NCT03474263WithdrawnPhase 2
A Phase 2a, Open-Label Biomarker Study of IC14 for the Treatment of Patients With
Conditions
Interventions
Trial Snapshot
- Phase
- Phase 2
- Status
- Withdrawn
- Sponsor
- Implicit Bioscience
- Locations
- 2
- Primary Endpoint
- Serum neurofilament
Study Overview
Brief Summary
Patients with rapidly progressive ALS will be assigned to IC14 intravenously on Day 1-4. This 4-day course will be repeated on Days 8-11. Patients will all undergo MR-PET scans at two time points: before treatment onset and after the last treatment cycle. This scan will measure areas of ALS disease activity and assess response to IC14 treatment. MR-PET scans will be compared to historical controls.
Detailed Description
This is an open-label, biomarkers-driven study.
Patients with rapidly progressive ALS will be assigned to the following dose regimen of IC14:
• 4 mg/kg intravenously on Day 1, followed by 2 mg/kg daily x 3 days on Days 2-4. This 4-day course will be repeated on Days 8-11.
Patients will be followed for 28 days after the last dose of study drug. Patients will all undergo [11C]-PBR28-MR-PET scans at two time points: before treatment onset and after the last treatment cycle.
Patients will be followed for 28 days after the last dose of study drug for safety.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Capable of providing informed consent and informed consent form signed prior to initiation of any study-specific procedures.
- •Familial or sporadic ALS defined as clinically possible, probable, or definite by El Escorial Criteria.
- •Rapidly progressive ALS defined by the Revised ALS Functional Rating Scale (ALSFRS-R) slope ≥1 (48 minus ALSFRS-R score at screening / disease duration in months ≥ 1).
- •Upper Motor Neuron Burden Score of ≥ 25 (out of 45) at screening
- •First symptoms of ALS within 3 years of the screening visit
- •Age between 18 and 80 years at the time of the screening visit.
- •Not taking riluzole or edaravone or on a stable dose of riluzole or edaravone for at least 3 months prior to screening visit.
- •Adequate bone marrow reserve, renal and liver function:
- •absolute neutrophil count ≥ 1500/µL
- •lymphocyte count < 6000/µL
- •platelet count ≥ 150,000/µL
- •hemoglobin ≥ 11 g/dL
- •creatinine clearance ≥ 60 mL/min
- •alanine transaminase (ALT) and/or aspartate transaminase (AST) ≤ 3x upper limits of normal (ULN)
- •total bilirubin ≤ 1.5x ULN
- •serum albumin ≥ 2.8 g/dL
- •Females of childbearing potential should be using and committed to continue using one of the following acceptable birth control methods:
- •Sexual abstinence (inactivity) for 1 month prior to screening through study completion; or
- •Intrauterine device (IUD) in place for at least 3 months prior to study through study completion; or
- •Stable hormonal contraception for at least 3 months prior to study through study completion; or
- •Surgical sterilization (vasectomy) of male partner at least 6 months prior to study.
- •To be considered of non-childbearing potential, females should be surgically sterilized (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 2 months prior to study) or be post-menopausal and at least 3 years since last menses.
- •Males with female partners of childbearing potential must use contraception through study completion.
- •Ability to safely lie flat for 90 min for magnetic resonance-positron emission tomography (MR-PET) procedures in the opinion of the Investigator.
- •Patients must also have a genotype associated with a high or mixed affinity translocator protein (TSPO) (Ala/Ala or Ala/Thr) and ability to safely undergo MR-PET scans based on the opinion of the Investigator.
Exclusion Criteria
- •Dependence on invasive or non-invasive ventilation, defined as being unable to lay supine without it, unable to sleep without it, or continuous daytime use; presence of tracheostomy at screening; or presence of diaphragm pacing system at screening.
- •Exposure to any experimental treatment for ALS within the last 30 days or five half-lives, whichever is longer.
- •Treatment within 12 months with immunomodulator or immunosuppressant agent (including but not limited to cyclophosphamide, cyclosporine, interferon-α, interferon-β-1a, rituximab, alemtuzumab, azathioprine, etanercept, infliximab, adalimumab, certolizumab, golimumab, anakinra, rilonacept, secukinumab, tocilizumab, mycophenolate mofetil, methotrexate, cell-depleting agents, total lymphoid irradiation, dimethyl fumarate). Treatment with intravenous immunoglobulin (IVIG) within 2 months. Non-steroidal anti-inflammatory drugs (NSAIDs) are acceptable.
- •Exposure at any time to any cell or gene therapies under investigation for the treatment of ALS.
- •Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other opportunistic infections; or major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks.
- •Live-attenuated vaccines within 30 days before dosing. Subjects must agree to forego live-attenuated vaccines throughout the study, including 60 days after the last dose of study drug.
- •History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
- •History of one or more of the following: cardiac insufficiency (New York Heart Association [NYHA] III/IV), uncontrolled cardiac arrhythmias, unstable ischemic heart disease, or uncontrolled hypertension (systolic blood pressure > 170 mmHg or diastolic blood pressure > 110 mmHg).
- •History of myocardial infarction, or cerebrovascular accident.
- •Unstable pulmonary, renal, hepatic, endocrine or hematologic disease.
- •Autoimmune disease, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to rheumatoid arthritis.
- •Evidence of active malignant disease, malignancies diagnosed within the previous 5 years, or breast cancer diagnosed within the previous 5 years (except skin cancers other than melanoma).
- •History of human immunodeficiency virus infection or other immunodeficiency illness.
- •Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days.
- •History of drug abuse (not including marijuana use) or alcoholism within the past 12 months.
- •Significant neuromuscular disease other than ALS.
- •Other ongoing disease that may cause neuropathy, such as toxin exposure, dietary deficiency, uncontrolled diabetes, hyperthyroidism, cancer, systemic lupus erythematosus or other connective diseases, infection with HIV, hepatitis B virus (HBV), or hepatitis C (HCV), Lyme disease, multiple myeloma, Waldenström's macroglobulinemia, amyloid, and hereditary neuropathy.
- •Pregnancy or breastfeeding.
- •Deprivation of freedom by administrative or court order.
- •Any contraindication to undergo magnetic resonance imaging (MRI) studies such as history of a cardiac pacemaker or pacemaker wires; metallic particles in the body; vascular clips in the head; prosthetic heart valves; or severe claustrophobia.
- •Unwilling or unable to discontinue benzodiazepine usage [other than lorazepam (Ativan®), clonazepam (Klonopin®), or zolpidem (Ambien®)] for one day prior to and during scanning.
- •Research imaging-related radiation exposure exceeds current institutional Radiology Department guidelines
Arms & Interventions
IC14 (monoclonal anti-CD14 antibody)
Experimental
Biologic: IC14 (monoclonal anti-CD14 antibody) 4 mg/kg intravenously followed by IC14 2 mg/kg intravenously on Days 2-4. This four-day cycle will be repeated on Days 8-11.
Intervention: Biologic: IC14 (monoclonal antibody against human CD14) (Biological)
Outcomes
Primary Outcomes
Serum neurofilament
Time Frame: one month
Serum neurofilament is a biomarker that has been shown to correlate with ALS severity
Urinary p75 neurotrophin receptor
Time Frame: one month
Urinary p75 neurotrophin receptor is a biomarker that has been shown to correlate with ALS severity
Glial Activation
Time Frame: one month
Glial activation measured in the motor region measured by \[11C\]-PBR28 positron emission tomography (PET). Studies have shown this marker localizes to areas of glial activation and correlates with disease progression and outcomes.
Secondary Outcomes
- Peak Plasma Concentration of IC14(one month)
- Incidence of Treatment-Emergent Adverse Events (Safety, Tolerability)(six weeks)
- Immunogenicity(six weeks)
- Pharmacodynamics(one month)
Investigators
Study Sites (2)
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