Phase 1 Dose Escalation and PK Study of Cu(II)ATSM in ALS/MND

Study Overview
=================
Brief Summary
-----------------
Multicenter, open-label , single and multiple dose-escalation and pharmacokinetic study

Detailed Description
-----------------
Multicenter, open-label, phase 1 study of Cu(II)ATSM administered orally to patients wit amyotrophic lateral sclerosis/motor neuron disease. The study will be conducted in three phases. In the first two phases, dose cohorts of six patients each will participate in a single dose pharmacokinetic study followed by a 28-day repeated daily dose study to establish the recommended phase 2 dose (RP2D). The first dose cohort will be treated at 3 mg/day; planned dose escalations are 6, 12, 24, and 48 mg/day, subject to observed safety assessments. In the third phase of the study, participants will be treated at the RP2D to confirm tolerability and assess preliminary evidence of efficacy. In both the dose escalation and expansion cohorts, once the first 28 days of treatment and assessments are completed, at the discretion of the investigator a patient may continue to receive Cu(II)ATSM treatment for a maximum of six 28-day treatment cycles.

Official Title
-----------------
A Phase 1 Single and Multiple Dose Escalation and Pharmacokinetic Study of Cu(II)ATSM Administered Orally to Patients With Amyotrophic Lateral Sclerosis/Motor Neuron Disease

Conditions
-----------------
Amyotrophic Lateral Sclerosis, Motor Neuron Disease

Intervention / Treatment
-----------------
* Drug: Cu(II)ATSM


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent prior to initiation of any study-specific procedures; Familial or sporadic ALS/MND defined as clinically possible, probable, or definite by Awaji-shima Consensus Recommendations; First ALS/MND symptoms occurred no more than 2 years prior to screening visit; Seated FVC ≥ 70% and SNP ≥ 50% of predicted value; Not taking riluzole or on a stable dose of riluzole for at least 4 weeks prior to screening visit (participants are not allowed to start taking riluzole during the study); Age between 18 and 75 years at time of informed consent; Patient has a competent caregiver who can and will be responsible for administration of study drug; Adequate bone marrow reserve, renal and liver function: absolute neutrophil count ≥ 1500/µL lymphocyte count < 48% platelet count ≥ 150,000/µL hemoglobin ≥ 11 g/dL creatinine clearance ≥ 60 mL/min (Cockroft & Gault formula) ALT and/or AST ≤ 2 x ULN total bilirubin ≤ 1.5 x ULN serum albumin ≥ 2.8 g/dL Women and men with partners of childbearing potential must take effective contraception while on study and women of childbearing potential must have a negative pregnancy test and be non-lactating at screening Exclusion Criteria: Inability to swallow oral medications or presence of GI disorder deemed to jeopardize intestinal absorption of Cu(II)ATSM Dependence of mechanical ventilation (non-invasive or invasive) for any part of day or night Exposure to any other investigational agent within 3 months or two investigational agents within 6 months prior to screening visit Active GI disease (except gastrointestingal reflux disease) within 30 days of screening visit Known immune compromising illness or treatment Presence of any of the following clinical conditions drug abuse or alcoholism unstable cardiac, pulmonary, renal, hepatic, endocrine or hematologic disorder active infectious disease AIDS or AIDS-related complex current malignancy unstable psychiatric illness, defined as psychosis or untreated major depression within 90 days of screening visit neuromuscular disease other than ALS/MND Dementia that may affect either outcome measures or patient understanding and/or compliance with study requirements and procedures Use of anticoagulants at therapeutic doses within 7 days prior to screening visit Current use of strong inducers or inhibitors of CYPs 2C19 and 2D6

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: Cu(II)ATSM<br>Cu(II)ATSM capsules, administered orally once daily | Drug: Cu(II)ATSM<br>* copper-containing synthetic small molecule<br>* Other names: diacetylbis(N(4)-methylthiosemicarbazonato) copper(II);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| recommended phase 2 dose as determined by the number of participants at each dose level with dose limiting toxicities |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related change in disease severity by ALS Functional Rating Scale - Revised (ALSFRS-R) |  | 24 months | 
| Treatment-related change in cognitive function by Edinburgh Cognitive and Behavioral Assessment (ECAS) score |  | 24 months | 
| Treatment-related change in respiratory function by seated forced vital capacity (FCV) |  | 24 months | 
| Treatment-related change in quality of life by ALSSQOL-R score |  | 24 months | 
| Treatment-related change in disease severity by transcranial magnetic stimulation (TMS) response |  | 24 months | 
| Peak Cu(II)ATSM plasma concentration following administration of a single dose based on blood draws taken at 1, 2, 4, 8 and 24 hours after dosing |  | 12 months | 
| Area under the Cu(II)ATSM plasma concentration versus time curve (AUC) following administration of a single dose based on blood draws taken at 1, 2, 4, 8 and 24 hours after dosing |  | 12 months | 
| Treatment-related change in respiratory function by sniff nasal pressure (SNP) test |  | 24 months |