Nilotinib in Huntington's Disease

NCT03764215 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: 2017-0440
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Based on strong pre-clinical evidence of the effects of Nilotinib on neurodegenerative pathologies, including autophagic clearance of neurotoxic proteins, neurotransmitters (dopamine and glutamate), immunity and behavior, the investigators conducted an open label pilot clinical trial in mid-to-advanced PD with dementia (PDD) and Dementia with Lewy Bodies (DLB) (stage 3-4) patients. Participants (N=12) were randomized 1:1 to once daily oral dose of 150mg and 300mg Nilotinib for 6 months. The investigators data suggests that Nilotinib penetrates the brain and inhibits CSF Abelson (Abl) activity via reduction of phosphorylated Abl in agreement with pre-clinical data. Several studies suggest that CSF alpha-Synuclein and Abeta42 are decreased and CSF total Tau and p-Tau are increased in PD and DLB. The investigators data shows attenuation of loss of CSF alpha-Synuclein and Abeta40/42 with 300mg (50% of the CML dose) compared to 150mg Nilotinib after 6 months treatment. CSF homovanillic acid (HVA), which is a by-product of dopamine metabolism, is significantly increased; and CSF total Tau and p-Tau are significantly reduced (N=5, P\<0.05) with 300mg Nilotinib between baseline and 6 months treatment. Despite the reduction of L-Dopa replacement therapies in our study, the Unified Parkinson's Disease Rating Scale (UDPRS) I-IV scores improved with 150mg (3.5 points) and 300mg (11 points) from baseline to 6 months and worsened (13.7 points and 11.4 points) after 3 months withdrawal of 150mg and 300mg, respectively. Other non-motor functions e.g. constipation was resolved in all patients and cognition was also improved (3.5 points) using both the Mini-Mental Status Exam (MMSE) or the Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) between baseline and 6 months. MMSE scores returned to baseline after 3 months of Nilotinib withdrawal. These data are very compelling to evaluate the effects of Nilotinib in an open label proof-of-concept study in patients with HD.

Conditions

Huntington Disease

Outcome Measures

Primary Outcomes (3)

• Number of participants experiencing any Adverse events and Serious Adverse Events

  will be measured using the occurrence of adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug. AEs of interest are defined as QTc prolongation, myelosuppression, hepatotoxicity and pancreatitis as listed in Table 1. These AEs will be tracked over the course of the trial and reviewed by the data and safety monitoring board (DSMB) at scheduled meetings and in real time. SAEs and AEs are known to be related to drug use at 800mg daily in cancer. A small safety trial using lower oral daily doses of 150 mg and 300 mg Nilotinib in 12 PD patients showed one cardiac SAE over a six-month treatment period. Based on preliminary clinical data, investigator's brochure (IB) and scheduled EKGs and lab tests, SAEs and AEs will be evaluated real-time and on case-by-case basis.

  3 months

• CSF levels of biomarkers linked to Disease symptoms Chorea and behavioral symptoms

  Prior studies from our group showed that Nilotinib treatment increases the CSF levels of HVA, suggesting alteration of dopamine level. We will evaluate the effects of potential changes of dopamine levels on Chorea and behavioral symptoms in HD participants. We will use an adaptive study design that will allow examination of the effects of 150mg Nilotinib once daily in 10 HD participants. If participants in this group do not exhibit worsening chorea or behavioral changes, then 300mg Niloitnib will be given to a new group of 10 additional participants. These potential AEs will be tracked over the course of the trial and reviewed by the DSMB at scheduled meetings and in real time.

  3 months

• Number of participants tolerating the drug by the ability of remaining on treatment

  for a given participant will be defined as the ability of participants to remain on treatment. Overall tolerability of the drug will be defined as an acceptable number of up to 25% discontinuations.

  3 months

Study Arms (1)

Group 1

EXPERIMENTAL

Ten (10) participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If Nilotinib 150 mg per mouth daily dose is tolerated by the 1st group of 10 participants for 3 months, another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.

Drug: Nilotinib 150 MG

Interventions

Nilotinib 150 MG DRUG

10 participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If this dose is tolerated another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.

Group 1

Eligibility Criteria

• Age: 25 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative (LAR).
• Patients between the age of 25-90 years, medically stable
• Clinical diagnosis of HD with either a confirmed family history or positive CAG repeat (CAG≥35)
• MoCA ≥ 22
• Able to perform the TMT-B in ≤240 seconds
• Total Functional Capacity 7-12
• Stable concomitant medical and/or psychiatric illnesses, in the judgement of the PI.
• QTc interval 350-460 ms, inclusive
• Participants must be willing to undergo LP at baseline and 3 months after treatment

You may not qualify if:

• Patients with hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥461 ms
• Concomitant drugs known to prolong the QTc interval and history of any cardiovascular disease, including myocardial infarction or cardiac failure, angina, arrhythmia
• History or presence of cardiac conditions including:
• Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke)
• Congestive heart failure
• First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances
• Any history of Torsade de Pointes
• Treatment with any of the following drugs at the time of screening or the preceding 30 days, and/or planned use over the course of the trial:
• Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine)
• Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, Trazodone, etc.)
• Strong CYP3A4 inhibitors (including grapefruit juice). The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) must be avoided. Grapefruit products may also increase serum concentrations of Nilotinib. Should treatment with any of these agents be required, therapy with Nilotinib should be interrupted.
• Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin, xarelto, etc.
• St. John's Wort and the concomitant use of strong other CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) must be avoided since these agents may reduce the concentration of Nilotinib.
• Abnormal liver function defined as AST and/or ALT \> 100% the upper limit of the normal
• Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal

Sponsors & Collaborators

• Georgetown University: lead

Study Sites (1)

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

RECRUITING

Related Publications (1)

• Pagan F, Hebron M, Valadez EH, Torres-Yaghi Y, Huang X, Mills RR, Wilmarth BM, Howard H, Dunn C, Carlson A, Lawler A, Rogers SL, Falconer RA, Ahn J, Li Z, Moussa C. Nilotinib Effects in Parkinson's disease and Dementia with Lewy bodies. J Parkinsons Dis. 2016 Jul 11;6(3):503-17. doi: 10.3233/JPD-160867.

  PMID: 27434297 RESULT

Related Links

• Translational Neurotherapeutics Program at Georgetown University Medical Center

MeSH Terms

Conditions

Huntington Disease

Interventions

nilotinib

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Central Study Contacts

Hope Heller

CONTACT

202-687-1366; hope.heller@gunet.georgetown.edu

Robin Kuprewicz, MA

CONTACT

rk1028@georgetown.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Masking Details: We propose to perform an open label, Phase Ib, proof of concept study to evaluate the impact of low doses of Nilotinib treatment on safety, tolerability and biomarkers in participants with HD. We propose an adaptive design based on safety and tolerability of 150mg Nilotinib treatment for 3 months. We will first enroll 10 participants who will receive an oral dose of 150mg Nilotinib once daily (group 1) for 3 months. If these participants tolerate 150mg dose of Nilotinib, an additional 10 new HD participants (group 2) will be enrolled to evaluate the effects of 300 mg dose of Nilotinib for 3 months. We will then compare baseline with the effects of 3-months Nilotinib treatment within each group and between groups (1 and 2). Participants (group 1 and 2) will return for a follow up visit one month after the termination of 3-months treatment with Nilotinib and results will compared to baseline visits and end of study visits.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Huntington Disease Care, Education and Research Center at MedStar Georgetown University Hospital and Georgetown University Medical Center

Model Details: Ten (10) participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If this dose is tolerated another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.

Study Record Dates

• First Submitted: November 27, 2018
• First Posted: December 5, 2018
• Study Start: November 15, 2018
• Primary Completion: November 30, 2020
• Study Completion: November 30, 2020
• Last Updated: February 20, 2020

Record last verified: 2020-02

Locations

US (1)