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

NCT ID: NCT01966666

Last Updated: 2020-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2019-09-30

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.

Detailed Description

The maximum tolerated dose of TPI-287 will be determined through a planned dose escalation over 3 sequential cohorts, each comprising of 11 participants randomized to either TPI-287 or placebo. TPI-287 or placebo will be administered as an intravenous infusion once every 3 weeks for 9 weeks, for a total of 4 infusions. Participants who successfully complete this phase will have the option of entering into the open label extension phase during which TPI-287 will be administered once every 3 weeks for an additional 6 weeks, for a total of 3 extra infusions.

Pre-medication of diphenhyramine 25 mg (Benadryl) will be given IV within 30 to 60 minutes prior to each study infusion in the study.

Safety and tolerability will be assessed through reporting of adverse events, physical and neurological testing, ECGs, as well as blood and urine analyses. Baseline and end-point measures of cognition and function, MRI brain scans, and cerebrospinal fluid (CSF) biomarker analyses will be used to determine preliminary efficacy of TPI-287 in mild-moderate AD. Pharmacokinetic and pharmacodynamic properties of TPI-287 will be calculated from blood plasma collected after the first infusion, and from CSF collected on the last visit of the placebo-controlled phase.

Conditions

Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: QUADRUPLE

Study Groups

TPI-287 low dose

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)

Group Type: EXPERIMENTAL

TPI-287 2 mg/m2

Intervention Type: 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.

Placebo

Intervention Type: DRUG

500mL 0.9% sodium chloride.

TPI-287 moderate dose

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)

Group Type: EXPERIMENTAL

TPI-287 6.3 mg/m2

Intervention Type: 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.

Placebo

Intervention Type: DRUG

500mL 0.9% sodium chloride.

TPI-287 high dose

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)

Group Type: EXPERIMENTAL

TPI-287 20 mg/m2

Intervention Type: 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.

Placebo

Intervention Type: DRUG

500mL 0.9% sodium chloride.

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

500mL 0.9% sodium chloride.

Interventions

TPI-287 2 mg/m2

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.

Intervention Type: DRUG

TPI-287 6.3 mg/m2

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.

Intervention Type: DRUG

TPI-287 20 mg/m2

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.

Intervention Type: DRUG

Placebo

500mL 0.9% sodium chloride.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Between 50 and 82 years of age (inclusive)

2. Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD dementia (McKhann et al. 2011)

3. MRI at Screening is consistent with AD (≤ 4 microhemorrhages, and no large strokes or severe white matter disease)

4. MHIS at Screening is ≤ 4

5. MMSE at Screening is between 14 and 26 (inclusive)

Exclusion Criteria

7. Has a reliable study partner who agrees to accompany the subject to visits, and spends at least 5 hours per week with the subject

8. Agrees to 2 lumbar punctures

9. Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations

10. 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.

1. Any medical condition other than AD that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia)

2. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof)

3. History of significant peripheral neuropathy

4. History of major psychiatric illness or untreated depression

5. 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

6. 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

7. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection

8. Current clinically significant viral infection

9. Major surgery within four weeks prior to Screening

10. Unable to tolerate MRI scan at Screening

11. 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

12. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule or study evaluations

13. Any previous exposure to microtubule inhibitors (including TPI 287) within 5 years of Screening. Treatment with microtubule inhibitors other than TPI287 while on study will not be allowed

14. Participation in another AD clinical trial within 3 months of Screening

15. Treatment with another investigational drug within 30 days of Screening. Treatment with investigational drugs other than TPI 287 while on study will not be allowed

16. Known hypersensitivity to the inactive ingredients in the study drug

17. Pregnant or lactating

18. Positive pregnancy test at Screening or Baseline (Day 1)

19. Cancer within 5 years of Screening, except for non-metastatic skin cancer.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 82 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Adam Boxer

Prinicpal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Adam L Boxer, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

UCSF Memory and Aging Center

San Francisco, California, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31710340 (View on PubMed)

Other Identifiers

TPI287-AD-001

Identifier Type: -

Identifier Source: org_study_id