Carmustine, Etoposide, Cytarabine, Melphalan, and Antithymocyte Globulin Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Autoimmune Neurologic Disease That Did Not Respond to Previous Therapy

Condition(s) targeted: Autoimmune Disorder

Intervention: anti-thymocyte globulin (Biological); carmustine (Drug); cytarabine (Drug); etoposide (Drug); melphalan (Drug); prednisone (Drug); autologous hematopoietic stem cell transplantation (Procedure); peripheral blood stem cell transplantation (Procedure); syngeneic bone marrow transplantation (Procedure); laboratory biomarker analysis (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Official(s) and/or principal investigator(s):
George Georges, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

This phase II trial studies how well carmustine, etoposide, cytarabine and melphalan together with antithymocyte globulin before a peripheral blood stem cell transplant works in treating patients with severe 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 peripheral blood 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

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 design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Incidence of grades 4-5 regimen-related toxicity as assessed by the Regimen Related Toxicity Scale

Secondary outcome:

Disease responses as assessed by clinical, laboratory and radiologic evaluation

Transplant-related mortality (TRM)

Engraftment kinetics

Efficacy of peripheral blood stem cell (PBSC) mobilization from syngeneic donors and autograft recipients

Detailed description: PRIMARY OBJECTIVES:

I. Evaluate the safety of high-dose carmustine, etoposide, Ara-c (cytarabine) and melphalan (BEAM) and Thymoglobulin (antithymocyte globulin) as a high-dose immunosuppressive treatment (HDIT) regimen in patients with severe, refractory neurological autoimmune disease.

SECONDARY OBJECTIVES:

I. Evaluate disease responses and the duration of response to HDIT and autologous hematopoietic stem cell transplantation (HSCT).

II. Determine the efficacy and safety of G-CSF (filgrastim) and prednisone or cyclophosphamide for hematopoietic stem mobilization in patients with neurological autoimmune diseases.

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 peripheral blood 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.

Minimum age: N/A. Maximum age: 70 Years. Gender(s): Both.

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-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 disease as approve 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

- 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 stand 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:

- 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

- Severe pulmonary dysfunction associated with a carbon monoxide diffusing capacity

(DLCO) (corrected for hemoglobin) < 40%, or requires supplemental oxygen

- 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 < 30ml/min/1. 73 m^2 body surface area

- Serum glutamic pyruvic 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

- Patients with a history of hypersensitivity to murine proteins

- 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

Colorado Blood Cancer Institute, Denver, Colorado 80218, United States; Recruiting
Richard A. Nash, Phone: 720-754-4800
Richard A. Nash, Principal Investigator

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States; Recruiting
George E. Georges, Phone: 206-667-6886
George E. Georges, Principal Investigator

Swedish Neuroscience Institute, Seattle, Washington 98122, United States; Recruiting
James Bowen, Phone: 206-320-2200
James Bowen, Principal Investigator

Starting date: June 2008
Last updated: January 17, 2013