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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02130869
Recruitment Status : Completed
First Posted : May 6, 2014
Last Update Posted : December 22, 2017
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Neuroblastoma Lymphoma High-risk Tumor 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 Phase 1

Detailed Description:

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 10, 2014
Actual Primary Completion Date : December 20, 2017
Actual Study Completion Date : December 20, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A: Neuroblastoma

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
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.
Other Name: Natural killer (NK) cell infusion

Biological: IL-2
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.
Other Names:
  • Interleukin-2
  • Aldesleukin
  • Proleukin(R)

Biological: hu14.18K322A
Participants with neuroblastoma (Group A) will receive hu14.18K322A intravenously (IV).
Other Names:
  • anti-GD2 antibody
  • Hu14.18K322MAB

Drug: Busulfan
Given IV - Group A only.
Other Names:
  • Busulfex(R)
  • Myleran(R)

Drug: Melphalan
Given IV - All groups.
Other Names:
  • L-phenylalanine mustard
  • Phenylalanine mustard
  • L-PAM
  • L-sarcolysin

Biological: GM-CSF
Given SQ - All groups.
Other Names:
  • Sargramostim
  • Leukine(R)

Device: Haploidentical natural killer cell infusion
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.
Other Name: NK cell infusion

Biological: G-CSF
Given SQ - All Groups.
Other Names:
  • Filgrastim
  • Neupogen(R)

Device: CliniMACS
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.
Other Name: Cell Selection System

Experimental: Group B: Lymphoma

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
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.
Other Name: Natural killer (NK) cell infusion

Biological: IL-2
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.
Other Names:
  • Interleukin-2
  • Aldesleukin
  • Proleukin(R)

Drug: Melphalan
Given IV - All groups.
Other Names:
  • L-phenylalanine mustard
  • Phenylalanine mustard
  • L-PAM
  • L-sarcolysin

Biological: GM-CSF
Given SQ - All groups.
Other Names:
  • Sargramostim
  • Leukine(R)

Drug: Bendamustine
Given IV - Group B only.
Other Names:
  • Treanda®
  • Bendamustine hydrochloride

Drug: Etoposide
Given IV - Group B and Group C. In case of etoposide reactions, etoposide phosphate will be given.
Other Names:
  • VP-16
  • Vepesid(R)

Drug: Cytarabine
Given IV - Group B only.
Other Name: ARA-C

Device: Haploidentical natural killer cell infusion
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.
Other Name: NK cell infusion

Biological: G-CSF
Given SQ - All Groups.
Other Names:
  • Filgrastim
  • Neupogen(R)

Drug: Etoposide phosphate
In case of etoposide reactions, etoposide phosphate will be given IV. - Group B and Group C only.
Other Name: Etopophos(R)

Device: CliniMACS
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.
Other Name: Cell Selection System

Experimental: Group C: High-Risk Tumors

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
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.
Other Name: Natural killer (NK) cell infusion

Biological: IL-2
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.
Other Names:
  • Interleukin-2
  • Aldesleukin
  • Proleukin(R)

Drug: Melphalan
Given IV - All groups.
Other Names:
  • L-phenylalanine mustard
  • Phenylalanine mustard
  • L-PAM
  • L-sarcolysin

Biological: GM-CSF
Given SQ - All groups.
Other Names:
  • Sargramostim
  • Leukine(R)

Drug: Etoposide
Given IV - Group B and Group C. In case of etoposide reactions, etoposide phosphate will be given.
Other Names:
  • VP-16
  • Vepesid(R)

Drug: Carboplatin
Given IV - Group C only.
Other Name: Inorganic heavy metal coordination complex

Device: Haploidentical natural killer cell infusion
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.
Other Name: NK cell infusion

Biological: G-CSF
Given SQ - All Groups.
Other Names:
  • Filgrastim
  • Neupogen(R)

Drug: Etoposide phosphate
In case of etoposide reactions, etoposide phosphate will be given IV. - Group B and Group C only.
Other Name: Etopophos(R)

Device: CliniMACS
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.
Other Name: Cell Selection System




Primary Outcome Measures :
  1. Percent of participants with positive ANC engraftment [ Time Frame: Day 35 post transplant ]
    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.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Up to one year after transplantation ]
    Overall survival is defined based on any death. The Kaplan-Meier Estimate will be provided.

  2. Disease-free survival [ Time Frame: Up to one year after transplantation ]
    Disease-free survival is defined based on any death, graft failure, or relapsed/resistant disease. The Kaplan-Meier Estimate will be provided.

  3. Incidence of relapse [ Time Frame: Up to one year after transplantation ]
    Cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event.

  4. Lymphocyte and hematopoietic reconstitution [ Time Frame: Up to one year after transplantation ]
    The hematopoietic cell recovery and engraftment rates will be reported with a Blyth-Still-Casella 95% confidence interval.

  5. Characteristics of the stem cell grafts [ Time Frame: Up to one year after transplantation ]
    Results will be reported and presented descriptively.

  6. Characteristics of the natural killer cell grafts. [ Time Frame: Up to one year after transplantation ]
    Results will be reported and presented descriptively.

  7. Overall survival of patients treated without stem cell manipulation or NK cell infusion due to off therapy criteria [ Time Frame: Up to one year after transplantation ]
    The Kaplan-Meier estimate will be provided for overall survival analysis.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02130869


Locations
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United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Brandon M. Triplett, MD St. Jude Children's Research Hospital
Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT02130869    
Other Study ID Numbers: ASCIST
NCI-2014-00275 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: May 6, 2014    Key Record Dates
Last Update Posted: December 22, 2017
Last Verified: December 2017

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by St. Jude Children's Research Hospital:
Autologous stem cell transplantation
Natural killer cells
Additional relevant MeSH terms:
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Lymphoma
Neuroblastoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cytarabine
Aldesleukin
Carboplatin
Etoposide
Etoposide phosphate
Melphalan
Busulfan
Interleukin-2
Bendamustine Hydrochloride
Mechlorethamine
Sargramostim
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors