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).

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.

The dose of TPI 287 will be escalated in sequential cohorts. In the low dose cohort 11 subjects each diagnosis (i.e., separate dose escalations will be performed for CBS and PSP) will be enrolled. The medium and high dose cohorts will be comprised of 11 subjects; combined CBS and PSPdiagnoses. Subjects will be assigned to cohorts in the order of study entry.

Pre-medications of diphenhyramine 25 mg (Benadryl), dexamethasone 10 mg, and famotidine 20 mg (or the H2 blocker ranitidine 50 mg) will be given IV within 60 minutes prior to each study infusion.

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.

Inclusion Criteria:

1. Between 50 and 85 years of age (inclusive);

2. Able to walk 5 steps with minimal assistance (stabilization of one arm or use of cane/walker);

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

4. MMSE at Screening is between 14 and 30 (inclusive);

5. FDA-approved AD medications are sometimes prescribed for CBS and PSP subjects, and are allowed as long as the dose is stable for 2 months prior to Screening. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to Screening;

6. FDA-approved Parkinson's medications are allowed as long as the dose is stable for 2 months prior to Screening;

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.

    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

11. 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

11. Meets 2013 consensus criteria for possible or probable corticobasal degeneration, CBS subtype (Armstrong et al. 2013).

Exclusion Criteria:

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

2. Any medical condition other than CBS or PSP that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);

3. A prominent and sustained response to levodopa therapy;

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

5. History of significant peripheral neuropathy;

6. History of major psychiatric illness or untreated depression;

7. 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 evaluations;

8. 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;

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

10. Current clinically significant viral infection;

11. Major surgery within four weeks prior to Screening;

12. Unable to tolerate MRI scan at Screening;

13. 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;

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

15. Previous exposure to microtubule inhibitors (including TPI 287) within 5 years of Screening. Treatment with microtubule inhibitors other than TPI 287 while on study will not be allowed;

16. Participation in another interventional clinical trial within 3 months of Screening;

17. 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;

18. Known hypersensitivity to the inactive ingredients in the study drug;

19. Pregnant or lactating;

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

21. Cancer within 5 years of Screening, except for non-metastatic skin cancer or non-metastatic prostate cancer not expected to cause significant morbidity or mortality within one year of baseline.

    For CBS Only:

22. History or evidence at Screening of cortical amyloid levels on 18F florbetapir PET scans consistent with underlying AD;

23. History of serum or plasma progranulin level less than one standard deviation below the normal subject mean for the laboratory performing the assay;

24. History or evidence at Screening of known disease-associated mutations in GRN or C9ORF72 genes to rule out CBS due to TDP-43 pathology;

25. History of known disease-associated mutations in ribosomal protein L3 [TDP- 43 gene (TARBP)], chromatin modifying protein 2B (CHMPB2) or valosin containing protein (VCP) genes or any other frontotemporal lobar degeneration (FTLD) causative genes discovered during the course of the trial and not associated with underlying tau pathology.