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

December 21, 2017 updated by: St. Jude Children's Research Hospital

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
8

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • St. Jude Children's Research Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

No older than 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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.
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 Names:
  • Cell Selection 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 Names:
  • 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:
  • Aldesleukin
  • Interleukin-2
  • 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:
  • Phenylalanine mustard
  • L-PAM
  • L-phenylalanine mustard
  • 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 Names:
  • NK cell infusion
Biological: G-CSF
Given SQ - All Groups.
Other Names:
  • Filgrastim
  • Neupogen(R)
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.
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 Names:
  • Cell Selection 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 Names:
  • 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:
  • Aldesleukin
  • Interleukin-2
  • Proleukin(R)
Drug: Melphalan
Given IV - All groups.
Other Names:
  • Phenylalanine mustard
  • L-PAM
  • L-phenylalanine mustard
  • 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 Names:
  • NK cell infusion
Biological: G-CSF
Given SQ - All Groups.
Other Names:
  • Filgrastim
  • Neupogen(R)
Drug: Bendamustine
Given IV - Group B only.
Other Names:
  • Bendamustine hydrochloride
  • Treanda®
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 Names:
  • ARA-C
Drug: Etoposide phosphate
In case of etoposide reactions, etoposide phosphate will be given IV. - Group B and Group C only.
Other Names:
  • Etopophos(R)
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.
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 Names:
  • Cell Selection 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 Names:
  • 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:
  • Aldesleukin
  • Interleukin-2
  • Proleukin(R)
Drug: Melphalan
Given IV - All groups.
Other Names:
  • Phenylalanine mustard
  • L-PAM
  • L-phenylalanine mustard
  • 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 Names:
  • NK cell infusion
Biological: G-CSF
Given SQ - All Groups.
Other Names:
  • Filgrastim
  • Neupogen(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: Etoposide phosphate
In case of etoposide reactions, etoposide phosphate will be given IV. - Group B and Group C only.
Other Names:
  • Etopophos(R)
Drug: Carboplatin
Given IV - Group C only.
Other Names:
  • Inorganic heavy metal coordination complex

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Day 35 post transplant

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
Up to one year after transplantation
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.
Up to one year after transplantation
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.
Up to one year after transplantation
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.
Up to one year after transplantation
Characteristics of the stem cell grafts
Time Frame: Up to one year after transplantation
Results will be reported and presented descriptively.
Up to one year after transplantation
Characteristics of the natural killer cell grafts.
Time Frame: Up to one year after transplantation
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
Time Frame: Up to one year after transplantation
The Kaplan-Meier estimate will be provided for overall survival analysis.
Up to one year after transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
St. Jude Children's Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 10, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 20, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 20, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 1, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 5, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 6, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 22, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 21, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ASCIST
  • NCI-2014-00275 (Registry Identifier: NCI Clinical Trial Registration Program)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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