Graft vs Host DiseasePhase 2NCT00025662
Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS
A Phase 2 study testing RFT5-SMPT-dgA and Isolex system in people with Graft vs Host Disease and Myelodysplastic Syndromes, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
This study will evaluate the safety and effectiveness of stem cell transplantation in which the donors T lymphocytes have undergone "selective depletion." Certain patients with cancers of the blood undergo transplantation of donated stem cells to generate new and normally functioning bone marrow. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Graft vs Host Disease, Myelodysplastic Syndromes, Leukemia
- What is being tested?
- RFT5-SMPT-dgA and Isolex system
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteUnited States
- Study dates
- May 2001to Feb 2008
- 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 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- DONOR
- HLA identical family donor, 18 to 75 years old
- Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke, no history of severe heart disease)
- Ability to comprehend the investigational nature of the study and provide informed consent
Who cannot join
- RECIPIENT
- Pregnant or lactating
- Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more
- Major anticipated illness or organ failure incompatible with survival from PBSC transplant
- Diffusion Capacity fir carbon monoxide (DLCO) less than 60% predicted
- Left ventricular ejection fraction less than 40%, or any angina.
Show all 15Show fewer
- Absolute lymphocyte count less than 300/mm(3)
- Serum creatinine greater than 2.5 mg/dl
- Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal
- HIV positive
- Other malignant diseases liable to relapse or progress within 2 years
- DONOR
- Pregnant or lactating
- HIV positive. Donors who are positive for Hepatitis B Virus, Hepatitis C Virus or human t-cell lymphoma virus (HTLV) will be used at the discretion of the investigator and with appropriate consent of the recipient
- Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of heart failure or unstable angina, platelet count less than 90,000/cu mm)
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Ex Vivo Selective Depletion of Alloreactive Donor T-Lymphocytes Using "RFT5-SMPT-dgA": Reducing GVHD Risk Associated With Matched, Nonmyeloablative, Stem Cell Transplant for Hematologic Malignancies in Older Adults
This study will evaluate the safety and effectiveness of stem cell transplantation in which the donors T lymphocytes have undergone "selective depletion." Certain patients with cancers of the blood undergo transplantation of donated stem cells to generate new and normally functioning bone marrow. In addition to producing the new bone marrow, the donor's T-lymphocytes also fight any tumor cells that might have remained in the body. This attack on tumor cells is called a "graft-versus-leukemia" (GVL) effect. However, another type of T-lymphocyte from the donor may cause what is called "graft-versus-host-disease" (GVHD), in which the donor cells recognize the patient's cells as foreign and mount an immune response to reject them. Selective depletion is a technique that was developed to remove the T-lymphocytes that cause harmful GVHD, while keeping those that produce the desirable GVL effect.
Read the detailed description
Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major complication after allogeneic stem cell transplantation. Although the most effective way to prevent GVHD is T cell depletion, this process results in poor immune function leading to increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a method of removing GVHD- producing effector cells while retaining a broad T cell repertoire, including preservation of 3rd party, antiviral and anti-tumor responses would be desirable. Preclinical studies from our lab have demonstrated that alloreactive T cells can be selectively removed from the donor lymphocyte pool in vitro with the use of a specific immunotoxin directed against the interleukin-2 receptor.
To test this clinically, we will perform nonmyeloablative allogeneic stem cell transplants in older patients with hematologic malignancies. Although these patients can be cured with this approach, they have significant morbidity and mortality from GVHD. At our institution, nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD of approximately 50%. Although well tolerated in younger patients, patients over the age of 50 years have a transplant-related mortality (TRM) of approximately 35%, which is mostly related to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to reduce GVHD mortality, while preserving the transplant efficacy.
Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral blood stem cell allograft from an HLA-identical sibling donor, containing "selectively-depleted" donor lymphocytes. To obtain such a graft, colony stimulating factor (G-CSF)-mobilized peripheral blood from the donor undergoes a positive cluster of differentiation (CD34) selection followed by a negative T cell selection using the "Nexell" Isolex 300i system. This stem cell-rich, T cell-depleted product will contain a CD34+ cell dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining after the positive CD34 selection, is then co-cultured for 72 hours with irradiated lymphocytes from the patient. The immunotoxin, RFT5-SMPT-dgA, is added during the last 24 hours of culture to remove alloreacting cells. The washed T cell product (CD3+ cell dose of 1-4 x 10(8)/kg) is cryopreserved. Following the preparative regimen, the patient receives successive infusions of the stem cell product and selected lymphocytes. All patients receive standard post transplant immunosuppression with cyclosporine for a minimum of 30 days, followed by dose reduction depending on the degree of donor lymphocyte chimerism.
The primary end point of this study is the incidence and severity of acute GVHD. We will also examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.
- Conditions
- Graft vs Host Disease, Myelodysplastic Syndromes, Leukemia, Leukemia, Myeloid, Leukemia, Myelomonocytic, Chronic, Leukemia, Lymphocytic
- Being tested
- RFT5-SMPT-dgA, Isolex system
- Keywords
- Peripheral Blood Stem Cell, Melphalan, Fludarabine, Donor Apheresis, Non-Myeloablative, MDS, Chronic Myeloid Leukemia, CML, Chronic Lymphocytic Leukemia, CLL, Lymphoma, Non-Hodgkin's Lymphoma, Hodgkin's Disease, Mantle Cell Lymphoma, Acute Myelogenous Leukemia (AML), Chronic Myeloid Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), Myelodysplasia (MDS), Acute Lymphoblastic Leukemia (ALL), Bone Marrow Transplant
- Medical subject headings
- Graft vs Host Disease, Myelodysplastic Syndromes, Leukemia, Leukemia, Myeloid, Leukemia, Myelomonocytic, Chronic, Leukemia, Lymphoid, Lymphoma, Lymphoma, Mantle-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RFT5-SMPT-dgADrug
Also called anti-interleukin-2 receptor immunotoxin
A specific anti-interleukin-2 receptor immunotoxin
Isolex systemDrug
Also called Nexell Isolex system
CD34 selection/ T cell depletion used this system
| Study group | Role | What they receive |
|---|---|---|
| RFT5-SMPT-dgA Isolex system | Experimental | RFT5-SMPT-dgA, a specific anti-interleukin-2 receptor immunotoxin used in allogeneic stem cell transplantation (SCT) in older patients with hematologic malignancies using a graft manipulation process Receives: Drug: RFT5-SMPT-dgA; Drug: Isolex system |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment-related Mortality
Nonrelapse mortality in the first 100 days of transplant expressed as a percentage of the total subjects.
This is different from outcome measure 3 (Cumulative Nonrelapse Mortality), which is cumulative non relapse mortality till December 2011.
Measured: 100 days after stem cell infusion
Secondary outcomes (2)
Overall Survival
Percent overall survival (actuarial) at analysis in Dec 2011.
Measured: Dec 2011.
Cumulative Non Relapse Mortality
Percent non relapse mortality (actuarial) at analysis in Dec 2011
Measured: Dec 2011.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2003 (estimated)
- Study startMay 2001
- Primary completionFeb 2008
- Study completionFeb 2008
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.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Graft vs Host DiseaseStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The 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
- 23 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- A. J Barrett, MD, Study chair, NHLBI, NIH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00025662
- Sponsor's protocol ID
- 010162
- Other IDs
- 01-H-0162
- Status last verified
- Sep 2016
- First submitted
- 11 Oct 2001
- Last updated
- 28 Oct 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Barrett J, Solomon S. The transition from bench to bedside: lessons learned in the creation of a new T-cell product for the clinic. Cytotherapy. 2004;6(6):593-5. doi: 10.1080/14653240410011936.
PubMed 15764025Solomon SR, Tran T, Carter CS, Donnelly S, Hensel N, Schindler J, Bahceci E, Ghetie V, Michalek J, Mavroudis D, Read EJ, Vitetta ES, Barrett AJ. Optimized clinical-scale culture conditions for ex vivo selective depletion of host-reactive donor lymphocytes: a strategy for GvHD prophylaxis in allogeneic PBSC transplantation. Cytotherapy. 2002;4(5):395-406. doi: 10.1080/146532402320775982.
PubMed 12473206Mielke S, Solomon SR, Barrett AJ. Selective depletion strategies in allogeneic stem cell transplantation. Cytotherapy. 2005;7(2):109-15. doi: 10.1080/14653240510018172.
PubMed 16040390Solomon SR, Mielke S, Savani BN, Montero A, Wisch L, Childs R, Hensel N, Schindler J, Ghetie V, Leitman SF, Mai T, Carter CS, Kurlander R, Read EJ, Vitetta ES, Barrett AJ. Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood. 2005 Aug 1;106(3):1123-9. doi: 10.1182/blood-2005-01-0393. Epub 2005 Apr 7.
PubMed 15817673
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ex Vivo Selective Depletion of Alloreactive Donor T-Lymphocytes Using "RFT5-SMPT-dgA": Reducing GVHD Risk Associated With Matched, Nonmyeloablative, Stem Cell Transplant for Hematologic Malignancies in Older Adults
- ClinicalTrials.gov ID
- NCT00025662
- Acronym / sponsor ID
- 010162
- Conditions
- Graft vs Host Disease, Myelodysplastic Syndromes, Leukemia, Leukemia, Myeloid, Leukemia, Myelomonocytic, Chronic, Leukemia, Lymphocytic
- Keywords
- Peripheral Blood Stem Cell, Melphalan, Fludarabine, Donor Apheresis, Non-Myeloablative, MDS, Chronic Myeloid Leukemia, CML
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- May 2001
- Primary completion
- Feb 2008 (actual)
- Study completion
- Feb 2008 (actual)
- First posted
- 27 Jan 2003 (estimated)
- Results
- Posted 13 Jan 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will evaluate the safety and effectiveness of stem cell transplantation in which the donors T lymphocytes have undergone "selective depletion." Certain patients with cancers of the blood undergo transplantation of donated stem cells to generate new and normally functioning bone marrow. In addition to producing the new bone marrow, the donor's T-lymphocytes also fight any tumor cells that might have remained in the body. This attack on tumor cells is called a "graft-versus-leukemia" (GVL) effect. However, another type of T-lymphocyte from the donor may cause what is called "graft-versus-host-disease" (GVHD), in which the donor cells recognize the patient's cells as foreign and mount an immune response to reject them. Selective depletion is a technique that was developed to remove the T-lymphocytes that cause harmful GVHD, while keeping those that produce the desirable GVL effect.
Detailed description
Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major complication after allogeneic stem cell transplantation. Although the most effective way to prevent GVHD is T cell depletion, this process results in poor immune function leading to increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a method of removing GVHD- producing effector cells while retaining a broad T cell repertoire, including preservation of 3rd party, antiviral and anti-tumor responses would be desirable. Preclinical studies from our lab have demonstrated that alloreactive T cells can be selectively removed from the donor lymphocyte pool in vitro with the use of a specific immunotoxin directed against the interleukin-2 receptor.
To test this clinically, we will perform nonmyeloablative allogeneic stem cell transplants in older patients with hematologic malignancies. Although these patients can be cured with this approach, they have significant morbidity and mortality from GVHD. At our institution, nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD of approximately 50%. Although well tolerated in younger patients, patients over the age of 50 years have a transplant-related mortality (TRM) of approximately 35%, which is mostly related to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to reduce GVHD mortality, while preserving the transplant efficacy.
Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral blood stem cell allograft from an HLA-identical sibling donor, containing "selectively-depleted" donor lymphocytes. To obtain such a graft, colony stimulating factor (G-CSF)-mobilized peripheral blood from the donor undergoes a positive cluster of differentiation (CD34) selection followed by a negative T cell selection using the "Nexell" Isolex 300i system. This stem cell-rich, T cell-depleted product will contain a CD34+ cell dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining after the positive CD34 selection, is then co-cultured for 72 hours with irradiated lymphocytes from the patient. The immunotoxin, RFT5-SMPT-dgA, is added during the last 24 hours of culture to remove alloreacting cells. The washed T cell product (CD3+ cell dose of 1-4 x 10(8)/kg) is cryopreserved. Following the preparative regimen, the patient receives successive infusions of the stem cell product and selected lymphocytes. All patients receive standard post transplant immunosuppression with cyclosporine for a minimum of 30 days, followed by dose reduction depending on the degree of donor lymphocyte chimerism.
The primary end point of this study is the incidence and severity of acute GVHD. We will also examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| RFT5-SMPT-dgA Isolex system | Experimental | Drug: RFT5-SMPT-dgA, Drug: Isolex systemRFT5-SMPT-dgA, a specific anti-interleukin-2 receptor immunotoxin used in allogeneic stem cell transplantation (SCT) in older patients with hematologic malignancies using a graft manipulation process |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- DONOR
- HLA identical family donor, 18 to 75 years old
- Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke, no history of severe heart disease)
- Ability to comprehend the investigational nature of the study and provide informed consent
Key exclusion criteria (15 listed)
- RECIPIENT
- Pregnant or lactating
- Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more
- Major anticipated illness or organ failure incompatible with survival from PBSC transplant
- Diffusion Capacity fir carbon monoxide (DLCO) less than 60% predicted
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 |
|---|---|---|
| RFT5-SMPT-dgAAlso: anti-interleukin-2 receptor immunotoxinA specific anti-interleukin-2 receptor immunotoxin | Drug | RFT5-SMPT-dgA Isolex system |
| Isolex systemAlso: Nexell Isolex systemCD34 selection/ T cell depletion used this system | Drug | RFT5-SMPT-dgA Isolex system |
Primary outcome
Treatment-related Mortality
Time frame: 100 days after stem cell infusion
Nonrelapse mortality in the first 100 days of transplant expressed as a percentage of the total subjects. This is different from outcome measure 3 (Cumulative Nonrelapse Mortality), which is cumulative non relapse mortality till December 2011.
2 secondary outcomes
Overall Survival
Time frame: Dec 2011.
Cumulative Non Relapse Mortality
Time frame: Dec 2011.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 15764025Barrett J, Solomon S. The transition from bench to bedside: lessons learned in the creation of a new T-cell product for the clinic. Cytotherapy. 2004;6(6):593-5. doi: 10.1080/14653240410011936.
- Background: PubMed 12473206Solomon SR, Tran T, Carter CS, Donnelly S, Hensel N, Schindler J, Bahceci E, Ghetie V, Michalek J, Mavroudis D, Read EJ, Vitetta ES, Barrett AJ. Optimized clinical-scale culture conditions for ex vivo selective depletion of host-reactive donor lymphocytes: a strategy for GvHD prophylaxis in allogeneic PBSC transplantation. Cytotherapy. 2002;4(5):395-406. doi: 10.1080/146532402320775982.
- Background: PubMed 16040390Mielke S, Solomon SR, Barrett AJ. Selective depletion strategies in allogeneic stem cell transplantation. Cytotherapy. 2005;7(2):109-15. doi: 10.1080/14653240510018172.
- Results publication: PubMed 15817673Solomon SR, Mielke S, Savani BN, Montero A, Wisch L, Childs R, Hensel N, Schindler J, Ghetie V, Leitman SF, Mai T, Carter CS, Kurlander R, Read EJ, Vitetta ES, Barrett AJ. Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood. 2005 Aug 1;106(3):1123-9. doi: 10.1182/blood-2005-01-0393. Epub 2005 Apr 7.
- NIH Clinical Center Detailed Web PageLink 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.
A. J Barrett, MD study chair
NHLBI, NIH
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 RFT5-SMPT-dgA and Isolex system in people with Graft vs Host Disease and Myelodysplastic Syndromes, run by National Heart, Lung, and Blood Institute (NHLBI) 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 4 inclusion and 15 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: finished, as of the sponsor's last update on 28 Oct 2016. 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 13 Jan 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?
Treatment-related Mortality (time frame: 100 days after stem cell infusion). 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 NCT00025662, which also lists 4 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 28 Oct 2016.