Autologous Stem Cell Transplant for Neurologic Autoimmune Diseases

Myasthenia Gravis Clinical Trial

Official title:

High-Dose Immunosuppressive Therapy Using Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) + Thymoglobulin Followed by Syngeneic or Autologous Hematopoietic Cell Transplantation for Patients With Autoimmune Neurologic Diseases

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00716066
• Other study ID #: 2260.00
• Secondary ID: NCI-2010-0040322
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 2008
• Est. completion date: January 31, 2030

Study information

• Verified date: January 2024
• Source: Fred Hutchinson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the side effects and how well carmustine, etoposide, cytarabine and melphalan together with antithymocyte globulin before a stem cell transplant works in treating patients with autoimmune neurologic disease that did not respond to previous therapy. In autoimmune neurological diseases, the patient's own immune system 'attacks' the nervous system which might include the brain/spinal cord and/or the peripheral nerves. Giving high-dose chemotherapy, including carmustine, etoposide, cytarabine, melphalan, and antithymocyte globulin, before a stem cell transplant weakens the immune system and may help stop the immune system from 'attacking' a patient's nervous system. When the patient's own (autologous) stem cells are infused into the patient they help the bone marrow make red blood cells, white blood cells, and platelets so the blood counts can improve.

Description:

OUTLINE: Patients receive carmustine intravenously (IV) on day -6, etoposide IV and cytarabine IV twice daily (BID) on days -5 to -2, melphalan IV on day -1, and antithymocyte globulin IV on days -2 and -1. Patients then undergo autologous or syngeneic stem cell transplant on day 0. Patients also receive prednisone orally (PO) once daily (QD) on days 7-21, followed by 2 week taper. After completion of study treatment, patients are followed up at 3 months, 1 year, and then annually thereafter for up to 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 53
• Est. completion date: January 31, 2030
• Est. primary completion date: January 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 71 Years

Eligibility

Inclusion Criteria:

• Patients with an autoimmune disorder of the central or peripheral nervous system will

be eligible; this will include:

• Primary Central Nervous System (CNS) vasculitis
• Rasmussen's encephalitis
• Autoimmune peripheral neuropathy (anti-Hu [Anna-1], anti-GM1 [GD1b], anti-MAG, anti-ganglioside, anti-sulfatide)
• Autoimmune cerebellar degeneration
• Gait Ataxia with Late age Onset Polyneuropathy (GALOP)
• Stiff Person Syndrome
• Chronic Inflammatory Demyelinating Polyneuropathy
• Myasthenia Gravis
• Lambert-Eaton myasthenic syndrome
• Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) / tropical spastic paraparesis (TSP)
• Opsoclonus/myoclonus (anti-Ri)
• Neuromyelitis optica
• Multiple sclerosis
• Other central or peripheral nervous system autoimmune diseases as approved by study neurologists and the Fred Hutchinson Cancer Research Center (FHCRC) faculty at Patient Care Conference (PCC)
• Patients must satisfy the criteria for a diagnosis of one of the severe neurological autoimmune disorders outlined
• Patients age =< 70 years
• Evidence of disease activity as outlined (e.g. gadolinium enhancement on magnetic resonance imaging of the brain or clinical progression)
• Patients must have failed at least 2 lines of standard therapy as outlined for the specific diseases
• DONOR: Sibling of any patient enrolled on this protocol proven by ABO typing, human leukocyte antigen (HLA) typing and variable number tandem repeat (VNTR) analysis to be syngeneic with the patient (e.g. identical twin)
• DONOR: Willing to undergo multiple apheresis procedures (except donors < 12 years who will undergo bone marrow harvests)

Exclusion Criteria:

• Age >= 71 years
• Pregnancy or expressed plans to become pregnant within 1 year of the procedure
• Patients who are serologically positive for human immunodeficiency virus (HIV)
• Patients with pulmonary, cardiac, hepatic or renal impairment that would limit their ability to receive cytoreductive therapy and compromise their survival; this should

include patients with any of the following:

• Severe pulmonary dysfunction associated with a carbon monoxide diffusing capacity (DLCO) (corrected for hemoglobin) < 60%, or requires supplemental oxygen; patients who are unable to perform pulmonary function test (because of underlying disease) will be excluded if the oxygen saturation is < 92% on room air
• Uncontrolled malignant arrhythmias, or clinical evidence of congestive heart failure (New York class III-IV) or ejection fraction < 50%
• Renal disease with estimated glomerular filtration rate (GFR) by creatinine clearance or iothalamate clearance < 50 ml/min/1.73 m^2 body surface area
• Serum glutamate pyruvate transaminase (SGPT)/aspartate aminotransferase (AST) > 3 times normal or direct bilirubin greater than 2.5 mg/dL on two repeated tests
• Active uncontrolled infection
• Demonstrated lack of compliance with prior medical care
• Patients whose life expectancy is limited by illness other than their neurological condition
• Patients with evidence of myelodysplasia
• Active malignancy (excluding localized squamous cell or basal cell carcinoma of the skin)
• DONOR: Inadequate documentation that donor and recipient are syngeneic
• DONOR: Donors who do not fulfill criteria as apheresis donors as established by institutional guidelines
• DONOR: Concordant for autoimmune neurological disease(s) as determined by neurological evaluation

Related Conditions & MeSH terms

• Autoimmune Disease
• Autoimmune Diseases
• Autoimmune Diseases of the Nervous System
• Autoimmune Nervous System Disorder
• Autologous Transplant Autoimmune
• Central Nervous System Vasculitis
• Cerebellar Degeneration
• Chronic Inflammatory Demyelinating Polyneuropathy
• CIDP Transplant
• Encephalitis
• HCT for Neurologic Autoimmune Disorders
• Lambert Eaton Myasthenic Syndrome
• Lambert-Eaton Myasthenic Syndrome
• MS Stem Cell Transplant
• Multiple Sclerosis
• Multiple Sclerosis Stem Cell Transplant
• Multiple Sclerosis Transplant
• Muscle Weakness
• Myasthenia Gravis
• Myasthenia Gravis Transplant
• Myoclonus
• Nervous System Diseases
• Neurologic Autoimmune Disease
• Neuromyelitis Optica
• Ocular Motility Disorders
• Opsoclonus Myoclonus Syndrome
• Opsoclonus-Myoclonus Syndrome
• Polyneuropathies
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
• Rasmussen Subacute Encephalitis
• Sclerosis
• Stiff Person Syndrome
• Stiff-Person Syndrome
• Syndrome
• Vasculitis
• Vasculitis, Central Nervous System

Intervention

Biological:
• Anti-Thymocyte Globulin
Given IV

Procedure:
• Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous or syngeneic stem cell transplantation

Drug:
• Carmustine
Given IV
• Cytarabine
Given IV
• Etoposide
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Melphalan
Given IV

Procedure:
• Peripheral Blood Stem Cell Transplantation
Undergo autologous or syngeneic stem cell transplantation

Drug:
• Prednisone
Given PO

Procedure:
• Syngeneic Bone Marrow Transplantation
Undergo syngeneic bone marrow transplantation

Locations

Country	Name	City	State
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of grades 4-5 regimen-related toxicity	Assessed by the Regimen Related Toxicity Scale. Using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The development of a grade 4 to 5 toxicity of any of the included major organ systems within the first 365 days after transplant will be defined as regimen-related toxicity.	Up to 1 year post-transplant
Secondary	Transplant-related mortality	Defined as death within the first 100 days of transplant due to transplant-related complications.	Within 100 days post-transplant
Secondary	Disease responses	Assessed by clinical, laboratory and radiologic evaluation	Up to 5 years
Secondary	Engraftment kinetics	Monitored for engraftment kinetics of granulocytes, platelets and red cells post-transplant.	Over first 60 days post-transplant
Secondary	Number of subjects achieving greater than or equal to 4.0 x 10^6 CD34+ cells/kg, after up to two peripheral blood stem cell mobilizations	Efficacy of peripheral blood stem cell mobilization as evaluated by total number of harvested CD34+cells/kg, for autologous transplant.	Baseline to post mobilization, assessed up to 20 days after starting final mobilization (up to two mobilizations)
Secondary	Number of subjects with an exacerbation of autoimmune disease symptoms secondary to G-CSF (filgrastim) during peripheral blood stem cell mobilization	Subjects are evaluated by standardized clinical neurologic tests specific to autoimmune disease type.	Baseline to post mobilization, assessed up to 20 days after starting final mobilization (up to two mobilizations)