Autologous Stem Cell Transplant for Neurologic Autoimmune Diseases

• ClinicalTrials.gov Identifier: NCT00716066
• Recruitment Status: Recruiting
• First Posted: July 16, 2008
• Last Update Posted: May 26, 2023
• Sponsor: Fred Hutchinson Cancer Center
• Information provided by (Responsible Party): Fred Hutchinson Cancer Center

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Autoimmune Disease; Neurologic Autoimmune Disease; Autologous Transplant Autoimmune; Multiple Sclerosis Transplant; MS Stem Cell Transplant; Multiple Sclerosis Stem Cell Transplant; Stiff Person Syndrome; HCT for Neurologic Autoimmune Disorders; CIDP Transplant; Myasthenia Gravis Transplant; Autoimmune Nervous System Disorder; Central Nervous System Vasculitis; Cerebellar Degeneration; Chronic Inflammatory Demyelinating Polyneuropathy; Lambert Eaton Myasthenic Syndrome; Myasthenia Gravis; Neuromyelitis Optica; Opsoclonus Myoclonus Syndrome; Rasmussen Subacute Encephalitis	Biological: Anti-Thymocyte Globulin; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Drug: Carmustine; Drug: Cytarabine; Drug: Etoposide; Other: Laboratory Biomarker Analysis; Drug: Melphalan; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Prednisone; Procedure: Syngeneic Bone Marrow Transplantation	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: June 2008
• Estimated Primary Completion Date: January 30, 2028
• Estimated Study Completion Date: June 30, 2033

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (immunosuppressive therapy followed by transplant); Patients receive carmustine IV on day -6, etoposide IV and cytarabine IV 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 PO QD on days 7-21, followed by 2 week taper.

Biological: Anti-Thymocyte Globulin; Given IV; Other Names: Antithymocyte Globulin; Antithymocyte Serum; ATG; ATGAM; ATS; Thymoglobulin; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous or syngeneic stem cell transplantation; Other Name: Autologous Stem Cell Transplantation; Drug: Carmustine; Given IV; Other Names: BCNU; Becenum; Becenun; BiCNU; Bis(chloroethyl) Nitrosourea; Bis-Chloronitrosourea; Carmubris; Carmustin; Carmustinum; FDA 0345; Gliadel; N,N'-Bis(2-chloroethyl)-N-nitrosourea; Nitrourean; Nitrumon; SK 27702; SRI 1720; WR-139021; 154-93-8; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosar-U; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; 147-94-4; Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16-213; VP-16; VP-16-213; 33419-42-0; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Melphalan; Given IV; Other Names: Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-Sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; 148-82-3; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous or syngeneic stem cell transplantation; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Drug: Prednisone; Given PO; Other Names: .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltasone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Orasone; Panafcort; Panasol-S; Paracort; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisonum; Prednitone; Promifen; Servisone; SK-Prednisone; 53-03-2; Procedure: Syngeneic Bone Marrow Transplantation; Undergo syngeneic bone marrow transplantation

Outcome Measures

Primary Outcome Measures :

1. Incidence of grades 4-5 regimen-related toxicity [ Time Frame: Up to 1 year post-transplant ]
   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.

Secondary Outcome Measures :

1. Transplant-related mortality [ Time Frame: Within 100 days post-transplant ]
   Defined as death within the first 100 days of transplant due to transplant-related complications.
2. Disease responses [ Time Frame: Up to 5 years ]
   Assessed by clinical, laboratory and radiologic evaluation
3. Engraftment kinetics [ Time Frame: Over first 60 days post-transplant ]
   Monitored for engraftment kinetics of granulocytes, platelets and red cells post-transplant.
4. 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 [ Time Frame: Baseline to post mobilization, assessed up to 20 days after starting final mobilization (up to two mobilizations) ]
   Efficacy of peripheral blood stem cell mobilization as evaluated by total number of harvested CD34+cells/kg, for autologous transplant.
5. Number of subjects with an exacerbation of autoimmune disease symptoms secondary to G-CSF (filgrastim) during peripheral blood stem cell mobilization [ Time Frame: Baseline to post mobilization, assessed up to 20 days after starting final mobilization (up to two mobilizations) ]
   Subjects are evaluated by standardized clinical neurologic tests specific to autoimmune disease type.

Eligibility Criteria

• Ages Eligible for Study: up to 71 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Bernie McLaughlin; 206.667-4916; bmclaugh@fredhutch.org

Locations

United States, Colorado

Colorado Blood Cancer Institute; Recruiting

Denver, Colorado, United States, 80218

Contact: Richard A. Nash 720-754-4800 Richard.Nash@Healthonecares.com

Contact: Tori Leland 303-218-4264 Victoria.Leland@HealthONEcares.com

Principal Investigator: Richard A. Nash

United States, Washington

Fred Hutch/University of Washington Cancer Consortium; Recruiting

Seattle, Washington, United States, 98109

Contact: Bernie McLaughlin 206-667-4916 bmclaugh@fredhutch.org

Principal Investigator: George E. Georges

Swedish Medical Center-First Hill; Recruiting

Seattle, Washington, United States, 98122-4307

Contact: Bernie McLaughlin 206-667-4916 bmclaugh@fredhutch.org

Principal Investigator: James Bowen

Sponsors and Collaborators

Fred Hutchinson Cancer Center

Investigators

• Principal Investigator: George Georges; Fred Hutch/University of Washington Cancer Consortium

More Information

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00716066
• Other Study ID Numbers: 2260.00; NCI-2010-00403 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2260.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); RG9213030 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• First Posted: July 16, 2008
• Last Update Posted: May 26, 2023
• Last Verified: February 2023

Keywords provided by Fred Hutchinson Cancer Center:

neurologic autoimmune disease; autologous transplant autoimmune; multiple sclerosis transplant; MS stem cell transplant; multiple sclerosis stem cell transplant; Stiff Person Syndrome; HCT for neurologic autoimmune disorders; CIDP transplant; myasthenia gravis transplant

Additional relevant MeSH terms:

Lambert-Eaton Myasthenic Syndrome; Opsoclonus-Myoclonus Syndrome; Stiff-Person Syndrome; Syndrome; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Myasthenia Gravis; Muscle Weakness; Multiple Sclerosis; Encephalitis; Polyneuropathies; Neuromyelitis Optica; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Myoclonus; Nervous System Diseases; Ocular Motility Disorders; Autoimmune Diseases of the Nervous System; Vasculitis, Central Nervous System; Vasculitis; Autoimmune Diseases; Disease; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Demyelinating Diseases; Immune System Diseases; Brain Diseases; Central Nervous System Diseases; Neuroinflammatory Diseases; Vascular Diseases