Acute LeukaemiaPhase 1NCT02123836
Natural Killer Cells in Acute Leukaemia and Myelodysplastic Syndrome
A Phase 1 study testing NK cells in people with Acute Leukaemia and Myelodysplastic Syndrome, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
A novel method has been developed to expand natural (NK) cells and enhance their cytotoxicity against cancer cells while maintaining low killing capacity against non-transformed cells. Read more about this study
- Who is it for?
- Ages 6 to 80 years
- Conditions the study is for
- Acute Leukaemia, Myelodysplastic Syndrome
- What is being tested?
- NK cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteSingapore
- Study dates
- Apr 2014to Oct 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 6 to 80 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- From 6 to 80 years old at time of consent.
- Patients with the following haematological diseases:
- Acute myeloid leukaemia (de novo or secondary)
- Myelodysplastic syndromes (RAEB I/II)
- T-cell acute lymphoblastic leukaemia (T-ALL)
- Patients must have been treated with prior standard intensive chemotherapy upfront, which will be defined according to institutional practice for each respective disease, and may include allogeneic haematopoietic stem cell transplantation.
Show all 20Show fewer
- Patients must have persistent detectable residual leukaemia following initial treatment with intensive chemotherapy. Residual leukaemia is defined as the presence of >=0.01%-20% blasts in the bone marrow by flow cytometry.
- High risk AML patients with either High risk cytogenetics or FLT3-ITD mutation or Acute megakaryoblastic leukaemia in non-Down's Therapy related leukaemia or Myelodysplastic syndrome
- will qualify for NKEXPSIN either after Induction I chemotherapy or Induction II chemotherapy regardless of residual disease.
- At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation therapy.
- Shortening fraction greater than or equal to 25%.
- Glomerular filtration rate greater than or equal to 60ml/min.
- Pulse oximetry greater than or equal to 92% on room air.
- Direct bilirubin less than or equal to 3x Upper Limit of Normal (ULN).
- Karnofsky performance score of greater than or equal to 50.
- Has a suitable adult family member donor available for NK cell donation.
- Ability to provide informed consent. Otherwise, a legally authorized representative (LAR) must be present throughout the consent process and is allowed to give consent on the patient's behalf.
- At least 21 years old at time of consent.
- A family member with a greater than or equal to 3 of 6 HLA match to recipient
- Ability to provide informed consent. Otherwise, a legally authorized representative must be present throughout the consent process and is allowed to give consent on the patient's behalf.
Who cannot join
- Currently has pleural or pericardial effusion.
- Receiving more than the equivalent of prednisone 10 mg daily.
- Lactating or pregnant. Negative serum or urine pregnancy test result must be within 7 days prior to enrolment.
- HIV positive. Negative results must be within 60 days prior to enrolment.
- Lactating or pregnant. Negative serum or urine pregnancy test result must be within 7 days prior to enrolment.
Trial locations and contacts
1 site in 1 country.
Singapore1 site, 1 recruiting
- Recruiting
National University Hospital
Singapore, 119074
Frances Yeap, MBBS, (65) 6779 5555, frances_yeap@nuhs.edu.sg
Dario Campana, MBBS
About this study
Official title: Pilot Study of Expanded, Activated Haploidentical Natural Killer Cell Infusions for Non-B Lineage Acute Leukaemia and Myelodysplastic Syndrome
A novel method has been developed to expand natural (NK) cells and enhance their cytotoxicity against cancer cells while maintaining low killing capacity against non-transformed cells. In this method, donor NK cells are expanded by co-culture with the irradiated K562 cell line modified to express membrane bound IL-15 and 41BB ligand (K562-mb15-41BBL). Expression of these proteins in conjunction with unknown stimuli provided by K562 cells promotes selective growth of NK cells. Then, the expanded NK cell population is depleted of T cells to prevent graft versus host disease (GVHD). Expanded and activated NK cells showed powerful anti-leukemic activity against acute myeloid leukemia (AML) cells in vitro and in animal models of leukemia.Unpublished laboratory results also demonstrated that T-cell acute lymphoblastic leukaemia (T-ALL) is extremely sensitive to the cytotoxicity exerted by the expanded and activated NK cells.
The present study represents the translation of the laboratory findings into clinical application. The study proposes to determine the feasibility, safety and efficacy of infusing expanded NK cells into patients who have AML or T-lineage ALL which is resistant to standard therapy as demonstrated by persistent minimal residual disease (MRD). Patients with myelodysplastic syndrome (MDS), who are at high risk to develop AML will also be eligible for the study. In this patient cohort, the study will also investigate the in vivo lifespan and phenotype of the expanded NK cells.
The main hypothesis to be tested in this study is that infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML or T-ALL.
Read the detailed description
The study will enroll 20 eligible subjects who will receive NK cell infusion to test whether infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML/MDS or T-ALL.The study aims to infuse a target dose of 10 x 107 CD56+ cells/kg, however, as the actual cell dose obtained will vary depending on the donor harvest, the accepted range for cell infusion will be 0.5-20 x 107 CD56+ cells/kg. On day -10, eligible donors (adult family member of recipient) will undergo apheresis once. A second apheresis procedure may be needed to obtain the required cell count from the donor. NK cells will be expanded in co-culture with irradiated (100 Gy) K562-mb15-41BBL cells in closed culture containers for 10 days. Prior to NK cell infusion on Day 0, recipients will undergo screening evaluations and will receive cyclophosphamide, Fludarabine, IL-2, and supportive medications (e.g. mesna). Cytokine regimen of IL-2 will be initiated on the evening of day -1 (dose 1 of 6). IL-2 will be continued at a dose of 1 million units/m2 subcutaneously 3 times per week for 2 weeks (6 doses total). Post-infusion follow-up procedures for up to 1 year from the day of NK cell infusion include physical examination, Complete Blood Count, and metabolic/chemistry studies. The effects of NK cell infusion will also be determined by comparing MRD levels before and after treatment. MRD blood and bone marrow levels will be collected at baseline and at specified time points (until 1 year from the day of NK cell infusion). NK cell donors will be recruited from the family members of the patient recipient. Potential donors aged 21 years old will be consented and will undergo the required screening tests and human leukocyte antigen (HLA) typing. Since 20 eligible subjects will be enrolled as NK cell recipients, 20 donors will also be recruited for this study. Ineligible NK cell donors will have to be replaced.
- Conditions
- Acute Leukaemia, Myelodysplastic Syndrome
- Being tested
- NK cells
- Medical subject headings
- Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NK cellsBiological
7 days of preparatory treatment are given before the NK cell infusion. Chemotherapy will be given over 6 days. This chemotherapy will promote donor NK cells engraftment. After which, a drug called Interleukin-2 (IL-2) will be given as an injection just under the skin three times per week for at least 2 weeks (total of 6 doses). This treatment is used to help keep the donor NK cells alive.
Blood cells will be collected from an eligible and suitable family donor 10 days before infusion. The collection sample will be processed to remove red blood cells and as many T-cells as possible. T-cells from the donor might cause these donor cells to attack the body, usually the skin, liver, and intestines.
NK cells will be activated in the National University Hospital lab and ready for infusion on Day 0.
The NK cells will then be infused into the vein, through a peripheral catheter.
| Study group | Role | What they receive |
|---|---|---|
| NK cells | Experimental | Peripheral blood cell will be collected by apheresis from donors. Peripheral blood mononucleated cells will be cultured with irradiated K562-mb15-41BBL cells and low dose (10 IU/mL) IL-2 for 10 days. After T-cell depletion, expanded activated NK cells will be infused. Before infusion, patients will receive immunosuppressive therapy to promote temporary engraftment of NK cells. After infusion, they will receive IL-2 to support NK cell viability and expansion in vivo. The effects of NK cell infusion will be determine by comparing MRD levels before and after treatment. Receives: Biological: NK cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
Minimal Residual Disease (MRD) levels
MRD blood levels will be tested at baseline, weekly during the first 2 months and monthly thereafter
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Apr 2014 (estimated)
- Study startApr 2014
- Primary completionSep 2020 (estimated)
- Study completionOct 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Acute LeukaemiaStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Frances Yeap, MBBS, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02123836
- Sponsor's protocol ID
- NKEXPSIN-2013/01
- Status last verified
- Apr 2019
- First submitted
- 24 Apr 2014
- Last updated
- 16 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009 May 1;69(9):4010-7. doi: 10.1158/0008-5472.CAN-08-3712. Epub 2009 Apr 21.
PubMed 19383914Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005 Jul 1;106(1):376-83. doi: 10.1182/blood-2004-12-4797. Epub 2005 Mar 8.
PubMed 15755898Fujisaki H, Kakuda H, Imai C, Mullighan CG, Campana D. Replicative potential of human natural killer cells. Br J Haematol. 2009 Jun;145(5):606-13. doi: 10.1111/j.1365-2141.2009.07667.x. Epub 2009 Mar 26.
PubMed 19344420
Study at a glance
From the registry record, last updated by the sponsor on 16 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study of Expanded, Activated Haploidentical Natural Killer Cell Infusions for Non-B Lineage Acute Leukaemia and Myelodysplastic Syndrome
- ClinicalTrials.gov ID
- NCT02123836
- Acronym / sponsor ID
- NKEXPSIN-2013/01
- Conditions
- Acute Leukaemia, Myelodysplastic Syndrome
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Study start
- Apr 2014
- Primary completion
- Sep 2020 (estimated)
- Study completion
- Oct 2020 (estimated)
- First posted
- 28 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A novel method has been developed to expand natural (NK) cells and enhance their cytotoxicity against cancer cells while maintaining low killing capacity against non-transformed cells. In this method, donor NK cells are expanded by co-culture with the irradiated K562 cell line modified to express membrane bound IL-15 and 41BB ligand (K562-mb15-41BBL). Expression of these proteins in conjunction with unknown stimuli provided by K562 cells promotes selective growth of NK cells. Then, the expanded NK cell population is depleted of T cells to prevent graft versus host disease (GVHD). Expanded and activated NK cells showed powerful anti-leukemic activity against acute myeloid leukemia (AML) cells in vitro and in animal models of leukemia.Unpublished laboratory results also demonstrated that T-cell acute lymphoblastic leukaemia (T-ALL) is extremely sensitive to the cytotoxicity exerted by the expanded and activated NK cells.
The present study represents the translation of the laboratory findings into clinical application. The study proposes to determine the feasibility, safety and efficacy of infusing expanded NK cells into patients who have AML or T-lineage ALL which is resistant to standard therapy as demonstrated by persistent minimal residual disease (MRD). Patients with myelodysplastic syndrome (MDS), who are at high risk to develop AML will also be eligible for the study. In this patient cohort, the study will also investigate the in vivo lifespan and phenotype of the expanded NK cells.
The main hypothesis to be tested in this study is that infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML or T-ALL.
Detailed description
The study will enroll 20 eligible subjects who will receive NK cell infusion to test whether infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML/MDS or T-ALL.The study aims to infuse a target dose of 10 x 107 CD56+ cells/kg, however, as the actual cell dose obtained will vary depending on the donor harvest, the accepted range for cell infusion will be 0.5-20 x 107 CD56+ cells/kg. On day -10, eligible donors (adult family member of recipient) will undergo apheresis once. A second apheresis procedure may be needed to obtain the required cell count from the donor. NK cells will be expanded in co-culture with irradiated (100 Gy) K562-mb15-41BBL cells in closed culture containers for 10 days. Prior to NK cell infusion on Day 0, recipients will undergo screening evaluations and will receive cyclophosphamide, Fludarabine, IL-2, and supportive medications (e.g. mesna). Cytokine regimen of IL-2 will be initiated on the evening of day -1 (dose 1 of 6). IL-2 will be continued at a dose of 1 million units/m2 subcutaneously 3 times per week for 2 weeks (6 doses total). Post-infusion follow-up procedures for up to 1 year from the day of NK cell infusion include physical examination, Complete Blood Count, and metabolic/chemistry studies. The effects of NK cell infusion will also be determined by comparing MRD levels before and after treatment. MRD blood and bone marrow levels will be collected at baseline and at specified time points (until 1 year from the day of NK cell infusion). NK cell donors will be recruited from the family members of the patient recipient. Potential donors aged 21 years old will be consented and will undergo the required screening tests and human leukocyte antigen (HLA) typing. Since 20 eligible subjects will be enrolled as NK cell recipients, 20 donors will also be recruited for this study. Ineligible NK cell donors will have to be replaced.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| NK cells | Experimental | Biological: NK cellsPeripheral blood cell will be collected by apheresis from donors. Peripheral blood mononucleated cells will be cultured with irradiated K562-mb15-41BBL cells and low dose (10 IU/mL) IL-2 for 10 days. After T-cell depletion, expanded activated NK cells will be infused. Before infusion, patients will receive immunosuppressive therapy to promote temporary engraftment of NK cells. After infusion, they will receive IL-2 to support NK cell viability and expansion in vivo. The effects of NK cell infusion will be determine by comparing MRD levels before and after treatment. |
Who may qualify
- Ages
- 6 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (20 listed)
- From 6 to 80 years old at time of consent.
- Patients with the following haematological diseases:
- Patients must have been treated with prior standard intensive chemotherapy upfront, which will be defined according to institutional practice for each respective disease, and may include allogeneic haematopoietic stem cell transplantation.
- Patients must have persistent detectable residual leukaemia following initial treatment with intensive chemotherapy. Residual leukaemia is defined as the presence of >=0.01%-20% blasts in the bone marrow by flow cytometry.
- will qualify for NKEXPSIN either after Induction I chemotherapy or Induction II chemotherapy regardless of residual disease.
Key exclusion criteria (5 listed)
- Currently has pleural or pericardial effusion.
- Receiving more than the equivalent of prednisone 10 mg daily.
- Lactating or pregnant. Negative serum or urine pregnancy test result must be within 7 days prior to enrolment.
- HIV positive. Negative results must be within 60 days prior to enrolment.
- Lactating or pregnant. Negative serum or urine pregnancy test result must be within 7 days prior to enrolment.
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 |
|---|---|---|
| NK cells7 days of preparatory treatment are given before the NK cell infusion. Chemotherapy will be given over 6 days. This chemotherapy will promote donor NK cells engraftment. After which, a drug called Interleukin-2 (IL-2) will be given as an injection just under the skin three times per week for at least 2 weeks (total of 6 doses). This treatment is used to help keep the donor NK cells alive. Blood cells will be collected from an eligible and suitable family donor 10 days before infusion. The collection sample will be processed to remove red blood cells and as many T-cells as possible. T-cells from the donor might cause these donor cells to attack the body, usually the skin, liver, and intestines. NK cells will be activated in the National University Hospital lab and ready for infusion on Day 0. The NK cells will then be infused into the vein, through a peripheral catheter. | Biological | NK cells |
Primary outcome
Minimal Residual Disease (MRD) levels
Time frame: 1 year
MRD blood levels will be tested at baseline, weekly during the first 2 months and monthly thereafter
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2019.
- Background: PubMed 19383914Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009 May 1;69(9):4010-7. doi: 10.1158/0008-5472.CAN-08-3712. Epub 2009 Apr 21.
- Background: PubMed 15755898Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005 Jul 1;106(1):376-83. doi: 10.1182/blood-2004-12-4797. Epub 2005 Mar 8.
- Background: PubMed 19344420Fujisaki H, Kakuda H, Imai C, Mullighan CG, Campana D. Replicative potential of human natural killer cells. Br J Haematol. 2009 Jun;145(5):606-13. doi: 10.1111/j.1365-2141.2009.07667.x. Epub 2009 Mar 26.
- National University Cancer Institute, SingaporeLink 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.
Frances Yeap, MBBS principal investigator
National University Hospital, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing NK cells in people with Acute Leukaemia and Myelodysplastic Syndrome, run by National University Hospital, Singapore at 1 site in Singapore.
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 20 inclusion and 5 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: status not confirmed, as of the sponsor's last update on 16 Apr 2019. 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 Singapore. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Frances Yeap, MBBS ((65) 6779 5555, frances_yeap@nuhs.edu.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Minimal Residual Disease (MRD) levels (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02123836, which also lists 3 linked publications.
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 16 Apr 2019.