- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01679041
High Dose Chemo With Stem Cell Transplant as Treatment for Multiple Sclerosis That Failed Prior Treatment
A Phase II Study of High Dose Chemotherapy With Autologous Hematopoietic Progenitor Cell Transplant for Multiple Sclerosis That Failed at Least Two Lines of Therapy
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Multiple sclerosis is an inflammatory autoimmune disease characterized by loss of myelin and axonal damage, having typical contrast-enhanced MRI foci as an imaging counterpart. MS shows three main patterns of clinical course: relapsing/remitting, primary progressive and secondary progressive.Concerning disease pattern, secondary progressive is the standard indication, to avoid overtreatment in relapsing/remitting patients or ineffectual treatment in primary relapsing patients.
Currently, MS is the most common autoimmune disease that have been treated with autologous HPC transplants (Fagius et al, 2009; Burt et al, 2009; Saccardi et al, 2006). More than 350 consecutive cases have been reported by the EBMT over the last decade. Most patients who underwent autologous HPC transplant for MS in the early studies had secondary progressive MS, and relatively fewer had relapsing remitting disease, with a Kurtzke Expanded Disability Status Scale (EDSS) of 3.0-9.5 at the time of transplant. Significant objective and subjective improvements have been reported in up to 70% of these patients.
The following conditioning regimens will be used, with Alemtuzumab, Fludarabine, and Cyclophosphamide will be used for all patients. Prophylaxis of Acyclovir, Levaquin, and Fluconazole will be given to prevent infections. The autologous HPC will be infused within 48-72 hours of completing the chemotherapy. The patients will receive additional supportive care medications and treatments as necessary. Neutrophil engraftment will be defined as the day on which the ANC rises to > 500 cells/ml for two consecutive days. Platelet engraftment will be defined as the first day on which the platelet count rises to > 20,000/ml over a 7-day interval without transfusion support.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Texas
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Amarillo, Texas, United States, 79106
- Texas Oncology
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Amarillo, Texas, United States, 79106
- Amarillo Diagnostic Clinic
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Amarillo, Texas, United States, 79106
- Dr Ruby Saulog
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Age between 18-60, inclusive
Patients carry a diagnosis of multiple sclerosis, according to the McDonald's criteria for diagnosis (Polman et al, 2011).
Must have a neurologist providing the primary care for the MS and be willing to be evaluated for the multiple sclerosis by the two neurologists who are the co-investigators in the protocol.
Must be documented to be HIV negative.
An EDSS of 3.5 - 5.5
Patients must be able to give written consent.
Inflammatory disease despite primary disease modifying therapy with at least 6 months of interferon and another disease modifying therapy, including fingolimod,glativamir, natalizumab, and mitoxantrone. Failure is defined as two or more clinical relapses with documented neurologic changes (excluding sensory changes) within the year prior to the study. (NOTE: Relapses must have required treatment with corticosteroids). Failure may also be defined as one relapse (excluding sensory changes) treated with methylprednisone and, on a separate occasion within the previous 12 months, evidence of active inflammation (i.e. gadolinium enhancement on MRI scan of the CNS).
No previous history of allergic reaction to cyclophosphamide, G-CSF or mesna
Patients must not be pregnant
Failure to accept or comprehend irreversible sterility as a potential side effect of therapy.
Life expectancy of more than 6 months
No evidence of myelodysplastic syndrome on peripheral blood smear
Not allergic to cyclophosphamide, mesna, fludarabine or alemtuzumab
Baseline serum creatinine must be <1.5 mg/dL, left ventricular ejection fraction >55%, adequate pulmonary functions (oxygen saturation at room air of >90%), and AST and ALT not > 2x upper limits of normal, and no history of previous or active malignancy, except for localized cutaneous basal or squamous cell carcinoma in situ of the cervix.
Exclusion Criteria:
Diagnosis of primary progressive MS.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Single Arm
Conditioning regimens with Alemtuzumab, Fludarabine, and Cyclophosphamide will be used for all patients.
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Alemtuzumab 10 mg given IV on day 1 of the 5 day conditional regimen
Fludarabine 25mg/m2 daily given IV on days 1-5 of the 5 day conditioning regimen
Cyclophosphamide is given 3 gm/m2 for mobilization, and then repeated during 5 day conditioning regimen w/ doses of 50mg/kg/day on days 1-4
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To evaluate the toxicity of autologous HPC transplant in patients with multiple sclerosis that have failed at least two lines of disease modifier therapy
Time Frame: At 5 years post transplant
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All follow-up appointments will be carried out at Texas Oncology-Amarillo Cancer Center.
Patients will be monitored for clinical toxicities and using laboratory blood tests for renal functions, hepatic functions, and bone marrow functions at At discharge post-transplant, then again at 6 weeks, 3 months, 6 months, 9 months, 12 months and after that 6 monthly until death..
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At 5 years post transplant
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To evaluate the effectiveness of high dose chemotherapy with HPC transplant for multiple sclerosis sclerosis that has failed at least two lines of therapy
Time Frame: Assessed at baseline, tat 3 months, 6 months, 9 months, 12 months, and then after every 12 months until death
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hen rechecked Neurologic evaluations will be carried out in the offices of the two neurology co-Investigators and the information provided to the transplant physicians for record.
Patient will also undergo a repeat MRI scan at 3 months, 6 months, 9 months, 12 months, and then after every 12 months until death, after the transplant to evaluate changes in the number of MS plaques.
Subsequent MRI scan will be determined by the patient's neurologist as is needed clinically.
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Assessed at baseline, tat 3 months, 6 months, 9 months, 12 months, and then after every 12 months until death
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Seah Lim, MD, Texas Oncology
Publications and helpful links
General Publications
- Fagius J, Lundgren J, Oberg G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler. 2009 Feb;15(2):229-37. doi: 10.1177/1352458508096875. Epub 2008 Sep 19.
- Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, Oyama Y, Russell EJ, Stern J, Muraro P, Rose J, Testori A, Bucha J, Jovanovic B, Milanetti F, Storek J, Voltarelli JC, Burns WH. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009 Mar;8(3):244-53. doi: 10.1016/S1474-4422(09)70017-1. Epub 2009 Jan 29. Erratum In: Lancet Neurol. 2009 Apr;8(4):309. Stefosky, Dusan [corrected to Stefoski, Dusan].
- Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366.
- Burt RK, Marmont A, Oyama Y, Slavin S, Arnold R, Hiepe F, Fassas A, Snowden J, Schuening F, Myint H, Patel DD, Collier D, Heslop H, Krance R, Statkute L, Verda L, Traynor A, Kozak T, Hintzen RQ, Rose JW, Voltarelli J, Loh Y, Territo M, Cohen BA, Craig RM, Varga J, Barr WG. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum. 2006 Dec;54(12):3750-60. doi: 10.1002/art.22256. No abstract available.
- Kimiskidis V, Sakellari I, Tsimourtou V, Kapina V, Papagiannopoulos S, Kazis D, Vlaikidis N, Anagnostopoulos A, Fassas A. Autologous stem-cell transplantation in malignant multiple sclerosis: a case with a favorable long-term outcome. Mult Scler. 2008 Mar;14(2):278-83. doi: 10.1177/1352458507082604. Epub 2007 Oct 17.
- Lim SH, Kell J, al-Sabah A, Bashi W, Bailey-Wood R. Peripheral blood stem-cell transplantation for refractory autoimmune thrombocytopenic purpura. Lancet. 1997 Feb 15;349(9050):475. doi: 10.1016/S0140-6736(05)61187-7. No abstract available.
- Mancardi GL, Murialdo A, Rossi P, Gualandi F, Martino G, Marmont A, Ciceri F, Schenone A, Parodi RC, Capello E, Comi G, Uccelli A. Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis. Mult Scler. 2005 Jun;11(3):367-71. doi: 10.1191/1352458505ms1181cr.
- Pasquini MC, Griffith LM, Arnold DL, Atkins HL, Bowen JD, Chen JT, Freedman MS, Kraft GH, Mancardi GL, Martin R, Muraro PA, Nash RA, Racke MK, Storek J, Saccardi R. Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies. Biol Blood Marrow Transplant. 2010 Aug;16(8):1076-83. doi: 10.1016/j.bbmt.2010.03.012. Epub 2010 Mar 18.
- Passweg J, Tyndall A. Autologous stem cell transplantation in autoimmune diseases. Semin Hematol. 2007 Oct;44(4):278-85. doi: 10.1053/j.seminhematol.2007.08.001.
- Saccardi R, Di Gioia M, Bosi A. Haematopoietic stem cell transplantation for autoimmune disorders. Curr Opin Hematol. 2008 Nov;15(6):594-600. doi: 10.1097/MOH.0b013e3283136700.
- Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, Havrdova E, Carreras E, Saiz A, Lowenberg B, te Boekhorst PA, Gualandio F, Openshaw H, Longo G, Pagliai F, Massacesi L, Deconink E, Ouyang J, Nagore FJ, Besalduch J, Lisukov IA, Bonini A, Merelli E, Slavino S, Gratwohl A, Passweg J, Tyndall A, Steck AJ, Andolina M, Capobianco M, Martin JL, Lugaresi A, Meucci G, Saez RA, Clark RE, Fernandez MN, Fouillard L, Herstenstein B, Koza V, Cocco E, Baurmann H, Mancardi GL; Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006 Dec;12(6):814-23. doi: 10.1177/1352458506071301.
- Tyndall A, Gratwohl A. Adult stem cell transplantation in autoimmune disease. Curr Opin Hematol. 2009 Jul;16(4):285-91. doi: 10.1097/MOH.0b013e32832aacb3.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Multiple Sclerosis
- Sclerosis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Immunological
- Cyclophosphamide
- Fludarabine
- Alemtuzumab
Other Study ID Numbers
- 20112015
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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