Lupus Erythematosus, SystemicPhase 2NCT00076752
Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus
A Phase 2 study testing fludarabine phosphate, cyclophosphamide and Rituxan (rituximab) in people with Lupus Erythematosus, Systemic, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This study will examine a new approach to treating patients with severe systemic lupus erythematosus (SLE) that involves collecting stem cells (cells produced by the bone marrow that develop into blood cells) from the patient, completely shutting down the patient's immune system, and then giving back the patient's… Read more about this study
- Who is it for?
- Ages 15 to 40 years
- Conditions the study is for
- Lupus Erythematosus, Systemic
- What is being tested?
- fludarabine phosphate, cyclophosphamide and Rituxan (rituximab)
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 30 Jan 2004to 15 Oct 2013
- 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 15 to 40 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
None listed.
Who cannot join
- 1. Inability to provide written informed consent prior to entry in the protocol
- 2. Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening
- 3. Women of childbearing potential who are not practicing or who are unwilling to practice birth control during the entire study
- 4. Men who are unwilling to practice birth control for the first 6 months after the transplant
- 5. Evidence of infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
- 6. History of malignancy other than basal cell carcinoma of the skin
Show all 15Show fewer
- 7. Carbon monoxide diffusing capacity (DLCO) corrected less than 45%
- 8. Left ventricular ejection fraction (LVEF) less than 45%, determined by ECHO cardiogram or MUGA
- 9. Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) greater than 2x upper limit of normal (unless active myopathy is proven by elevation of serum aldolase levels and the patient has no obvious hepatic disease) and/or bilirubin greater than 2.0 (unless due to isolated hemolysis).
- 10. Calculated glomerular filtration rate less than 30 ml/min using the modification of diet in renal disease (MDRD) equation estimate:
- Glomerular filtration rate (GFR) (ml/min/173 m^2) =186.3 x (Pcr) exponential -1.154 x (age) exponential -0.203 x 1.212 (if black) x 0.742 (if female)
- 11. Late flare (patients who have target organ flare, that is not within the time frame defined as early flare, will not be considered as treatment failures until they receive the minimally required therapy for this flare episode and fail to respond to it)
- 12. Abnormal bone marrow cytogenetics
- 13. Significant concurrent medical condition or any significant circumstance that could affect the patient's ability to tolerate or complete the study
- 14. Live vaccines within 4 weeks of starting the priming regimen
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: A Pilot Study of Intensified Lymphodepletion Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Systemic Lupus Erythematosus
This study will examine a new approach to treating patients with severe systemic lupus erythematosus (SLE) that involves collecting stem cells (cells produced by the bone marrow that develop into blood cells) from the patient, completely shutting down the patient's immune system, and then giving back the patient's stem cells. SLE is a chronic, inflammatory disorder of the immune system that can affect many organs. It is called an autoimmune disease because the patient's lymphocytes (white blood cells that normally protect against invading organisms), go out of control and attack the body's own tissues.
Patients between 15 and 40 years of age with severe SLE affecting a major organ that is resistant to standard treatment may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, skin tuberculin test, and radiology studies to evaluate the extent of disease. They have endocrinology, nutrition, dental, and social work consultations, ultrasound or MUGA (multi-gated acquisition scan) scan heart imaging, electrocardiogram and lung function tests, bone marrow biopsy, and lymph node aspirate. Depending on which organs are affected, patients may have additional tests, such as lumbar puncture (spinal tap), kidney or lung biopsy, MRI (magnetic resonance imaging) of the brain and spinal cord, and PET (positron emission tomography) scan. They also complete quality of life questionnaires and have disability functional testing and neurocognitive (thinking) assessments.
Read more
Participants have a central venous line (plastic tube) inserted into a neck or chest vein for administering stem cells and medicines and for drawing blood. They undergo seven apheresis procedures during the course of the study to collect stem cells for transplant and for research. For apheresis, whole blood is collected through a needle in an arm vein and directed to a cell-separating machine where the white cells are extracted and the rest of the blood is returned to the patient through the same needle.
Patients are primed with three medications (methylprednisolone, rituximab, and cyclophosphamide) through the central line to help control the disease. In addition, a medication called G-CSF (growth colony stimulating factor) is injected under the skin for several days to boost production of stem cells. After enough stem cells have been collected for transplantation (infusion through the central line), patients are admitted to the hospital for an 8-day conditioning regimen followed by transplantation. The conditioning treatment consists of rituximab, fludarabine, and cyclophosphamide to eliminate all the white blood cells from the blood and bone marrow. The stem cells are then infused and the patient is closely monitored by a team of physicians and nurses. When the stem cells have engrafted, the bone marrow has recovered, and the patient feels well enough - usually 2 to 3 weeks after transplant - the patient is discharged from the hospital. Prednisone tapering begins as soon as feasibly possible, but no later then 28 days after transplant.
Patients return to the National Institutes of Health (NIH) Clinical Center for frequent follow-up visits during the first 2 to 3 months following transplant. The time between visits is then extended to once every 3 months the first year, then every 6 months the second year, and then at least yearly for 5 years after the transplant. These visits include a physical examination, blood and urine tests, lumbar puncture (if there is central nervous system involvement), other appropriate biopsies and tests as needed to monitor the patient's health, short apheresis procedures to collect blood for research purposes, and quality of life questionnaires. Some select procedures will be optional. Bone marrow biopsies and lymph node aspirates are done at beginning and at 6, 12, and 24 months after transplant. PET scans are done at 1, 6, 12, and 24 months.
...
Read the detailed description
Background:
- Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can involve almost any organ and can range in severity from mild to life-threatening. In spite of significant improvements in survival of SLE patients over last 20 years, a small but significant portion of patients still develop progressive therapy-refractory disease that impairs organ function and overall survival.
- Since 1996, more than 500 patients have been treated worldwide in pilot trials of autologous hematopoietic stem cell transplantation (autoHSCT) for autoimmune diseases, including about 80 patients with SLE.
- The rationale for autoHSCT in autoimmune disease is to ablate autoreactive immune effectors and allow reconstitution of a new self-tolerant immune system from the hematopoietic stem cell. Studies have demonstrated acceptable safety and promising short term efficacy of high-dose cyclophosphamide-based (200 mg/kg) autoHSCT for about 60% of patients with advanced refractory SLE and reacquisition of sensitivity to conventional drugs have been demonstrated in many cases. However, these trials were designed to address the primary endpoint of safety and were inadequate for assessing the disease response.
-Numerous questions about the true efficacy of autoHSCT, optimal transplant regimen, patient selection and mechanisms of action remain unaddressed.
Objectives:
- The primary objective is to assess the rate of continuous relapse-free complete clinical responses at 24 months post-transplant, with statistical power of 84% to detect, if greater than 70 percent of patients meet the primary endpoint.
- The long-term goal of this research is to develop a basis for future transplant protocols that would incorporate new cellular or other immunotherapeutic interventions to further improve results of transplants with the ultimate goal to cure SLE.
Eligibility:
-Subjects age 15-40 years who fulfill at least 4 of the 11 criteria for SLE as defined by the
American College of Rheumatology
-Have severe and active lupus, refractory to immunosuppressive therapy. Included are subjects with nephritis, central nervous system (CNS) lupus, pulmonary lupus or hematologic disease
Design:
- Fourteen patients with active and standard dose cyclophosphamide-resistant SLE will be enrolled on this phase II pilot study.
- Study design is intended to improve the efficacy of autoHSCT. A lymphoablative conditioning regimen (rituximab, fludarabine and cyclophosphamide) is explored for the first time in autoimmune disease.
- The treatment schedule consists of two parts; the priming regimen prior to stem cell mobilization and collection, and the conditioning regimen with transplant.
- In contrast to other studies, this study has precisely defined eligibility and disease response criteria with strict schema of tapering immunosuppression that should allow accurate interpretation of the treatment results.
- The study includes a carefully chosen battery of laboratory research studies designed to investigate SLE biology and mechanisms of post-transplant responses.
- Conditions
- Lupus Erythematosus, Systemic
- Being tested
- fludarabine phosphate, cyclophosphamide, Rituxan (rituximab), filgrastim, methylprednisolone
- Keywords
- Refractory SLE, Immunoablation, Immunological Recovery, Efficacy, Mechanism of Disease, Lupus, Systemic Lupus Erythematosus, SLE
- Medical subject headings
- Lupus Erythematosus, Systemic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Also called Fludara
Conditioning and transplant regimen: 30 mg/m^2 day intravenous infusion over 30 minutes daily, 4 days (transplant days -6, -5, -4, -3)
cyclophosphamideDrug
Also called Cytoxan
Priming regimen: 2000 mg/m^2 intravenous infusion over 2 hours, day 2. Conditioning and transplant regimen: 1200 mg/m^2 day intravenous infusion daily, 4 days (-6, -5, -4, -3).
Rituxan (rituximab)Biological
Also called Rituximab
Priming regimen: 375 mg/m^2 intravenous day 1, 4. Conditioning and transplant regimen: 750 mg/m^2 intravenous infusion, day -7.
filgrastimBiological
Also called GCSF (growth colony stimulating factor)
Priming regimen: 10 micrograms/kg/day subcutaneous, starting day 6. Conditioning and transplant regimen: 5 micrograms/kg/day subcutaneous, day +1 until ANC >500 microliters.
Also called Medrol
Priming regimen:1000 mg intravenous over 30 minutes, day 1.
immunologic techniqueOther
Lymphoablative regimen using cyclophosphamide, rituximab, and fludarabine followed by a CD34 cell selected autologous stem cell transplant.
laboratory biomarker analysisOther
Standard human immunology research laboratory ex vivo studies.
autologous hematopoietic stem cell transplantationProcedure or surgery
Day 0, product will be infused rapidly intravenously after premedication with diphenhydramine 25-60 mg orally or intravenous.
DiphenhydramineDrug
Also called Benadryl
Conditioning and transplant regimen 25-50 mg orally or intravenously.
MesnaDrug
Also called Mesnex
Priming regimen: 600 mg/m^2 intravenous immediately prior to cyclophosphamide and repeat at 4 and 7 hours after the first dose, day 2. Conditioning and transplant regimen:1200 mg/m^2 per day continuous 24 hour intravenous infusion, daily for 4 days, start concurrently with the start of cyclophosphamide.
| Study group | Role | What they receive |
|---|---|---|
| Autologous HSCT in SLE | Experimental | Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion. Receives: Drug: fludarabine phosphate; Drug: cyclophosphamide; Biological: Rituxan (rituximab); Biological: filgrastim; Drug: methylprednisolone; Other: immunologic technique; Other: laboratory biomarker analysis; Procedure: autologous hematopoietic stem cell transplantation; Drug: Diphenhydramine; Drug: Mesna |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relapse-free Complete Clinical Response
Complete clinical response is defined as complete clinical response in the target organ and no clinical signs of active lupus as determined by a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of ≤3; prednisone ≤10mg/day at 6 months and ≤5mg/day at 12 months or later.
Measured: 60 months
Secondary outcomes (15)
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Measured: 18 months
Anti-Nuclear Antibody
Anti-Nuclear antibody is a well accepted biological clinical laboratory marker of systemic lupus. Range of normal values is 0-0.9 EU.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Extractable Nuclear Antigen (ENA)
Extractable nuclear antigen is a well accepted biological clinical laboratory marker of systemic lupus. Range of normal values is 0-19.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Anti-Double Stranded Deoxyribonucleic Acid (DNA) Antibody
Anti-Double stranded deoxyribonucleic acid antibody is a well accepted biological clinical laboratory marker especially specific for systemic lupus. Range of normal values is 0-24 IU.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Anti-Smith-Ribonuclear Protein Antibody
Anti-Smith-Ribonuclear protein antibody is a well accepted biological clinical laboratory marker of systemic lupus.Range of normal values is 0-19 EU.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months and 2 years.
White Blood Cells
The white blood cell test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 3.4-9.6 K/uL.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Absolute Neutrophil Count
The absolute neutrophil count test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 1.29-7.5 K/uL.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Absolute Lymphocyte Count
The absolute lymphocyte count test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 0.45-4.9 K/uL.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Platelet Count
The platelet count test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 162-380 K/uL.
Measured: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Cluster of Differentiation 3 (CD3) + Cells
The CD3+Cells test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 650-2108 uL.
Measured: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Cluster of Differentiation 4 (CD4) + Cells
The CD4 + Cells test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 358-1259 uL.
Measured: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Cluster of Differentiation 8 (CD8) + Cells
The CD8 + Cells test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 194-836 u/L.
Measured: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Cluster of Differentiation 19 (CD19) + Cells
The CD19 + Cells test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 47-409 u/L.
Measured: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Natural Killer Cells
The natural killer cells test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Range of normal values is 87-505 uL.
Measured: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
The SLEDAI activity index test was performed to investigate immunological efficacy and mechanisms of response after lymphodepleting auto-hematopoietic stem cell transplant for systemic lupus erythematosus. Complete clinical response is defined as complete clinical response in the target organ and no clinical signs of active lupus as determined by a SLEDAI score of ≤3; partial response is at least 50% improvement in general disease activity as measured by SLEDAI. Remission is a SLEDAI score <3 and prednisone <10mg/day. 6+ indicates active disease requiring therapy. A score of 0 indicates a better outcome and a score greater then 6+ indicates a worse outcome.
Measured: Day -7, day 0, 1 month, 3 months, 6 months, 1 year, 18 months, 2 years and 3 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Feb 2004 (estimated)
- Study start30 Jan 2004
- Primary completion15 Oct 2013
- Study completion15 Oct 2013
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 (5)Papers the sponsor has linked to this study.
- Other trials for Lupus Erythematosus, SystemicStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)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
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Steven Pavletic, M.D., National Cancer Institute (NCI)
- Investigators
- Steven Pavletic, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00076752
- Sponsor's protocol ID
- 040095
- Other IDs
- 04-C-0095
- Status last verified
- Dec 2020
- First submitted
- 2 Feb 2004
- Last updated
- 5 Jan 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001 Nov;1(2):147-53. doi: 10.1038/35100573.
PubMed 11905822Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D'Agostino RB, Kuller LH. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1;145(5):408-15. doi: 10.1093/oxfordjournals.aje.a009122.
PubMed 9048514Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001 Sep;2(9):764-6. doi: 10.1038/ni0901-764. No abstract available.
PubMed 11526379Illei GG, Cervera R, Burt RK, Doria A, Hiepe F, Jayne D, Pavletic S, Martin T, Marmont A, Saccardi R, Voskuyl AE, Farge D. Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann Rheum Dis. 2011 Dec;70(12):2071-4. doi: 10.1136/ard.2010.148049. Epub 2011 Aug 26.
PubMed 21873334Goklemez S, Hasni S, Hakim FT, Muraro PA, Pirsl F, Rose J, Memon S, Fowler DF, Steinberg SM, Baker EH, Panch SR, Gress R, Illei GG, Lipsky PE, Pavletic SZ. Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus. Rheumatology (Oxford). 2022 Aug 3;61(8):3317-3328. doi: 10.1093/rheumatology/keab877.
PubMed 34875023
Study at a glance
From the registry record, last updated by the sponsor on 5 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of Intensified Lymphodepletion Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Systemic Lupus Erythematosus
- ClinicalTrials.gov ID
- NCT00076752
- Acronym / sponsor ID
- 040095
- Conditions
- Lupus Erythematosus, Systemic
- Keywords
- Refractory SLE, Immunoablation, Immunological Recovery, Efficacy, Mechanism of Disease, Lupus, Systemic Lupus Erythematosus, SLE
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 30 Jan 2004
- Primary completion
- 15 Oct 2013 (actual)
- Study completion
- 15 Oct 2013 (actual)
- First posted
- 3 Feb 2004 (estimated)
- Results
- Posted 10 Jun 2014
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 examine a new approach to treating patients with severe systemic lupus erythematosus (SLE) that involves collecting stem cells (cells produced by the bone marrow that develop into blood cells) from the patient, completely shutting down the patient's immune system, and then giving back the patient's stem cells. SLE is a chronic, inflammatory disorder of the immune system that can affect many organs. It is called an autoimmune disease because the patient's lymphocytes (white blood cells that normally protect against invading organisms), go out of control and attack the body's own tissues.
Patients between 15 and 40 years of age with severe SLE affecting a major organ that is resistant to standard treatment may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, skin tuberculin test, and radiology studies to evaluate the extent of disease. They have endocrinology, nutrition, dental, and social work consultations, ultrasound or MUGA (multi-gated acquisition scan) scan heart imaging, electrocardiogram and lung function tests, bone marrow biopsy, and lymph node aspirate. Depending on which organs are affected, patients may have additional tests, such as lumbar puncture (spinal tap), kidney or lung biopsy, MRI (magnetic resonance imaging) of the brain and spinal cord, and PET (positron emission tomography) scan. They also complete quality of life questionnaires and have disability functional testing and neurocognitive (thinking) assessments.
Participants have a central venous line (plastic tube) inserted into a neck or chest vein for administering stem cells and medicines and for drawing blood. They undergo seven apheresis procedures during the course of the study to collect stem cells for transplant and for research. For apheresis, whole blood is collected through a needle in an arm vein and directed to a cell-separating machine where the white cells are extracted and the rest of the blood is returned to the patient through the same needle.
Patients are primed with three medications (methylprednisolone, rituximab, and cyclophosphamide) through the central line to help control the disease. In addition, a medication called G-CSF (growth colony stimulating factor) is injected under the skin for several days to boost production of stem cells. After enough stem cells have been collected for transplantation (infusion through the central line), patients are admitted to the hospital for an 8-day conditioning regimen followed by transplantation. The conditioning treatment consists of rituximab, fludarabine, and cyclophosphamide to eliminate all the white blood cells from the blood and bone marrow. The stem cells are then infused and the patient is closely monitored by a team of physicians and nurses. When the stem cells have engrafted, the bone marrow has recovered, and the patient feels well enough - usually 2 to 3 weeks after transplant - the patient is discharged from the hospital. Prednisone tapering begins as soon as feasibly possible, but no later then 28 days after transplant.
Patients return to the National Institutes of Health (NIH) Clinical Center for frequent follow-up visits during the first 2 to 3 months following transplant. The time between visits is then extended to once every 3 months the first year, then every 6 months the second year, and then at least yearly for 5 years after the transplant. These visits include a physical examination, blood and urine tests, lumbar puncture (if there is central nervous system involvement), other appropriate biopsies and tests as needed to monitor the patient's health, short apheresis procedures to collect blood for research purposes, and quality of life questionnaires. Some select procedures will be optional. Bone marrow biopsies and lymph node aspirates are done at beginning and at 6, 12, and 24 months after transplant. PET scans are done at 1, 6, 12, and 24 months.
...
Detailed description
Background:
- Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can involve almost any organ and can range in severity from mild to life-threatening. In spite of significant improvements in survival of SLE patients over last 20 years, a small but significant portion of patients still develop progressive therapy-refractory disease that impairs organ function and overall survival.
- Since 1996, more than 500 patients have been treated worldwide in pilot trials of autologous hematopoietic stem cell transplantation (autoHSCT) for autoimmune diseases, including about 80 patients with SLE.
- The rationale for autoHSCT in autoimmune disease is to ablate autoreactive immune effectors and allow reconstitution of a new self-tolerant immune system from the hematopoietic stem cell. Studies have demonstrated acceptable safety and promising short term efficacy of high-dose cyclophosphamide-based (200 mg/kg) autoHSCT for about 60% of patients with advanced refractory SLE and reacquisition of sensitivity to conventional drugs have been demonstrated in many cases. However, these trials were designed to address the primary endpoint of safety and were inadequate for assessing the disease response.
-Numerous questions about the true efficacy of autoHSCT, optimal transplant regimen, patient selection and mechanisms of action remain unaddressed.
Objectives:
- The primary objective is to assess the rate of continuous relapse-free complete clinical responses at 24 months post-transplant, with statistical power of 84% to detect, if greater than 70 percent of patients meet the primary endpoint.
- The long-term goal of this research is to develop a basis for future transplant protocols that would incorporate new cellular or other immunotherapeutic interventions to further improve results of transplants with the ultimate goal to cure SLE.
Eligibility:
-Subjects age 15-40 years who fulfill at least 4 of the 11 criteria for SLE as defined by the
American College of Rheumatology
-Have severe and active lupus, refractory to immunosuppressive therapy. Included are subjects with nephritis, central nervous system (CNS) lupus, pulmonary lupus or hematologic disease
Design:
- Fourteen patients with active and standard dose cyclophosphamide-resistant SLE will be enrolled on this phase II pilot study.
- Study design is intended to improve the efficacy of autoHSCT. A lymphoablative conditioning regimen (rituximab, fludarabine and cyclophosphamide) is explored for the first time in autoimmune disease.
- The treatment schedule consists of two parts; the priming regimen prior to stem cell mobilization and collection, and the conditioning regimen with transplant.
- In contrast to other studies, this study has precisely defined eligibility and disease response criteria with strict schema of tapering immunosuppression that should allow accurate interpretation of the treatment results.
- The study includes a carefully chosen battery of laboratory research studies designed to investigate SLE biology and mechanisms of post-transplant responses.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Autologous HSCT in SLE | Experimental | Drug: fludarabine phosphate, Drug: cyclophosphamide, Biological: Rituxan (rituximab), Biological: filgrastim, Drug: methylprednisolone, Other: immunologic technique, Other: laboratory biomarker analysis, Procedure: autologous hematopoietic stem cell transplantation, Drug: Diphenhydramine, Drug: MesnaAutologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE). SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion. |
Who may qualify
- Ages
- 15 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (0 listed)
Key exclusion criteria (15 listed)
- 1. Inability to provide written informed consent prior to entry in the protocol
- 2. Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening
- 3. Women of childbearing potential who are not practicing or who are unwilling to practice birth control during the entire study
- 4. Men who are unwilling to practice birth control for the first 6 months after the transplant
- 5. Evidence of infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
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 |
|---|---|---|
| fludarabine phosphateAlso: FludaraConditioning and transplant regimen: 30 mg/m^2 day intravenous infusion over 30 minutes daily, 4 days (transplant days -6, -5, -4, -3) | Drug | Autologous HSCT in SLE |
| cyclophosphamideAlso: CytoxanPriming regimen: 2000 mg/m^2 intravenous infusion over 2 hours, day 2. Conditioning and transplant regimen: 1200 mg/m^2 day intravenous infusion daily, 4 days (-6, -5, -4, -3). | Drug | Autologous HSCT in SLE |
| Rituxan (rituximab)Also: RituximabPriming regimen: 375 mg/m^2 intravenous day 1, 4. Conditioning and transplant regimen: 750 mg/m^2 intravenous infusion, day -7. | Biological | Autologous HSCT in SLE |
| filgrastimAlso: GCSF (growth colony stimulating factor)Priming regimen: 10 micrograms/kg/day subcutaneous, starting day 6. Conditioning and transplant regimen: 5 micrograms/kg/day subcutaneous, day +1 until ANC >500 microliters. | Biological | Autologous HSCT in SLE |
| methylprednisoloneAlso: MedrolPriming regimen:1000 mg intravenous over 30 minutes, day 1. | Drug | Autologous HSCT in SLE |
| immunologic techniqueLymphoablative regimen using cyclophosphamide, rituximab, and fludarabine followed by a CD34 cell selected autologous stem cell transplant. | Other | Autologous HSCT in SLE |
| laboratory biomarker analysisStandard human immunology research laboratory ex vivo studies. | Other | Autologous HSCT in SLE |
| autologous hematopoietic stem cell transplantationDay 0, product will be infused rapidly intravenously after premedication with diphenhydramine 25-60 mg orally or intravenous. | Procedure or surgery | Autologous HSCT in SLE |
| DiphenhydramineAlso: BenadrylConditioning and transplant regimen 25-50 mg orally or intravenously. | Drug | Autologous HSCT in SLE |
| MesnaAlso: MesnexPriming regimen: 600 mg/m^2 intravenous immediately prior to cyclophosphamide and repeat at 4 and 7 hours after the first dose, day 2. Conditioning and transplant regimen:1200 mg/m^2 per day continuous 24 hour intravenous infusion, daily for 4 days, start concurrently with the start of cyclophosphamide. | Drug | Autologous HSCT in SLE |
Primary outcome
Relapse-free Complete Clinical Response
Time frame: 60 months
Complete clinical response is defined as complete clinical response in the target organ and no clinical signs of active lupus as determined by a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of ≤3; prednisone ≤10mg/day at 6 months and ≤5mg/day at 12 months or later.
15 secondary outcomes
Number of Participants With Adverse Events
Time frame: 18 months
Anti-Nuclear Antibody
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Extractable Nuclear Antigen (ENA)
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Anti-Double Stranded Deoxyribonucleic Acid (DNA) Antibody
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Anti-Smith-Ribonuclear Protein Antibody
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months and 2 years.
White Blood Cells
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Absolute Neutrophil Count
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Absolute Lymphocyte Count
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Platelet Count
Time frame: Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.
Cluster of Differentiation 3 (CD3) + Cells
Time frame: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Cluster of Differentiation 4 (CD4) + Cells
Time frame: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Cluster of Differentiation 8 (CD8) + Cells
Time frame: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Cluster of Differentiation 19 (CD19) + Cells
Time frame: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Natural Killer Cells
Time frame: Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
Time frame: Day -7, day 0, 1 month, 3 months, 6 months, 1 year, 18 months, 2 years and 3 years.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jan 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 11905822Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001 Nov;1(2):147-53. doi: 10.1038/35100573.
- Background: PubMed 9048514Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D'Agostino RB, Kuller LH. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1;145(5):408-15. doi: 10.1093/oxfordjournals.aje.a009122.
- Background: PubMed 11526379Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001 Sep;2(9):764-6. doi: 10.1038/ni0901-764. No abstract available.
- Results publication: PubMed 21873334Illei GG, Cervera R, Burt RK, Doria A, Hiepe F, Jayne D, Pavletic S, Martin T, Marmont A, Saccardi R, Voskuyl AE, Farge D. Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann Rheum Dis. 2011 Dec;70(12):2071-4. doi: 10.1136/ard.2010.148049. Epub 2011 Aug 26.
- Derived from this study: PubMed 34875023Goklemez S, Hasni S, Hakim FT, Muraro PA, Pirsl F, Rose J, Memon S, Fowler DF, Steinberg SM, Baker EH, Panch SR, Gress R, Illei GG, Lipsky PE, Pavletic SZ. Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus. Rheumatology (Oxford). 2022 Aug 3;61(8):3317-3328. doi: 10.1093/rheumatology/keab877.
- Individual participant dataSharing planned: No
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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.
Steven Pavletic, M.D. principal investigator
National Cancer Institute (NCI)
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 phosphate, cyclophosphamide and Rituxan (rituximab) in people with Lupus Erythematosus, Systemic, run by National Cancer Institute (NCI) 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 0 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 5 Jan 2021. 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 10 Jun 2014). 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?
Relapse-free Complete Clinical Response (time frame: 60 months). 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 NCT00076752, which also lists 5 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 5 Jan 2021.