High Dose Chemo With Stem Cell Transplant as Treatment for Multiple Sclerosis That Failed Prior Treatment

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the toxicity and the effectiveness of high dose chemotherapy with HPC transplant Multiple Sclerosis that has failed at least two lines of therapy

Detailed Description
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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.

Official Title
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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

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Alemtuzumab
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Conditioning regimens with Alemtuzumab, Fludarabine, and Cyclophosphamide will be used for all patients. | Drug: Alemtuzumab<br>* Alemtuzumab 10 mg given IV on day 1 of the 5 day conditional regimen<br>Drug: Fludarabine<br>* Fludarabine 25mg/m2 daily given IV on days 1-5 of the 5 day conditioning regimen<br>Drug: Cyclophosphamide<br>* 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<br>|

What is the study measuring?
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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 | 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.. | At 5 years post transplant | 

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 | 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. | Assessed at baseline, tat 3 months, 6 months, 9 months, 12 months, and then after every 12 months until death |