Safety Study of TPI-287 to Treat CBS and PSP

NCT02133846 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: TPI287-4RT-001
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to determine the safety and tolerability \[maximum tolerated dose (MTD) within planned dosing range\] of intravenous (IV) infusions of TPI 287 administered once every 3 weeks for 9 weeks (for a total of 4 infusions) in patients with primary four repeat tauopathies (4RT), corticobasal syndrome (CBS; also called corticobasal degeneration, CBD) or progressive supranuclear palsy (PSP).

Conditions

Primary Four Repeat Tauopathies (4RT); Corticobasal Syndrome (CBS); Progressive Supranuclear Palsy (PSP); Corticobasal Degeneration (CBD)

Keywords

4RT, CBS, PSP, CBD, TPI-287

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose of TPI-287 in patients with primary 4RT; CBS or PSP.

  To determine the safety and tolerability \[maximum tolerated dose (MTD) within planned dosing range\] of intravenous (IV) infusions of TPI 287 administered once every 3 weeks for 9 weeks (for a total of 4 infusions) in patients with primary four repeat tauopathies (4RT): corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP).

  21 months (first subject enrolled to last subject completed)

Secondary Outcomes (1)

• TPI-287 levels in blood plasma and cerebrospinal fluid

  21 months (first subject enrolled to last subject completed)

Other Outcomes (5)

• CSF biomarkers

  Screening and 1 Week after completion of the fourth study infusion

• Brain MRI scan

  Screening and 2 Weeks after last double-blind infusion

• Degree of disability

  Baseline and 1 Week after completion 4th infusion

Study Arms (4)

TPI-287 low dose

EXPERIMENTAL

2 mg/m2 of TPI-287 administered as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions)

Drug: TPI 287 2 mg/m2; Drug: Placebo

TPI-287 moderate dose

EXPERIMENTAL

6.3 mg/m2 of TPI-287 administered as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions).

Drug: Placebo; Drug: TPI-287 6.3 mg/m2

TPI-287 high dose

EXPERIMENTAL

20 mg/m2 of TPI-287 administered as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions)

Drug: TPI-287 20 mg/m2; Drug: Placebo

Placebo

PLACEBO COMPARATOR

0.9% sodium chloride as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions)

Drug: Placebo

Interventions

TPI 287 2 mg/m2 DRUG

2 mg/m2 of TPI-287 diluted with 500mL 0.9% sodium chloride. TPI-287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class.Drug: Placebo Drug: Placebo 500mL 0.9% sodium chloride.

TPI-287 low dose

TPI-287 20 mg/m2 DRUG

20 mg/m2 of TPI-287 diluted with 500mL 0.9% sodium chloride. TPI-287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class

TPI-287 high dose

Placebo DRUG

500mL 0.9% sodium chloride

Placebo; TPI-287 high dose; TPI-287 low dose; TPI-287 moderate dose

TPI-287 6.3 mg/m2 DRUG

6.3 mg/m2 of TPI-287 diluted with 500mL 0.9% sodium chloride. TPI-287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class

TPI-287 moderate dose

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Between 50 and 85 years of age (inclusive);
• Able to walk 5 steps with minimal assistance (stabilization of one arm or use of cane/walker);
• MRI at Screening is consistent with CBS or PSP (≤ 4 microhemorrhages, and no large strokes or severe white matter disease);
• MMSE at Screening is between 14 and 30 (inclusive);

You may not qualify if:

• FDA-approved Parkinson's medications are allowed as long as the dose is stable for 2 months prior to Screening;
• Has a reliable study partner who agrees to accompany the subject to visits, and spends at least 5 hours per week with the subject;
• Agrees to 2 lumbar punctures;
• Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations;
• Males and all WCBP agree to abstain from sex or use an adequate method of contraception for the duration of the study and for 30 days after the last dose of study drug.
• Adequate contraceptive methods include those with a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as complete abstinence from sexual intercourse with a potentially fertile partner, and some double barrier methods (condom with spermicide) in conjunction with use by the partner of an intrauterine device (IUD), diaphragm with spermicide, oral contraceptives, birth control patch or vaginal ring, oral, or injectable or implanted contraceptives.
• For this study, a woman who has been surgically sterilized or who has been in a state of amenorrhea for more than two years will be deemed not to be of childbearing potential;
• For PSP Only
• Meets National Institute of Neurological Disorders and Stroke - Society for Progressive Supranuclear Palsy (NINDS-SPSP) probable or possible PSP criteria (Litvan et al. 1996a), as modified for the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) clinical trial (Bensimon et al. 2009).
• For CBS Only
• \. Meets 2013 consensus criteria for possible or probable corticobasal degeneration, CBS subtype (Armstrong et al. 2013).
• Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD (McKhann et al. 2011);
• Any medical condition other than CBS or PSP that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);
• A prominent and sustained response to levodopa therapy;
• History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);

Sponsors & Collaborators

• University of California, San Francisco: lead
• CBD Solutions: collaborator
• Tau Consortium: collaborator

Study Sites (2)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

Related Publications (6)

• Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, Boxer AL, Dickson DW, Grossman M, Hallett M, Josephs KA, Kertesz A, Lee SE, Miller BL, Reich SG, Riley DE, Tolosa E, Troster AI, Vidailhet M, Weiner WJ. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013 Jan 29;80(5):496-503. doi: 10.1212/WNL.0b013e31827f0fd1.

  PMID: 23359374 BACKGROUND

• Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, Goetz CG, Golbe LI, Grafman J, Growdon JH, Hallett M, Jankovic J, Quinn NP, Tolosa E, Zee DS. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996 Jul;47(1):1-9. doi: 10.1212/wnl.47.1.1.

  PMID: 8710059 BACKGROUND

• Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN; NNIPPS Study Group. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain. 2009 Jan;132(Pt 1):156-71. doi: 10.1093/brain/awn291. Epub 2008 Nov 23.

  PMID: 19029129 BACKGROUND

• McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.

  PMID: 21514250 BACKGROUND

• Brunden KR, Trojanowski JQ, Smith AB 3rd, Lee VM, Ballatore C. Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease. Bioorg Med Chem. 2014 Sep 15;22(18):5040-9. doi: 10.1016/j.bmc.2013.12.046. Epub 2013 Dec 30.

  PMID: 24433963 BACKGROUND

• Tsai RM, Miller Z, Koestler M, Rojas JC, Ljubenkov PA, Rosen HJ, Rabinovici GD, Fagan AM, Cobigo Y, Brown JA, Jung JI, Hare E, Geldmacher DS, Natelson-Love M, McKinley EC, Luong PN, Chuu EL, Powers R, Mumford P, Wolf A, Wang P, Shamloo M, Miller BL, Roberson ED, Boxer AL. Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2020 Feb 1;77(2):215-224. doi: 10.1001/jamaneurol.2019.3812.

  PMID: 31710340 DERIVED

MeSH Terms

Conditions

Corticobasal Degeneration; Supranuclear Palsy, Progressive; Color Vision Defects

Interventions

TPI-287

Condition Hierarchy (Ancestors)

Tauopathies; Neurodegenerative Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Ophthalmoplegia; Ocular Motility Disorders; Cranial Nerve Diseases; Paralysis; Neurologic Manifestations; Eye Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Vision Disorders; Sensation Disorders; Cone Dystrophy; Eye Diseases, Hereditary

Study Officials

• Adam Boxer, MD, PhD

  UCSF Memory and Aging Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Adam Boxer, M.D., Ph.D.

Study Record Dates

• First Submitted: May 6, 2014
• First Posted: May 8, 2014
• Study Start: May 1, 2014
• Primary Completion: September 1, 2019
• Study Completion: September 1, 2019
• Last Updated: April 15, 2020

Record last verified: 2020-04

Locations

US (2)