Biomarker Validation Following Sargramostim Treatment in Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
Investigators will evaluate the safety of a 48 week regimen of Leukine administered as a weight-based dose at 3 ug/kg/ day for 5 days followed by a 2-day holiday. This 48 week long study will extend the prior biomarker evaluations observed in a previous study. Clinical signs and symptoms will be measured by personal well-being, physical, and neurological examinations (UPDRS Parts I, II, III, and IV assessments) and blood tests (CBC with differential, total T cell count, and a comprehensive metabolic sera panel). Leukapheresis will be performed to collect large numbers of immune cells for biomarker testing and immune phenotyping. Additionally, the investigators will determine whether immune deficits of PD are consistent during baseline data collection, and the potential Leukine-induced motor control and mobility improvements will be determined by UPDRS part I, II, III, and IV scores off treatment and on treatment.

Detailed Description
-----------------
Primary Objectives: There are two main study goals. First, the investigators will determine the safety of a 48 week regimen of Leukine administered as a weight-based dose at 3 µg/kg/day for 5 days, followed by a 2-day holiday. This 48 weeks (n=10) pilot study will continue to assess the safety of Leukine for treatment of Parkinson's disease (PD). Clinical signs and symptoms will be measured by personal well-being, physical, and neurological examinations (UPDRS Parts I, II, III, and IV assessments) and blood tests (CBC with differential, total T cell count, and a comprehensive metabolic sera panel). Due to fragility of the patient population and prior recorded adverse events the proposed dose reductions are justified. Second, in future preparations for an intended broader number of patient enrollments, the investigators wish to functionally examine any or all putative relevant biomarker assessments. Secondary Objectives: The investigators will examine over a time of 48 weeks, effects of treatment on defined adaptive immune deficits in PD as measured by analysis of peripheral blood mononuclear cells collected before and during Leukine therapy. The investigators will assess the individual T cell parameters that include links between T cell function and subset analyses and clinical neurological signs and symptoms. These immune parameters will be serially examined as they may contribute to the immune deficits in PD. Thus, timed analyses of changes in T cell phenotypes and/or function will be completed. In addition, the investigators will assess the functional stability of the immune deficits in PD. To this end, the investigators will examine T cell subsets in PD patients in this study against prior results. The investigators will determine whether the immune deficits of PD are consistent during baseline data collection. The investigators will evaluate the potential Leukine-induced motor control and mobility improvements by assessing UPDRS part I, II, III, and IV scores of treatment and on treatment. Additionally, over the course of this 48 week treatment study, investigators will also be assessing various biomarkers within plasma, peripheral blood, and the total lymphocyte and monocyte populations isolated from leukapheresis before Leukine therapy and after 24 and 48 weeks of treatment. Identified biomarkers will be correlated to disease severity and progression as assessed by UPDRS. Serum will also be collected to determine the generation of anti-drug neutralizing antibodies that may develop due to the dosing scheme.

Official Title
-----------------
A Phase 1, Open-label Study to Validate Treatment-induced Biomarkers Following Sargramostim Treatment in Parkinson's Disease

Conditions
-----------------
Parkinson's Disease and Parkinsonism

Intervention / Treatment
-----------------
* Drug: Sargramostim


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Onset of bradykinesia and 1 or both of the following: rest tremor and/or rigidity Asymmetric onset of clinical signs Progressive motor symptoms Age at onset 35-85 years Duration of PD symptoms of at least 3 years Female subjects must be either: Not pregnant, not breastfeeding, and not planning on becoming pregnant during the study; Not of childbearing potential, defined as one who has been postmenopausal for at least 1 year and with follicle stimulating hormone (FSH) levels in the laboratory defined postmenopausal range, or has been surgically sterilized, or has had a hysterectomy at least 3 months prior to the start of this trial; or If of childbearing potential, must agree to use an effective method of avoiding pregnancy to the end of the trial and must have a negative serum beta-human chorionic gonadotropin (β-HCG) test. Effective methods of avoiding pregnancy are contraceptive methods used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap), abstinence, or a sterile sexual partner. Must be stage 4 or less according to the Hoehn and Yahr scale Exclusion Criteria: Atypical features indicative of a Parkinson-Plus disorder (Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal Degeneration (CBD)) including cerebellar signs, supranuclear gaze palsy, apraxia and other cortical signs, or prominent autonomic failure Neuroleptic treatment at time of onset of parkinsonism Active treatment with a neuroleptic at time of study entry History of repeated strokes with stepwise progression of parkinsonism History of repeated head injury History of definite encephalitis More than one blood relative diagnosed with PD Prominent gait imbalance early in the course (< 5 years) Mini-mental state examination score <26 Hematological malignancy or coagulopathy Abnormal blood analyses: hematocrit <30; WBC>11.5; clinically significant laboratory data (e.g. alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 3x the upper limit of normal [ULN]), or any abnormal laboratory value that could interfere with the assessment of safety in the judgment of the investigator; significant abnormalities on the clinical examination, vital signs, and clinical chemistry or hematology results (excluding findings of Parkinson's disease), that may interfere with the study or present a safety risk for the subject as judged by the clinical investigator charged in the care of study participants Serious medical illness or co-morbidity that may interfere with participation in the study Brain surgery for parkinsonism (DBS, cell implantation, gene therapy) History of an autoimmune disorder or systemic inflammatory disorder deemed significant by physician Immunostimulatory or immunosuppressive treatment (including amphet-amines or systemic corticosteroids) within 90 days Exclusively unilateral parkinsonism for longer than 3 years Known hypersensitivity to GM-CSF, yeast-derived products Current lithium treatment Individuals with current diagnoses of alcohol or substance abuse/dependence Anyone who is not appropriate for participation in this research protocol as deemed by the principal or co-investigator Anyone who has previously been treated with GM-CSF as an immunomodulatory therapy Anyone with poor venous access Anyone who has any illnesses or events that would cause a neurological abnormality, apart from Parkinson's disease. Subjects with allergies or sensitivities to yeast products. Subjects that have received a flu shot within the past 3 weeks.

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leukine Treatment<br>48 week regimen of Leukine administered as a weight-based dose at 3 µg/kg/day for 5 days (week), followed by a 2-day holiday (weekend) | Drug: Sargramostim<br>* Recombinant human GM-CSF produced by recombinant DNA technology using a yeast (S. cerevisiae) expression system<br>* Other names: Leukine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in incidence of adverse events over time | The safety of Leukine administration in PD will be examined by documenting abnormal results from CBC with differential, total T cell count, or comprehensive metabolic panel analyses; abnormal physical and or neurological exam findings; abnormal levels of antibodies to GM-CSF; clinically increasing Unified Parkinson's disease Rating Scale (UPDRS) part I, II, III, and IV scores as determined by the examining physician; and other adverse events. Adverse event logs will be reported every 4 weeks. | every 6 months during the course of treatment, up to 48 weeks until drug cessation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Treatment Biomarkers over time | During the baseline visit and at 24 weeks and 48 weeks post-Leukine initiation, subjects will undergo leukapheresis to collect large amounts of monocytes and lymphocytes for biomarker evaluations. Cells will be harvested and subjected to proteomic and transcriptomic tests to assess therapeutic response and treatment-induced biomarkers. Biomarkers assessed will be proteins levels along with corresponding gene levels determined as fold change from baseline. | every 6 months during the course of treatment, up to 48 weeks until drug cessation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Leukine, sargramostim, biomarker