NeuroblastomaPhase 2NCT00698009
Haploidentical Natural Killer (NK) Cells in Patients With Relapsed or Refractory Neuroblastoma
A Phase 2 study testing Fludarabine, Cyclophosphamide and Natural Killer Cell Infusion in people with Neuroblastoma, run by M.D. Anderson Cancer Center at 1 site in United States.
Trial summary
Primary: Evaluate safety, feasibility, persistence, and anti-tumor effect of infused haploidentical donor-derived natural killer (NK) cells and low-dose interleukin-2 (IL-2). Secondary: Quantification of cytokine levels; Assessment of NK cell immunophenotype and function. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- Fludarabine, Cyclophosphamide and Natural Killer Cell Infusion
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2008to Jun 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Inclusion Criteria: (Must be met within 28 days prior to initiating lymphodepleting conditioning regimen) The first two patients enrolled in this protocol, if they have undergone a previous autologous transplant, will need to be at least 6 months post-transplant and/or have available prior cryopreserved autologous peripheral blood stem cells. This criterion safeguards against the possibility that the lymphodepletion regimen may lead to prolonged myelosuppression in this patient population.
- Evidence of relapse or progression of neuroblastoma after autologous peripheral blood stem-cell transplantation or similar aggressive therapy; high risk neuroblastoma that is refractory to standard induction therapy.
- Measurable disease, with at least one of the following: One or more measurable radiographic abnormalities (X-ray, CT, MRI, PET); MIBG (metaiodobenzylguanidine) scan with uptake at a minimum of 1 site; Bone marrow with tumor cells seen on routine morphology (not by neuron specific enolase (NSE) staining or by immunocytology only). If the only bony or soft tissue lesion available for evaluation has been previously irradiated, the lesion must either a) have viable neuroblastoma on biopsy at least 4 weeks after radiation therapy or b) have measurable growth in the lesion after radiation.
- Donor must be related to the recipient.
- Off all systemic chemotherapeutic agents or retinoids for at least 21 days prior to NK infusion.
- Platelets >/= 50,000 * 10^ 9/L and hemoglobin (Hgb) >/= 9 g/dL, unsupported by transfusions in last seven days.
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- absolute neutrophil count (ANC) >/= 1,000 * 10^ 9/L, unsupported by cytokines in last seven days.
- Off prednisone or other immunosuppressive medications for at least 3 days prior to both the lymphodepleting regimen and the NK infusion (This excludes chronic low dose steroids for adrenal replacement which may be continued).
- Karnofsky score or Lansky score >/= 60.
- Adequate renal function defined as: Serum creatinine (Cr), for adults less than or equal to 2 mg/dL, for children less than or equal to 2 mg/dL or less than or equal to 2 times upper limit of normal (ULN) for age (whichever is less). If these criteria are not met, then recipient must have a Cr clearance greater than 60 mL/min/1.73m^2.
- Adequate liver function defined as: Total bilirubin </=2 mg/dL and serum glutamate pyruvate transaminase (SGPT/Alanine aminotransferase, ALT) </= 2.5 * ULN for age (unless Gilbert's disease or abnormal liver function due to primary disease).
- Pulmonary symptoms controlled by medication and pulse oximetry greater than or equal to 92% room air.
- Females of childbearing potential (non childbearing is defined as premenarchal, greater than one year post-menopausal or surgically sterilized) must have a negative serum pregnancy test obtained within 2 weeks prior to registration and may not be breast feeding during the study. All males and females of childbearing potential are required to use a form of contraception considered effective and medically acceptable by the Investigator during the time of the study.
- Donor must meet standard medical eligibility criteria for allogeneic stem cell donation and be able and willing to undergo apheresis.
- Donor must have infectious disease marker testing [Hepatitis B, Hepatitis C, HIV, cytomegalovirus (CMV), Syphilis (RPR), Chagas, human T-cell lymphoma virus (HTLV), and West Nile Virus] and complete blood count (CBC), differential and platelet studies that meet standard medical eligibility criteria for allogeneic blood stem cell donation within 7 days of apheresis.
- Donor, if a female of childbearing potential (non-childbearing is defined as premenarchal, greater than one year post-menopause or surgically sterilized), must have a negative serum pregnancy test obtained within 14 days of apheresis and may not be breast feeding.
Who cannot join
- Exclusion Criteria: These criteria apply to both the start of the lymphodepleting regimen and to the NK infusion
- Evidence of HIV (human immunodeficiency virus) disease or positive serology for HIV.
- Currently requiring supplemental oxygen or on a ventilator.
- Currently undergoing dialysis.
- New detected cardiac arrhythmia not controlled with medical management within prior 72 hour period.
- Hypotension requiring pressor support within prior 72 hour period.
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- Uncontrolled infection, daily fever greater than or equal to 39 degrees Celsius or new positive culture for bacteria, fungus, or virus within the 72 hours prior to NK-cell infusion.
- Ascites requiring paracentesis within prior 72 hour period.
- Seizure activity, clinically detectable encephalopathy or new focal neurologic deficits within prior 72 hour period.
- Donor may not have an uncontrolled infection within 7 days of apheresis.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Study to Infuse Haploidentical Natural Killer Cells in Patients With Relapsed or Refractory Neuroblastoma
Primary:
Evaluate safety, feasibility, persistence, and anti-tumor effect of infused haploidentical donor-derived natural killer (NK) cells and low-dose interleukin-2 (IL-2).
Secondary:
- Quantification of cytokine levels;
- Assessment of NK cell immunophenotype and function.
Read the detailed description
Experimental Therapy:
NK cells are part of the immune system (the cells in the body that naturally fight disease and infection). NK cells can sometimes destroy tumor cells, and they may be better at destroying tumor cells when the NK cells are "mismatched" for certain proteins called human leukocyte antigens (HLA). This can be determined by looking at the donor's and the recipient's HLA types and by checking for other specialized proteins on the donor's NK cells (called killer immunoglobulin receptors [KIR]).
The NK cells will be collected from the donor's blood and then processed using an experimental device called a CliniMACS device. This device is designed to separate out the NK cells from the rest of the donor's collected white blood cells, using a special magnet. Before being infused into the recipient (you, if you choose to take part), the collected NK cells will be treated with a study drug called interleukin-2 (IL-2) in order to try to activate the NK cells' killing ability. You will also receive IL-2 injections to try to help the NK cells survive after infusion and possibly increase in number.
Screening Tests:
Within 28 days before you can start treatment on this study, you will have "screening tests" to help the study doctor decide if you are eligible to take part in this study. The following tests will be performed:
- To check the status of the disease, you will have bone marrow aspirations and biopsies performed. To collect a bone marrow biopsy and aspirate, up to 2 areas of the hip bone are numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a needle.
- For another check of the status of the disease, you will most likely need to have computed tomography (CT) scans of the neck, sinuses, chest, stomach area (abdomen), and hip area (pelvis), and the brain.
- If the doctor thinks it is necessary, the status of the disease will also be checked with standard/routine tests such as positron emission tomography (PET) scans, iodine-131-meta- iodobenzylguanidine (MIBG -- a test that uses injected radioactive material and a special scanner to locate a tumor), and/or a bone scan.
- To measure your heart rate and level of oxygen in the blood, you will have a pulse oximetry test. This test uses a clothespin-shaped device that goes on the finger for about a minute.
- You will have a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate).
- Your medical history will be recorded.
- Blood (about 4 tablespoons) will be drawn for routine tests and to check for diseases (infections such as the human immunodeficiency virus [HIV]). You will be told the results of this test for any diseases. If you have one of these infections, you will probably not be able to participate in this study.
- Urine or an additional 4 teaspoons of blood may also be drawn for other routine tests to check the disease status.
- Blood (up to 6 tablespoons) will be drawn and used to test for HLA and KIR typing, and you and the donor will be told the results of this test.
- Females who are able to have children must have a negative serum pregnancy test (as part of the blood sample described above, or possibly an additional 1 teaspoon).
These screening tests would also need to be repeated before an additional NK cell infusion for this study, in order to see if you continue to be eligible to receive one. This will be described further below.
Identifying an Eligible Donor:
Your relative, who must share half of your HLA genes to be eligible for the study, will be tested to see if his or her KIR molecule has the "mismatch" that researchers believe should help the donor's NK cells to target the tumor cells in your body.
The donor's blood will also be tested to guard against the possibility of transmitting an infection to you during the NK cell infusion.
Samples of the donor's blood will be used to help researchers develop future tests that will be used to track how long the infused NK cells survive and function in recipients' bodies. In order to help track the cells after infusion, researchers prefer (but do not require) that if you are a female recipient, your donor should be male and if you are a male recipient, your donor should be female.
Conditioning Phase:
If you are found to be eligible to take part in this study, you will start the "conditioning" phase of this study within 4 weeks after the screening tests. Over the course of 6 days, you will receive chemotherapy with cyclophosphamide and fludarabine to weaken your immune system in order to help the survival of the infused NK cells, and then mesna to protect your bladder from side effects that cyclophosphamide may cause.
Cyclophosphamide, fludarabine, and mesna will preferably be infused through an indwelling catheter (a tube that remains in a vein, such as tunneled in the arm or through the chest). If you already have an indwelling catheter in place, you will not need to have a new one placed. If a new catheter is needed, however, you will be asked to sign a separate informed consent form for its placement.
The Conditioning schedule is the following:
-Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2, you will receive fludarabine by vein, over about 30 minutes.
On Days -5 and -4, you will receive cyclophosphamide by vein, over about 2 hours each time.
-Five times per day on Days -5 and -4, you will receive mesna by vein, over about 15 minutes each time.
Infusion of NK Cells:
On Day 0 you will receive the NK cells by vein, preferably through an indwelling catheter. The doctor will decide what amount of NK cells will be infused, which will affect how long the infusion lasts, but usually it lasts less than 1 hour.
To help prevent an allergic reaction to the infused cells (such as fever and chills), you will receive Benadryl (diphenhydramine) by vein, over 15-30 minutes, and Tylenol (acetaminophen) by mouth. You will also receive fluids by vein to help decrease the risk of kidney damage.
You or a caregiver will be trained in how to perform the IL-2 injections yourself. This drug will be injected under the skin for 9 doses over the course of 3 weeks.
If the doctor decides you are not eligible to receive the NK cell infusion on Day 0, you will be taken off study without receiving the donor's NK cells. The collected NK cells will be thrown away.
Blood Test for Measuring NK Cell Survival:
Blood (up to 4 teaspoons each time) will be drawn and tested to see how long the NK cells survive in your body. This blood will be drawn on Day 0 (before the NK cell infusion and again 2 hours later) and on Days 2, 7, 14, 21, and 28. (It is possible that this blood draw schedule will stop earlier if the disease gets worse or the infused NK cells can no longer be seen.)
Possible Additional NK Cell Infusion:
If the neuroblastoma responds and you did not suffer a new intolerable side effect from the NK cells, then you may be eligible to receive 1 additional infusion of NK cells. If so, the rest of the study procedures would be the same as before (the screening tests to determine your eligibility, the requirement that the donor still be eligible, the Conditioning Phase with chemotherapy, the IL-2 injections, and the blood tests). You must use the same donor as before, if he or she is still eligible.
Hospitalization:
So that you can be monitored for side effects, you will need to stay in the hospital from Day -6 until after the NK cell infusion (or longer if medically necessary).
Follow-Up Visits:
After your final NK cell infusion, you will return for follow-up visits at least 3 times a week during the first 3 weeks. Then you will return for follow-up visits at around Day +28 and again 3 months after the last NK cell infusion. Following your 3 month visit, you will be asked to return for follow-up visits every 3 months up until one year after the last NK cell infusion. Below is a schedule of what will be done at each visit:
- Initial 3 weeks post infusion (3 times per week):
- Any changes in your medical history will be recorded, and a physical exam will be performed.
- Blood (up to 2 tablespoons) will be drawn for routine tests.
Day 28, at 3, 6, 9, and 12 months after infusion visits:
- Any changes in your medical history will be recorded, and a physical exam will be performed.
- Blood (up to 2 tablespoons) will be drawn for routine tests.
- Urine or an additional 4 teaspoons of blood may be drawn for other routine tests to check the disease status.
- CT scans of the neck, sinus, chest, abdomen, and pelvis will be performed, and a CT of the brain may also be performed if the study doctor feels it is needed.
MIBG scan may be performed if your tumor was positive on MIBG scan in the past or if your doctor feels it is needed.
-Bone marrow biopsies/aspirations may be performed once in the first month, then may be done at each visit if you had neuroblastoma in your bone marrow at the time you started on the study or if your doctor feels it is necessary.
PET scan and/or bone scan may be performed sometime in Months 2 or 3, and again in months 6 -12 if your doctor feels it is needed.
This is an investigational study. Cyclophosphamide, fludarabine, mesna, and IL-2 are commercially available but not FDA approved for use in neuroblastoma. Injecting IL-2 under the skin is not FDA approved for use in increasing the production of NK cells. The CliniMACS device is not commercially available or FDA approved. Infusing NK cells in patients with neuroblastoma is also considered experimental. At this time and for this purpose, NK cell infusions and the CliniMACS device are being used in research only.
Up to 10 recipients and 10 donors will take part in this study. All will be enrolled at M. D. Anderson.
- Conditions
- Neuroblastoma
- Being tested
- Fludarabine, Cyclophosphamide, Natural Killer Cell Infusion, Mesna, Interleukin-2
- Keywords
- Neuroblastoma, Natural Killer Cell, NK Cell Infusion, Haploidentical Natural Killer (NK) Cells, Fludarabine, Fludarabine Phosphate, Fludara, Cyclophosphamide, Cytoxan, Neosar, Interleukin-2, IL-2, Proleukin, Mesna, Mesnex, Infusion of NK cells, Pediatric NK Cell Infusion, Pediatric Neuroblastoma, Pediatric NK, Pediatric
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FludarabineDrug
Also called Fludarabine Phosphate, Fludara
25 mg/m^2 By Vein Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2.
CyclophosphamideDrug
Also called Cytoxan, Neosar
60 mg/kg By Vein Daily Over 2 Hours On Days -5 and -4
Natural Killer Cell InfusionBiological
Also called Infusion of NK cells, NK Cell Infusion
Natural Killer Cell Infusion on Day 0.
MesnaDrug
Also called Mesnex
12 mg/kg By Vein, Over about 15 minutes, Five Times Per Day on Days -5 and -4.
Interleukin-2Drug
Also called IL-2, Proleukin
Received under skin three times weekly for 9 total doses following NK Cell Infusion:
For patients weighing 45 kg or more, dose administered is 10 Million units three times weekly for 9 total doses. For patients less than 45 kg, dose administered is 5 Million units/m2 (max dose 10 Million units) three times weekly for 9 total doses.
| Study group | Role | What they receive |
|---|---|---|
| Fludarabine + Cyclophosphamide + NK Cell Infusion | Experimental | Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion. Receives: Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Natural Killer Cell Infusion; Drug: Mesna; Drug: Interleukin-2 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Participant Disease Response
Neuroblastoma International Response Criteria: Complete Response (CR): No evidence of disease (primary and metastasis) clinically \& radiographic studies, (homovanillic acid (HVA)/vanillylmandelic acid (VMA) normal). Very Good Partial Response (VGPR): >90% reduction in primary tumor, resolution all metastatic tumor except bone. No new bone lesions and improvement on scan of all pre-existing lesions; HVA/VMA decreased >90%. Partial Response (PR): 50-90% reduction primary and all measurable metastatic lesions, 0-1 bone marrow samples with tumor; scans of bone lesions same as VGPR. HVA/VMA decreased 50-90%. Mixed Response (MR): > 50% reduction any measurable disease (primary or metastases); no new lesions; <25% increase in any existing lesion (exclude bone marrow evaluation). No Response (NR): No new lesions; < 25% increase in existing lesion. Progressive Disease (PD): Any new lesions. Increase <25% in measurable lesion, previous negative bone marrow positive for tumor.
Measured: 1 Year for overall patient response, or until disease progression
Number of Participants Infused Haploidentical Donor-derived Natural Killer (NK) Cells and Low-dose Interleukin-2 (IL-2)
Feasibility of an infused allogeneic donor NK cell product and IL-2 following a cyclophosphamide and fludarabine preparative regimen to treat relapsed neuroblastoma after autologous peripheral blood stem cell (PBSC) transplant where feasibility is defined as being able to infuse NK cells on day 0.
Measured: 21 days, up to 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2008 (estimated)
- Study startJun 2008
- Primary completionJun 2012
- Study completionJun 2012
Why it stopped: Slow accrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Susan S. Kelly, MD, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00698009
- Sponsor's protocol ID
- 2006-0752
- Status last verified
- Sep 2020
- First submitted
- 12 Jun 2008
- Last updated
- 24 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study to Infuse Haploidentical Natural Killer Cells in Patients With Relapsed or Refractory Neuroblastoma
- ClinicalTrials.gov ID
- NCT00698009
- Acronym / sponsor ID
- 2006-0752
- Conditions
- Neuroblastoma
- Keywords
- Neuroblastoma, Natural Killer Cell, NK Cell Infusion, Haploidentical Natural Killer (NK) Cells, Fludarabine, Fludarabine Phosphate, Fludara, Cyclophosphamide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Slow accrual.
- Enrolment
- 1 participants (actual)
- Lead sponsor
- M.D. Anderson Cancer CenterUniversity, hospital or other
- Study start
- Jun 2008
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 16 Jun 2008 (estimated)
- Results
- Posted 22 Nov 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Primary:
Evaluate safety, feasibility, persistence, and anti-tumor effect of infused haploidentical donor-derived natural killer (NK) cells and low-dose interleukin-2 (IL-2).
Secondary:
- Quantification of cytokine levels;
- Assessment of NK cell immunophenotype and function.
Detailed description
Experimental Therapy:
NK cells are part of the immune system (the cells in the body that naturally fight disease and infection). NK cells can sometimes destroy tumor cells, and they may be better at destroying tumor cells when the NK cells are "mismatched" for certain proteins called human leukocyte antigens (HLA). This can be determined by looking at the donor's and the recipient's HLA types and by checking for other specialized proteins on the donor's NK cells (called killer immunoglobulin receptors [KIR]).
The NK cells will be collected from the donor's blood and then processed using an experimental device called a CliniMACS device. This device is designed to separate out the NK cells from the rest of the donor's collected white blood cells, using a special magnet. Before being infused into the recipient (you, if you choose to take part), the collected NK cells will be treated with a study drug called interleukin-2 (IL-2) in order to try to activate the NK cells' killing ability. You will also receive IL-2 injections to try to help the NK cells survive after infusion and possibly increase in number.
Screening Tests:
Within 28 days before you can start treatment on this study, you will have "screening tests" to help the study doctor decide if you are eligible to take part in this study. The following tests will be performed:
- To check the status of the disease, you will have bone marrow aspirations and biopsies performed. To collect a bone marrow biopsy and aspirate, up to 2 areas of the hip bone are numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a needle.
- For another check of the status of the disease, you will most likely need to have computed tomography (CT) scans of the neck, sinuses, chest, stomach area (abdomen), and hip area (pelvis), and the brain.
- If the doctor thinks it is necessary, the status of the disease will also be checked with standard/routine tests such as positron emission tomography (PET) scans, iodine-131-meta- iodobenzylguanidine (MIBG -- a test that uses injected radioactive material and a special scanner to locate a tumor), and/or a bone scan.
- To measure your heart rate and level of oxygen in the blood, you will have a pulse oximetry test. This test uses a clothespin-shaped device that goes on the finger for about a minute.
- You will have a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate).
- Your medical history will be recorded.
- Blood (about 4 tablespoons) will be drawn for routine tests and to check for diseases (infections such as the human immunodeficiency virus [HIV]). You will be told the results of this test for any diseases. If you have one of these infections, you will probably not be able to participate in this study.
- Urine or an additional 4 teaspoons of blood may also be drawn for other routine tests to check the disease status.
- Blood (up to 6 tablespoons) will be drawn and used to test for HLA and KIR typing, and you and the donor will be told the results of this test.
- Females who are able to have children must have a negative serum pregnancy test (as part of the blood sample described above, or possibly an additional 1 teaspoon).
These screening tests would also need to be repeated before an additional NK cell infusion for this study, in order to see if you continue to be eligible to receive one. This will be described further below.
Identifying an Eligible Donor:
Your relative, who must share half of your HLA genes to be eligible for the study, will be tested to see if his or her KIR molecule has the "mismatch" that researchers believe should help the donor's NK cells to target the tumor cells in your body.
The donor's blood will also be tested to guard against the possibility of transmitting an infection to you during the NK cell infusion.
Samples of the donor's blood will be used to help researchers develop future tests that will be used to track how long the infused NK cells survive and function in recipients' bodies. In order to help track the cells after infusion, researchers prefer (but do not require) that if you are a female recipient, your donor should be male and if you are a male recipient, your donor should be female.
Conditioning Phase:
If you are found to be eligible to take part in this study, you will start the "conditioning" phase of this study within 4 weeks after the screening tests. Over the course of 6 days, you will receive chemotherapy with cyclophosphamide and fludarabine to weaken your immune system in order to help the survival of the infused NK cells, and then mesna to protect your bladder from side effects that cyclophosphamide may cause.
Cyclophosphamide, fludarabine, and mesna will preferably be infused through an indwelling catheter (a tube that remains in a vein, such as tunneled in the arm or through the chest). If you already have an indwelling catheter in place, you will not need to have a new one placed. If a new catheter is needed, however, you will be asked to sign a separate informed consent form for its placement.
The Conditioning schedule is the following:
-Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2, you will receive fludarabine by vein, over about 30 minutes.
On Days -5 and -4, you will receive cyclophosphamide by vein, over about 2 hours each time.
-Five times per day on Days -5 and -4, you will receive mesna by vein, over about 15 minutes each time.
Infusion of NK Cells:
On Day 0 you will receive the NK cells by vein, preferably through an indwelling catheter. The doctor will decide what amount of NK cells will be infused, which will affect how long the infusion lasts, but usually it lasts less than 1 hour.
To help prevent an allergic reaction to the infused cells (such as fever and chills), you will receive Benadryl (diphenhydramine) by vein, over 15-30 minutes, and Tylenol (acetaminophen) by mouth. You will also receive fluids by vein to help decrease the risk of kidney damage.
You or a caregiver will be trained in how to perform the IL-2 injections yourself. This drug will be injected under the skin for 9 doses over the course of 3 weeks.
If the doctor decides you are not eligible to receive the NK cell infusion on Day 0, you will be taken off study without receiving the donor's NK cells. The collected NK cells will be thrown away.
Blood Test for Measuring NK Cell Survival:
Blood (up to 4 teaspoons each time) will be drawn and tested to see how long the NK cells survive in your body. This blood will be drawn on Day 0 (before the NK cell infusion and again 2 hours later) and on Days 2, 7, 14, 21, and 28. (It is possible that this blood draw schedule will stop earlier if the disease gets worse or the infused NK cells can no longer be seen.)
Possible Additional NK Cell Infusion:
If the neuroblastoma responds and you did not suffer a new intolerable side effect from the NK cells, then you may be eligible to receive 1 additional infusion of NK cells. If so, the rest of the study procedures would be the same as before (the screening tests to determine your eligibility, the requirement that the donor still be eligible, the Conditioning Phase with chemotherapy, the IL-2 injections, and the blood tests). You must use the same donor as before, if he or she is still eligible.
Hospitalization:
So that you can be monitored for side effects, you will need to stay in the hospital from Day -6 until after the NK cell infusion (or longer if medically necessary).
Follow-Up Visits:
After your final NK cell infusion, you will return for follow-up visits at least 3 times a week during the first 3 weeks. Then you will return for follow-up visits at around Day +28 and again 3 months after the last NK cell infusion. Following your 3 month visit, you will be asked to return for follow-up visits every 3 months up until one year after the last NK cell infusion. Below is a schedule of what will be done at each visit:
- Initial 3 weeks post infusion (3 times per week):
- Any changes in your medical history will be recorded, and a physical exam will be performed.
- Blood (up to 2 tablespoons) will be drawn for routine tests.
Day 28, at 3, 6, 9, and 12 months after infusion visits:
- Any changes in your medical history will be recorded, and a physical exam will be performed.
- Blood (up to 2 tablespoons) will be drawn for routine tests.
- Urine or an additional 4 teaspoons of blood may be drawn for other routine tests to check the disease status.
- CT scans of the neck, sinus, chest, abdomen, and pelvis will be performed, and a CT of the brain may also be performed if the study doctor feels it is needed.
MIBG scan may be performed if your tumor was positive on MIBG scan in the past or if your doctor feels it is needed.
-Bone marrow biopsies/aspirations may be performed once in the first month, then may be done at each visit if you had neuroblastoma in your bone marrow at the time you started on the study or if your doctor feels it is necessary.
PET scan and/or bone scan may be performed sometime in Months 2 or 3, and again in months 6 -12 if your doctor feels it is needed.
This is an investigational study. Cyclophosphamide, fludarabine, mesna, and IL-2 are commercially available but not FDA approved for use in neuroblastoma. Injecting IL-2 under the skin is not FDA approved for use in increasing the production of NK cells. The CliniMACS device is not commercially available or FDA approved. Infusing NK cells in patients with neuroblastoma is also considered experimental. At this time and for this purpose, NK cell infusions and the CliniMACS device are being used in research only.
Up to 10 recipients and 10 donors will take part in this study. All will be enrolled at M. D. Anderson.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Fludarabine + Cyclophosphamide + NK Cell Infusion | Experimental | Drug: Fludarabine, Drug: Cyclophosphamide, Biological: Natural Killer Cell Infusion, Drug: Mesna, Drug: Interleukin-2Fludarabine 25 mg/m^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (16 listed)
- Inclusion Criteria: (Must be met within 28 days prior to initiating lymphodepleting conditioning regimen) The first two patients enrolled in this protocol, if they have undergone a previous autologous transplant, will need to be at least 6 months post-transplant and/or have available prior cryopreserved autologous peripheral blood stem cells. This criterion safeguards against the possibility that the lymphodepletion regimen may lead to prolonged myelosuppression in this patient population.
- Evidence of relapse or progression of neuroblastoma after autologous peripheral blood stem-cell transplantation or similar aggressive therapy; high risk neuroblastoma that is refractory to standard induction therapy.
- Measurable disease, with at least one of the following: One or more measurable radiographic abnormalities (X-ray, CT, MRI, PET); MIBG (metaiodobenzylguanidine) scan with uptake at a minimum of 1 site; Bone marrow with tumor cells seen on routine morphology (not by neuron specific enolase (NSE) staining or by immunocytology only). If the only bony or soft tissue lesion available for evaluation has been previously irradiated, the lesion must either a) have viable neuroblastoma on biopsy at least 4 weeks after radiation therapy or b) have measurable growth in the lesion after radiation.
- Donor must be related to the recipient.
- Off all systemic chemotherapeutic agents or retinoids for at least 21 days prior to NK infusion.
Key exclusion criteria (10 listed)
- Exclusion Criteria: These criteria apply to both the start of the lymphodepleting regimen and to the NK infusion
- Evidence of HIV (human immunodeficiency virus) disease or positive serology for HIV.
- Currently requiring supplemental oxygen or on a ventilator.
- Currently undergoing dialysis.
- New detected cardiac arrhythmia not controlled with medical management within prior 72 hour period.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FludarabineAlso: Fludarabine Phosphate, Fludara25 mg/m^2 By Vein Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. | Drug | Fludarabine + Cyclophosphamide + NK Cell Infusion |
| CyclophosphamideAlso: Cytoxan, Neosar60 mg/kg By Vein Daily Over 2 Hours On Days -5 and -4 | Drug | Fludarabine + Cyclophosphamide + NK Cell Infusion |
| Natural Killer Cell InfusionAlso: Infusion of NK cells, NK Cell InfusionNatural Killer Cell Infusion on Day 0. | Biological | Fludarabine + Cyclophosphamide + NK Cell Infusion |
| MesnaAlso: Mesnex12 mg/kg By Vein, Over about 15 minutes, Five Times Per Day on Days -5 and -4. | Drug | Fludarabine + Cyclophosphamide + NK Cell Infusion |
| Interleukin-2Also: IL-2, ProleukinReceived under skin three times weekly for 9 total doses following NK Cell Infusion: For patients weighing 45 kg or more, dose administered is 10 Million units three times weekly for 9 total doses. For patients less than 45 kg, dose administered is 5 Million units/m2 (max dose 10 Million units) three times weekly for 9 total doses. | Drug | Fludarabine + Cyclophosphamide + NK Cell Infusion |
Primary outcome
Participant Disease Response
Time frame: 1 Year for overall patient response, or until disease progression
Neuroblastoma International Response Criteria: Complete Response (CR): No evidence of disease (primary and metastasis) clinically \& radiographic studies, (homovanillic acid (HVA)/vanillylmandelic acid (VMA) normal). Very Good Partial Response (VGPR): >90% reduction in primary tumor, resolution all metastatic tumor except bone. No new bone lesions and improvement on scan of all pre-existing lesions; HVA/VMA decreased >90%. Partial Response (PR): 50-90% reduction primary and all measurable metastatic lesions, 0-1 bone marrow samples with tumor; scans of bone lesions same as VGPR. HVA/VMA decreased 50-90%. Mixed Response (MR): > 50% reduction any measurable disease (primary or metastases); no new lesions; <25% increase in any existing lesion (exclude bone marrow evaluation). No Response (NR): No new lesions; < 25% increase in existing lesion. Progressive Disease (PD): Any new lesions. Increase <25% in measurable lesion, previous negative bone marrow positive for tumor.
Number of Participants Infused Haploidentical Donor-derived Natural Killer (NK) Cells and Low-dose Interleukin-2 (IL-2)
Time frame: 21 days, up to 1 year
Feasibility of an infused allogeneic donor NK cell product and IL-2 following a cyclophosphamide and fludarabine preparative regimen to treat relapsed neuroblastoma after autologous peripheral blood stem cell (PBSC) transplant where feasibility is defined as being able to infuse NK cells on day 0.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- UT MD Anderson Cancer CenterLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Susan S. Kelly, MD principal investigator
M.D. Anderson Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Fludarabine, Cyclophosphamide and Natural Killer Cell Infusion in people with Neuroblastoma, run by M.D. Anderson Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 24 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Nov 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Participant Disease Response (time frame: 1 Year for overall patient response, or until disease progression). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Sep 2020.