A Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of TPI-287 in Alzheimer's Disease

NCT01966666 | Completed Phase 1 DMC

• 1 other identifier: TPI287-AD-001
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to determine the highest dose of TPI-287 that is safe and tolerable when administered as an intravenous infusion to participants with mild to moderate Alzheimer's disease (AD), to measure pharmacokinetic properties of the drug as well as to gauge preliminary efficacy of TPI-287 on disease progression.

Conditions

Alzheimer's Disease

Keywords

Alzheimer's disease; mild to moderate

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose of TPI-287

  Planned dose range of intravenous infusions of TPI-287 administered once every 3 weeks for 9 weeks. The dose will be escalated in 3 sequential cohorts and participants will be monitored for adverse events to determine safety and tolerability.

  up to 13 weeks post initial dosing

Secondary Outcomes (1)

• TPI-287 levels in blood plasma and cerebrospinal fluid

  Screening and Week 10

Other Outcomes (6)

• CSF biomarkers of Alzheimer's disease

  Screening and Week 10

• Brain MRI scan

  Screening and Week 11

• Cognition

  Screening and Week 11

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

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

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.

TPI-287 low 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

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

Eligibility Criteria

• Age: 50 Years - 82 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Between 50 and 82 years of age (inclusive)
• Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD dementia (McKhann et al. 2011)
• MRI at Screening is consistent with AD (≤ 4 microhemorrhages, and no large strokes or severe white matter disease)
• MHIS at Screening is ≤ 4
• MMSE at Screening is between 14 and 26 (inclusive)

You may not qualify if:

• 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.
• Any medical condition other than AD that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia)
• History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof)
• History of significant peripheral neuropathy
• History of major psychiatric illness or untreated depression
• Neutrophil count \<1,500/mm3, platelets \<100,000/mm3, serum creatinine \>1.5 x upper limit of normal (ULN), total bilirubin \>1.5 x ULN, alanine aminotransferase (ALT) \>3 x ULN, aspartate aminotransferase (AST) \>3 x ULN, or INR \>1.2 at Screening or baseline evaluations
• Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of study data
• Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection
• Current clinically significant viral infection
• Major surgery within four weeks prior to Screening
• Unable to tolerate MRI scan at Screening
• Any contraindication to or unable to tolerate lumbar puncture at Screening, including use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to Screening

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

UCSF Memory and Aging Center

San Francisco, California, 94158, United States

Location

Related Publications (1)

• 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

Alzheimer Disease

Interventions

TPI-287

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Adam L Boxer, M.D., Ph.D.

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prinicpal Investigator

Study Record Dates

• First Submitted: October 14, 2013
• First Posted: October 21, 2013
• Study Start: November 1, 2013
• Primary Completion: September 1, 2019
• Study Completion: September 1, 2019
• Last Updated: April 14, 2020

Record last verified: 2020-04

Locations

US (1)