cells for infusion are prepared using the CliniMACS System. | Biological: CD133+ selected autologous stem cell infusion<br>* Hematopoietic stem cells will be collected from children with high-risk solid tumors. After collection, they will be immuno-magnetically selected using CD133 as a marker in efforts to reduce tumor cell contamination in the stem cell graft. After high dose chemotherapy, those selected stem cells will be infused, followed shortly thereafter by an infusion of haploidentical natural killer cells.<br>* Other names: Natural killer (NK) cell infusion;Biological: IL-2<br>* Following infusion of haploidentical natural killer cells, interleukin-2 (IL-2) subcutaneously (SQ) will be given to support the in vivo survival of donor NK cells.<br>* Other names: Proleukin(R);Drug: Melphalan<br>* Given IV - All groups.<br>* Other names: L-sarcolysin;Biological: GM-CSF<br>* Given SQ - All groups.<br>* Other names: Leukine(R);Drug: Bendamustine<br>* Given IV - Group B only.<br>* Other names: Bendamustine hydrochloride;Drug: Etoposide<br>* Given IV - Group B and Group C. In case of etoposide reactions, etoposide phosphate will be given.<br>* Other names: Vepesid(R);Drug: Cytarabine<br>* Given IV - Group B only.<br>* Other names: ARA-C;Device: Haploidentical natural killer cell infusion<br>* NK cell product will be collected from donors using leukapheresis procedures. The autologous hematopoietic stem cell graft product will be positively selected using the investigational CliniMACS device and CD133 Microbead reagent. Following standard laboratory procedures, the NK cell product will be enumerated and assessed for viable cell content. NK cells will be infused by slow IV push over 3 to 15 minutes immediately after processing, evaluation and release testing.<br>* Other names: NK cell infusion;Biological: G-CSF<br>* Given SQ - All Groups.<br>* Other names: Neupogen(R);Drug: Etoposide phosphate<br>* In case of etoposide reactions, etoposide phosphate will be given IV. - Group B and Group C only.<br>* Other names: Etopophos(R);Device: CliniMACS<br>* The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.<br>* Other names: Cell Selection System;|
| Experimental: Group C: High-Risk Tumors<br>All participants first receive standard of care high-dose chemotherapy specific to their tumor type. Group C participants receive melphalan, etoposide (or etoposide phosphate), carboplatin, CD133+ selected autologous stem cell infusion, IL-2, haploidentical natural killer cell infusion, G-CSF, and GM-CSF. Cells for infusion are prepared using the CliniMACS System. | Biological: CD133+ selected autologous stem cell infusion<br>* Hematopoietic stem cells will be collected from children with high-risk solid tumors. After collection, they will be immuno-magnetically selected using CD133 as a marker in efforts to reduce tumor cell contamination in the stem cell graft. After high dose chemotherapy, those selected stem cells will be infused, followed shortly thereafter by an infusion of haploidentical natural killer cells.<br>* Other names: Natural killer (NK) cell infusion;Biological: IL-2<br>* Following infusion of haploidentical natural killer cells, interleukin-2 (IL-2) subcutaneously (SQ) will be given to support the in vivo survival of donor NK cells.<br>* Other names: Proleukin(R);Drug: Melphalan<br>* Given IV - All groups.<br>* Other names: L-sarcolysin;Biological: GM-CSF<br>* Given SQ - All groups.<br>* Other names: Leukine(R);Drug: Etoposide<br>* Given IV - Group B and Group C. In case of etoposide reactions, etoposide phosphate will be given.<br>* Other names: Vepesid(R);Drug: Carboplatin<br>* Given IV - Group C only.<br>* Other names: Inorganic heavy metal coordination complex;Device: Haploidentical natural killer cell infusion<br>* NK cell product will be collected from donors using leukapheresis procedures. The autologous hematopoietic stem cell graft product will be positively selected using the investigational CliniMACS device and CD133 Microbead reagent. Following standard laboratory procedures, the NK cell product will be enumerated and assessed for viable cell content. NK cells will be infused by slow IV push over 3 to 15 minutes immediately after processing, evaluation and release testing.<br>* Other names: NK cell infusion;Biological: G-CSF<br>* Given SQ - All Groups.<br>* Other names: Neupogen(R);Drug: Etoposide phosphate<br>* In case of etoposide reactions, etoposide phosphate will be given IV. - Group B and Group C only.<br>* Other names: Etopophos(R);Device: CliniMACS<br>* The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.<br>* Other names: Cell Selection System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of participants with positive ANC engraftment | Feasibility will be determined based on ANC engraftment defined as ANC ≥500/mm^3 for 3 consecutive tests performed on different days evaluated before day 35 post-transplant. If the study is considered feasible, the ANC engraftment rate will be 100% (95% Blyth-Still-Casella (BSC) CI: 76.45%-100%) without any failure, 92% (BSC 95% CI: 65.11%-99.57%) with 1 failure, and 83% (BSC 95% CI: 55%-96.95%) with 2 failures. In addition, if more than 2 (≥ 3) on-therapy patients die due to any protocol treatment-related causes during the first 12 months post-transplant across all groups (3 deaths among 36 participants), the study will be stopped. Deaths due to treatment not specified in this protocol will not be included in evaluation of this stopping rule. | Day 35 post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival is defined based on any death. The Kaplan-Meier Estimate will be provided. | Up to one year after transplantation | 
| Disease-free survival | Disease-free survival is defined based on any death, graft failure, or relapsed/resistant disease. The Kaplan-Meier Estimate will be provided. | Up to one year after transplantation | 
| Incidence of relapse | Cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. | Up to one year after transplantation | 
| Lymphocyte and hematopoietic reconstitution | The hematopoietic cell recovery and engraftment rates will be reported with a Blyth-Still-Casella 95% confidence interval. | Up to one year after transplantation | 
| Characteristics of the stem cell grafts | Results will be reported and presented descriptively. | Up to one year after transplantation | 
| Characteristics of the natural killer cell grafts. | Results will be reported and presented descriptively. | Up to one year after transplantation | 
| Overall survival of patients treated without stem cell manipulation or NK cell infusion due to off therapy criteria | The Kaplan-Meier estimate will be provided for overall survival analysis. | Up to one year after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autologous stem cell transplantation, Natural killer cells