8-K

UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): June 12, 2007

Tapestry Pharmaceuticals, Inc.
(Exact name of registrant as specified in its charter)

Delaware	0-24320	84-1187753
(State of incorporation)	(Commission File Number)	(IRS Employer Identification No.)

4840 Pearl East Circle, Suite 300W
Boulder, Colorado 80301
(Address of principal executive offices and zip code)

(303) 516-8500
(Registrant’s telephone number, including area code)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

o     Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

o     Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

o     Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

o     Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Item 7.01.  Regulation FD Disclosure.

The Company’s executive officers intend to conduct meetings with investors, stockholders and analysts and at investor conferences on or after June 13, 2007.  A copy of the presentation materials to be used at those meetings and from time to time thereafter is filed as Exhibit 99.1 hereto.  The Company does not intend to file any update of these presentation materials.  The fact that these presentation materials are being furnished should not be deemed an admission as to the materiality of any information contained in the materials.

The Company presented data from preclinical studies of TPI 287 at the 2007 Annual Meeting of the American Society of Cancer Research on April 15, 2007.  TPI 287 is a proprietary next-generation taxane being studied for the treatment of various forms of cancer.  A copy of the poster presentation of such data is filed as Exhibit 99.2 hereto.  This presentation was also the subject of a press release issued by the Company on April 15, 2007.  The Company is furnishing this poster presentation so that all information in the poster will be available generally to all persons who wish to review it.  The fact that this presentation is being furnished should not be deemed an admission as to the materiality of any information contained in the presentation.

Item 9.01 Financial Statements and Exhibits.

(d)           Exhibits

The following exhibits are filed with this Current Report on Form 8-K:

Exhibit No.	Description
99.1	Tapestry Pharmaceuticals, Inc. investor presentation materials to be used by the Company’s executive officers at meetings with investors, stockholders and analysts and at investor conferences beginning on or after June 13, 2007, and to be used from time to time thereafter.
99.2	Tapestry Pharmaceuticals, Inc. presentation of data from preclinical studies of TPI 287 at the 2007 Annual Meeting of the American Society of Cancer Research on April 15, 2007.

The information in this Form 8-K and the Exhibits attached hereto shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, except as shall be expressly set forth by specific reference in such filing.

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SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

Date: June 12, 2007	TAPESTRY PHARMACEUTICALS, INC.
	By:	/s/ Kai Larson
	Name:	Kai Larson
	Title:	Vice President, General Counsel

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INDEX TO EXHIBITS

Exhibit No.	Description
99.1	Tapestry Pharmaceuticals, Inc. investor presentation materials to be used by the Company’s executive officers at meetings with investors, stockholders and analysts and at investor conferences beginning on or after June 13, 2007, and to be used from time to time thereafter.
99.2	Tapestry Pharmaceuticals, Inc. presentation of data from preclinical studies of TPI 287 at the 2007 Annual Meeting of the American Society of Cancer Research on April 15, 2007.

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EX-99.1

Exhibit 99.1

Tapestry Pharmaceuticals, Inc. Needham & Company, LLC Biotechnology and Medical Technology Conference June 13, 2007

Forward Looking Statements This presentation contains forward-looking statements. These statements relate to future events or to our future financial performance and involve known and unknown risks, uncertainties and other factors which may cause our actual results, performances or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Each of these statements is based only on current information, estimates and expectations that are inherently subject to change and involve a number of risks and uncertainties. Forward-looking statements include, but are not limited to, statements about our product development efforts, in particular with respect to the clinical trial results and regulatory approval of TPI 287; the initiation, completion or success of preclinical studies and clinical trials; clinical trial initiation and completion dates, anticipated regulatory filing dates and regulatory approval for our product candidates; completion of our proposed public financing; our intentions to expand our capabilities and hire additional employees; anticipated operating losses, future revenues, research and development expenses, and the need for additional financing; our use of proceeds from this offering; and our financial performance. Any statement in this presentation that is not a statement of historical fact should be considered a forward-looking statement. In some cases, you can identify forward-looking statements by terms such as “project,” “believe,” “anticipate,” “plan,” “expect,” “estimate,” “intend,” “potential” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. We discuss many of these risks in the registration statement that we have on file with the Securities and Exchange Commission. The forward-looking statements contained herein are made as of the date hereof, and we undertake no obligation to update or revise them.

TPI 287: Proprietary Next Generation Taxane

More lipophilic than other taxanes A component of the molecule is designed to be hydrophilic How Is TPI 287 Different than other Taxanes? O H O O O H A c O O B z H O A c P h O O O H N H P h O P A C L I T A X E L O H O O O H H O O B z H O A c P h O O O H N H O O D O C E T A X E L O O O H A c O O B z H O A c O O O H N H O O T P I 2 8 7 O

TPI 287: Significantly Differentiated from Currently Marketed Taxanes TPI 287 has demonstrated the potential for: Differentially higher activity than taxanes in resistant tumors (mdr1) Both innately resistant tumors and those which develop resistance Oral activity and bioavailability Enables flexibility of dosing and scheduling for optimal combination therapy with other anti-cancer drugs Crossing the blood-brain barrier CNS tumors (primary or metastatic) Activity in tumors not currently approved for treatment by taxanes

TPI 287 Pre-clinical Biology Studies

TPI 287 is More Active than Comparator Agents in Resistant Cell Lines 55 5.5 Oxaliplatin 0.1000 Liver (resistant) 1.6 0.0072 Docetaxel 0.0046 Lung 80 38 0.8 0.2 Doxorubicin Doxorubicin 0.0100 0.0053 Uterine (resistant) Uterine 1.4 0.124 13.4 17.7 0.05 2.0 0.0003 Comparator IC50* 280 1.6 3900 3600 5.3 200 0.5 Cytotoxicity Index Cisplatin 0.0050 Prostate (resistant) Gemcitabine 0.0763 Pancreas Vincristine Vincristine 0.0034 0.0049 Neuroblastoma (resistant) Neuroblastoma Irinotecan 0.0095 Colon (resistant) Paclitaxel Paclitaxel 0.0100 0.0006 Breast (resistant) Breast Comparator^ TPI 287 IC50* Tumor Cell Line *µM concentrations ^Most effective drug used as comparator for in vitro cytotoxicity studies

Unlike other Taxanes, TPI 287 is not Actively Pumped Out of Cells by mdr1 Efflux Pump 17.40 9.31 paclitaxel 6.17 TPI 287 B->A A->B Compound 27.9 paclitaxel 15.1 22.8 TPI 287 B->A A->B Compound MDCKII-mdr1 permeability rate Caco-2 permeability rate Conclusions: TPI 287 is not a P-gp (mdr1) substrate TPI 287 may be orally bioavailable 4.9 8.39

 Multidrug Resistant Xenografts 0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0 1 11 21 31 41 Day % Tumor Volume TGI = Tumor Growth Inhibition, calculated at day indicated TGI on Day 13 0% 26% 20% 30% 60% Control Paclitaxel Docetaxel Abraxane TPI 287 0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1 11 21 31 Day % Tumor Volume TGI on Day 16 0% 13% 24% 38% 89% Neuroblastoma Colon Cancer

Oral and IV Efficacy of TPI 287 in Glioblastoma Xenograft Model TPI 287 IV Dosing 0 200 400 600 800 1000 1200 1400 1600 1800 2000 1 21 41 61 81 Day % Tumor Volume TPI 287 Oral Dosing 0 100 200 300 400 500 600 700 800 900 1 11 21 31 41 Day % Tumor Volume Control TPI 287

Intracranial Mouse GBM Xenograft Study ILS = Increased Life Span; measured at the median survival time (50% of mice alive) ILS 0% 45% 380% 650% Intracranial Mouse GBM Xenograft Study 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 Days % Survival Control TPI 287 Temozolamide Temozolamide + TPI 287

TPI 287: Pre-clinical Summary In vitro cell lines: Extremely potent activity in multiple cell lines, including tumors of the breast, colon, lung, pancreas, & prostate Greater activity (up to 3000-fold) compared to standard agents in resistant (mdr1 gene expressing) cell lines Tumor Xenograft Studies Greater activity than other taxanes in breast, colon, lung, and prostate tumors models that express mdr1 (resistant) Tumor Orthotopic Xenograft Studies Shows significant antitumor and survival benefit in human glioblastoma intracranially Combination with temozolamide (approved for human therapy of glioblastoma) shows significant additivity Oral bioavailability and efficacy demonstrated Potential for novel scheduling, combinations and strategies

TPI 287: Phase 1 Clinical Trials

Phase 1 Clinical Trials TPI 287-01 Weekly x 3 with one week rest (28 day cycle) Assessment of safety and efficacy after 30 patients enrolled (29 evaluable) Median age 60.5 years (24 – 86) 17 males/13 females TPI 287-02 Once every 3 weeks (21 day cycle) Assessment of safety and efficacy after 21 patients Median age 58 years (35 – 78) 7 males/14 females

Summary of Safety – Weekly Dosing (Based on June, 2007 ASCO presentation) Treatment with 150 mg/m2 well tolerated (Phase 2 recommended dose) with DLTs at 185 mg/m2 (neuropathy) Most patients experience Grades 1 or 2 severity adverse events (more at higher doses) fatigue (52% of patients) constipation (34% of patients) dyspnea (31% of patients) nausea (31% of patients) Severe (Grade 3) adverse events in 17 patients (57%) and Grade 4 in 3 patients (10%) Three patients had Grade 3 neuropathy which proved to be dose-limiting (2 had baseline neuropathy) There were no Grade 3 or 4 myelosuppressive events

Summary of Safety – 21-Day Dosing The MTD of TPI 287 at 160 mg/m2 is the recommended Phase 2 dose with DLTs at 185 mg/m2 (neuropathy and neutropenia) All patients experienced at least one adverse event, most frequently: Anemia (43% of patients) Neuropathy (43% of patients) Diarrhea, nausea, and vomiting (33% of patients) Grade 3 adverse events in 13 patients (62%) and Grade 4 adverse events in 7 patients (33%) Four patients had Grade 3 neuropathy (one had neuropathy at baseline) Three patients had neutropenia (one Grade 3 and two Grade 4) One patient had Grade 3 anemia

TPI 287: Summary of Efficacy Confirmed Partial Response in Pancreatic Cancer -> 11+ cycles in 21-day dosing schedule (51% decrease by RECIST)

TPI 287: Summary of Efficacy Response in Non-Small Cell Lung Cancer -> 57% decrease by RECIST over two cycles administered weekly

TPI 287: Summary of Efficacy Stable Disease Breast cancer Therapy over 4 previous months with progressive disease Stable disease over 7 cycles (21-day dosing) Pancreatic cancer Over 3 cycles in weekly dosing regimen 15% decrease by RECIST

TPI 287: Interesting Activity and Profile Data from Phase 1 Clinical Trials Presented at ASCO 2007 Two Phase 1 Clinical Trials Completed Weekly (3 out of 4 weeks) and once every 3 weeks Well tolerated in heavily pretreated patient population Achieved dose recommended for Phase 2 Side Effect profile Few serious myelosuppressive events Dose limiting toxicity neuropathy, usually exacerbation of prior neuropathy Efficacy Four patients showed clinical benefit Tumors that had been exposed to taxanes (lung, breast) Tumors that are not generally sensitive to taxanes (pancreatic)

TPI 287: Phase 2 Clinical Trial Designs

Hormone Refractory Prostate Cancer 80 Patients resistant to taxane therapy Stratify 40 Patients 40 Patients Innate Resistance < 3 months on taxanes Developed Resistance 3 months on taxane (Up to 10 cycles) Open-label, multi-center trial Dosing regimen: Q21 days, with potential for dose modification Go/No Go based on first 22 patients per strata TRIAL DESCRIPTION PRIMARY ENDPOINT / OBJECTIVE SECONDARY ENDPOINT Reduction in the level of the patients' prostate-specific antigen (PSA) or The "Response Evaluation Criteria in Solid Tumors" in patients with measurable disease, or Reduction in pain and/or analgesic use Patient's time to progression Currently ongoing Study to be completed in 1H 2008 TIMING

Glioblastoma Multiforme / Primary CNS Tumors Open-label, multi-center trial Up to 50 patients Patients with GBM that has recurred or progressed following prior radiation and temozolomide therapy Dosing regimen: Q7 days x 3 Q28 days Go/No Go based on 6 month PFS Six-month progression free survival (PFS) Evaluate any response to treatment including adverse events Initiate in the summer of 2007 Open-label, multi-center dose escalation trial Up to 60 patients Patients whose condition has recurred or progressed following prior temozolamide therapy Determine MTD of the combination of TPI 287 and temozolomide Response to treatment Pharmacokinetics of both TPI 287 and temozolomide Initiate in 2H 2007 PHASE II TRIAL: AS SINGLE AGENT IN GBM PHASE Ib/II TRIAL: IN COMBINATION WITH TEMOZOLAMIDE FOR 1o CNS TUMORS TRIAL DESCRIPTION PRIMARY ENDPOINT / OBJECTIVE SECONDARY ENDPOINT TIMING

Pancreatic Cancer 200 Patients after failure of gemcitabine therapy Randomize 100 Patients 100 Patients TPI 287 Fluoropyrimidine therapy (5-FU, Capecitabine) Randomized, multi-center trial Dosing regimen for TPI 287: Q7 days x 3 Q28 days, with potential for dose modification Evaluate subpopulations based on prognostic scores (e.g. tumor size, grade, CA 19-9 at baseline) TRIAL DESCRIPTION PRIMARY ENDPOINT / OBJECTIVE SECONDARY ENDPOINT Overall survival Evaluate progression-free survival, response, adverse events to treatment Initiate in 2H 2007 TIMING

TPI 287 Clinical Development Plan Development Stage Dosage Form Indication Pre - Clinical Phase I Phase II Phase III Next Milestone / Timing Hormone Refractory Prostate Cancer Complet e Ph ase II 1H 20 0 8 Glioblastoma Multiforme Initiate Ph ase II Summer 2 007 Primary CNS tumors ( Combination with temozolamide) Initiate Phase Ib 2H 2007 Pancreatic Cancer Initiate Ph ase II Summer 2 007 IV Exploratory Phase II (Multiple Tumor Types) Start dates : 2 H2007 – 1H 2008 Multiple Cancers Initiate P h ase lb/II PK study Summe r 2007 Oral Combination Trial (Tumor type TBD) Initiate Phase Ib/ II 2H 2007

Market and Corporate Overviews

Overview of WW Branded Taxane Market Source: Public Company Filings (a) Compound Annual Growth Rate (CAGR) for Abraxane covers 2005-2006 (Revenue in millions) (a) Opportunity for TPI 287 to grow the taxane market Taxanes are not currently used in several areas: Brain tumors Resistant tumors Oral dosage forms Combination therapy with other anti-cancer therapy with hematological toxicity 2000 - 2006 CAGR 4.6% 30.8% 21.4% (15.6%) $1,561 $1,112 $857 $934 $991 $747 $563 $686 $898 $1,188 $1,538 $1,784 $2,000 $2,198 $134 $175 $2,247 $2,936 $2,881 $2,775 $2,473 $2,046 $2,010 0 1,000 2,000 $3,000 2000 2001 2002 2003 2004 2005 2006 Taxol Taxotere Abraxane

Operating and Balance Sheet Data as of March 28, 2007 (in thousands, unaudited) Operating expenses (First Quarter 2007) Research and development $2,893 General and administrative 1,776 Operating loss 4,669 Other income (263) Net loss* $4,406 Cash, cash equivalents, short-term investments $18,198 Total assets $20,757 Long term debt, net $84 Total stockholders’ equity $18,338 Total shares outstanding 16,374 Outstanding options and warrants 19,507 * Includes non-cash equity compensation expense of $829K

Leonard Shaykin Chairman and CEO Donald Picker, Ph.D. President – Genta (Genasense®), Johnson Matthey (Carboplatin, Satraplatin and Picoplatin), GSK Sandra Silberman, M.D., Ph.D. CMO – Eisai (Halichondrin), Novartis (GleevecTM), Pfizer (TarcevaTM) Gordon Link CFO – Synergen, Deloitte & Touche Martin Batt COO – Grisanti, Galef & Goldress James McChesney, Ph.D. CSO – Natural Products Chemistry - Director of Research Institute of Pharmaceutical Sciences and former Chairman of the Department of Pharmacognosy, University of Mississippi David Emerson, Ph.D. VP of Cancer Biology - OSI, Gilead and GSK Gilles Tapolsky, Ph.D. VP of Product Development - Rhone Poulenc Rorer, Flamel Technologies Management Team

Scientific Advisory Board Paul A. Bunn, Jr., M.D. (Chair) Director of the University of Colorado Cancer Center, past president of American Society of Clinical Oncology (2002-2003), and former chairman of the Oncologic Drugs Advisory Committee (ODAC) for FDA S. Gail Eckhardt, M.D. Professor of Medicine and Director of the Developmental Therapeutics and GI Malignancies Programs at the University of Colorado Health Sciences Center in Denver Eric K. Rowinsky, M.D. CMO, Imclone, Former Director of the Institute for Drug Development, Cancer Therapy and Research Center and Clinical Professor of Medicine at the University of Medicine at the University of Texas Health Science Center at San Antonio Daniel D. Von Hoff, M.D. Professor of Medicine, Pathology, Molecular and Cellular Biology and the Director of the Arizona Health Sciences Center’s Cancer Therapeutics Program Susan Band Horwitz, Ph.D. Distinguished University Professor, Rose C. Falkenstein Professor of Cancer Research, and Co-Chair of the Department of Molecular Pharmacology at the Albert Einstein College of Medicine. Associate Director for Therapeutics at the Albert Einstein Cancer Center Patricia A. Pilia, Ph.D. Co-founder and Former Executive Vice President of Tapestry Pharmaceuticals, Former Assistant Professor of Pathology and Assistant Director of the Immunopathology Diagnostic and Research Laboratories in the Colleges of Medicine, Dental Medicine and Graduate Studies at the Medical University of South Carolina

Leonard P. Shaykin Chairman of the Board, Chief Executive Officer Stephen K. Carter, M.D. Former Senior Vice President, Worldwide Clinical Research and Development, Bristol-Myers Squibb and Deputy Director, Division of Cancer Treatment, National Cancer Institute George M. Gould, Esq. Attorney, Of Counsel, Gibbons, Del Deo, Dolan, Giffinger & Vecchione; formerly Vice President and Chief Patent Counsel of Hoffman-La Roche Arthur Hull Hayes, Jr., M.D. President, MediScience Associates a pharmaceutical consulting company; Former FDA Commissioner The Honorable Richard N. Perle Former U.S. Assistant Secretary of Defense Robert E. Pollack, Ph.D. Professor of Biological Sciences and Director of the Center for the Study of Science and Religion at Columbia University Elliot M. Maza, J.D., C.P.A. President and Chief Financial Officer of Intellect Neurosciences; formerly Partner at Ernst & Young and employed at Goldman Sachs & Co, and J.P. Morgan Securities Board of Directors

Investment Rationale Proprietary next generation taxane Potential for best in class Multiple Phase II programs Experienced oncology drug development team Large commercial opportunity Strong cash position Modest burn rate

Strategies for Life TM

EX-99.2

Exhibit 99.2

TPI 287 crosses the blood brain barrier and contributes to antitumor activity in the U251 glioblastoma intracranial tumor model in nude mice

David L. Emerson, Mark Jones, Carol Bell, Eric Brown - Tapestry Pharmaceuticals, Inc. (Boulder, CO)

Introduction

A major hurdle in the development of new brain tumor treatments is the ability of drugs to sufficiently cross the blood-brain barrier and achieve therapeutic drug levels. The taxanes, paclitaxel and docetaxel, have contributed significantly to therapeutic modalities in solid tumors of lung, ovarian, and breast, but have contributed little to the treatment of primary brain tumors such as glioblastoma. TPI 287 is a new taxane in development which avoids the MDR1 efflux pump, a major component in forming the blood-brain barrier. We examined the ability of TPI 287 to accumulate in brains of rodents. In addition, efficacy studies were performed in xenografts as single agent and in combination.

Methods

Chemical Structure of TPI 287

C46H63NO15
Mol. Wt. 869.99
(2’R,3’S)-2’-hydroxy-N-carboxy-3’-amino-5’-methyl-hexanoic,N-tert-butyl ester, 13 ester 5b-20-epoxy-1,2µ,4,7b,9µ,10µ,13µ-heptahydroxy-4,10-diacetate-2-benzoate-7,9-acrolein
 acetal-tax-11-ene

MDR1 P-glycoprotein Drug Efflux Pump Structural Model

MDR1 strucutre courtesy of the American Society of Biochemistry and Molecular Biology.
Seigneuret and Garnier-Suillerot, 2003, J. Biol. Chem. 278(32): 20115-30124.

Blood-Brain Barrier Penetrance Studies

TPI 287 was prepared fresh each day by formulating in 5% ethanol: 5% Cremophor EL: 90% D5W. For rat studies, male Spraque Dawley rats weighing between 225-275 g were dosed with 20mg/kg TPI 287, iv via tail vein. At specified times (5 rats per sample time), 15 min, 2 and 6 hr post-dose, samples were collected. Cerebrospinal fluid (CSF) was collected under isoflurane anesthesia, from the cisterna magna. A terminal blood sample was collected from each rat via cardiac puncture, using K2EDTA as anticoagulant, and plasma processed immediately. Whole brains were removed by dissection, collected on wet ice, weighed, and stored at -200C with all other samples until assayed.  For mouse experiments, male CD-1 mice weighing 20-30 g were dosed at 20 mg/kg TPI 287, iv via tail vein. Samples were collected at 5, 15 min, 2, 8, 32, 48, 72 and 96 hr post dose (4 mice per sample time). Terminal blood samples were collected and brains processed in identical fashion to rat study. No attempts were made to measure TPI 287 in mouse CSF.

The quantitation of TPI 287 was performed with an LC/MS/MS method with internal standards for plasma and brain homogenates.  CSF samples were run against the plasma standard curve. Duplicate standard curves were run before and after sample analysis. Calibration curves consisted of standards prepared in blank plasma and blank brain homogenates. A minimum of 5 standards were run for each curve with LLOQ @ 3nM (approx. 2.6ng/ml).

In Vivo Efficacy Studies

TPI 287 was evaluated in established U251 glioblastoma tumor xenografts. The primary endpoints for these experiments included mean tumor growth inhibition (TGI) or regression. Dosing of vehicle control and TPI 287 was based on a treatment schedule of q4dx3. Female Balb/c nude mice 8 weeks of age were acquired from NexGen BioSciences, (San Diego, CA) and acclimated for 4 days after arrival prior to sub-cutaneous implant of 5-10 X 106 tumor cells. Mice were observed daily for tumor growth. When tumor volume reached 100-300 mg, groups of 8 mice each were randomly assigned, and treatment with test articles was begun.  Tumor volumes were calculated by use of the formula:

Tumor Weight (mg)	=	Width2 (mm) x Length (mm)
		2

Tumor volumes and body weights were measured twice weekly. The study was terminated when the tumors reached an average size of approximately 2 grams.

Tumor Growth Inhibition

Tumor growth inhibition (%TGI) = 100(1-Wt/Wc); Wt = median tumor volume of treated group at time x; Wc= median tumor volume of control group at time x.

Log Cell Kill (LCK) = (T-C)/(3.32xTd); T is time in days for median tumor volume to reach 2 doublings in treated group; C is time in days for control group; Td is the tumor doubling time in days; Cures are excluded from T-C calculations.

Human U251 tumor cells, 1x106, were implanted intracerebrally (ic) with a 25 gauge needle in six-weeks-old male athymic NCR-nu/nu mice purchased from Taconic Farms (Germantown, NY). Day 1 after tumor implantation, animals were randomly assigned to treatment groups (n=10), and drug treatment initiated on a q4dx3 schedule. On each day of treatment, the appropriate amount of TPI 287 was formulated in 3% Cremophor® EL / 7% ethanol / 90% D5W at a concentration of 2 mg/mL.  A portion of this solution was then diluted with the complete vehicle to achieve the lower dosing concentration of 1.2 mg/mL.  Both concentrations of TPI 287 were then kept at 370C and injected within 30 minutes of formulation on the basis of exact body weight using a volume of 0.1 mL/10 g of body weight.  Temozolomide (Temodar®) was prepared on each day of injection in Klucel + Tween® 80 at a concentration of 4 mg/mL.  Temozolomide was administered within 5 minutes of formulation on the basis of exact body weight using a volume of 0.2 mL/10 g of body weight. The experiment consisted of five treatment groups of ten mice per group and a vehicle-treated control group with ten mice for a total of 60 mice on the first day of treatment.  TPI 287 was administered alone and in combination with temozolomide at dosages of 20 and 12 mg/kg/dose given intravenously (iv) every fourth day for a total of three injections (q4dx3).  Temozolomide was administered alone and in combination with TPI 287 at a dosage of 80 mg/kg/dose given by oral gavage (po) on a q4dx3 schedule.  In the combination groups TPI 287 was given 2 hr before the temozolomide. The control group (group 1) was treated with 3% Cremophor® EL / 7% ethanol / 90% D5W, which was administered iv on a q4dx3 schedule. Animals were monitored daily, and weighed twice weekly starting at first day of treatment. The study was terminated 100 days after tumor implantation, and any animal found moribund or whose body weight dropped below 14 g was euthanized. The number of 100-day survivors, median day of death, and the increase in lifespan based on median day of death was expressed as a percentage (%ILS). Statistical analysis was conducted using a life tables analysis (stratified Kaplan-Meier estimation followed by the Mantel-Haenszel log-rank test).  All animal studies were performed under approved IACUC protocols. The brain and CSF distribution studies were performed in rats and mice at Quest Pharmaceutical Services, and the U251 orthotopic tumor study was performed at Southern Research Institute. The sub-cutaneous tumor studies were performed at Tapestry Pharmaceuticals.

Results

Brain and CSF distribution of TPI 287 after single intravenous dose in rats is shown in Table 1, Figure 1. The CSF concentration of TPI 287 was only detectable at the earliest time point and is most likely due to very high protein binding of drug. The plasma concentration time curve shows typical drug elimination profile with limited sampling time, while the brain concentration of TPI 287 remains high throughout the 6 hours of sampling. The mouse plasma and brain concentrations of TPI 287 are shown in Table 2, Figure 2. The plasma concentration time curve shows typical PK profile while the brain concentration time curve shows a significant accumulation and longer tissue residence time. Table 3 further illustrates this difference where the Brain/Plasma ratio of TPI 287 increases with time. The mean brain concentration of TPI 287 at 96 hr post drug dose is 261+/-18 nM. Figure 3, Table 4 show the efficacy results of TPI 287 as single agent or dosed in combination with temozolomide. The single agent activity of TPI 287 was statistically significant relative to vehicle dose control group, but not as impressive as the combination dose results. The better response was seen in the combination group with the lower TPI 287 dosage, possibly because of toxicity of TPI 287 at the 20mg/kg/dose. While the effect of the combination treatment was very good, only the lower dosage of TPI 287 elicited a response that was statistically better than that of temozolomide alone. Figure 4 illustrates the efficacy of TPI 287 in the U251 glioblastoma subcutaneous xenograft model, and demonstrates nearly identical activity when dosed iv or orally. This further illustrates the potential of TPI 287 as a taxane which can be dosed as an oral chemotherapeutic agent. Finally, Figure 5 compares the efficacy of TPI 287 to the currently approved taxanes in a neuroblastoma xenograft model which is inherently resistant to chemotherapy. When compounds were dosed at equal toxic levels on a single cycle of therapy, TPI 287 demonstrated superior activity in this model.

Table1.  TPI-287 Concentrations in Rats Plasma, Brain, and CSF after a Single 20 mg/kg IV Dose

	Plasma Concentration (nM)
	Rats	Rats	Rats	Rats	Rats
Time (hr)	#1, 6, 11	#2, 7, 12	#3, 8, 13	#4, 9, 14	#5, 10, 15	Mean	SD
0.2	8613.490	12699.817	8993.649	455.084	11530.596	10459.388	1976.759
2	910.649	1587.472	1093.502	937.552	1521.184	1210.072	322.773
6	273.369	313.026	422.079	389.657	253.679	330.362	73.070

Rat #4, shown in red, was excluded as an outlier.

Brain TPI-287 Concentrations in Rats after a Single 20 mg/kg IV Dose

	Brain Concentration (nM)
	Rats	Rats	Rats	Rats	Rats
Time (hr)	#1, 6, 11	#2, 7, 12	#3, 8, 13	#4, 9, 14	#5, 10, 15	Mean	SD
0.25	4100.318	6637.070	6332.098	86.182	4143.134	5303.155	1369.978
2	3800.679	4161.607	4730.760	4229.314	4692.949	4323.062	390.760
6	4131.079	5014.374	4177.129	4181.375	4710.513	4442.894	398.265

Rat #4, shown in red, was excluded as an outlier.

CSF TPI-287 Concentrations in Rats after a Single 20 mg/kg IV Dose

	CSF Concentration (nM)
	Rats	Rats	Rats	Rats	Rats
Time (hr)	#1, 6, 11	#2, 7, 12	#3, 8, 13	#4, 9, 14	#5, 10, 15	Mean	SD
0.25	17.885	190.955	0.000	NC	12.050	9.978	9.121
2	BQL	BQL	BQL	BQL	BQL	BQL	NC
6	BQL	BQL	BQL	BQL	BQL	BQL	NC

BQL<5.000 ng/mL;  Some values may be listed as 0.000 for averaging.

NC = not calculated

Rat #4, shown in red, was excluded as an outlier.

Rat #2, shown in red, was excluded because CSF indicated the presence of blood.

Brain/Plasma TPI-287 Concentration Ratios in Rats after a Single 20 mg/kg IV Dose

	Brain/plasma Concentration ratio
	Rats	Rats	Rats	Rats	Rats
Time (hr)	#1, 6, 11	#2, 7, 12	#3, 8, 13	#4, 9, 14	#5, 10, 15	Mean	SD
0.25	0.476	0.523	0.704	NC	0.359	0.516	0.143
2	4.174	2.622	4.326	4.511	3.085	3.743	0.838
6	15.112	16.019	9.897	10.731	18.569	14.065	3.664

Figure 1. Plasma and Brain Concentration of TPI 287 After Single IV Dose in Rats.

Table 2 TPI 287 PK Parameters in Mice after Single IV Dose

Brain	Plasma
Cmax ng/ml 3726.6	Cmax ng/ml 1550.2
AUC(0-96) ng-hr/ml 64984.9	AUC (0-96) ng-hr/ml 16870.2
AUC (0-¥) ng-hr/ml 88742.9	AUC (0-¥) ng-hr/ml 16951.2
MRT (expo)hr 42.5	MRT (expo)hr 17.6
CL ml/hr 0.006	CL ml/hr 0.024

Figure 2. TPI 287 Concentration Time Curve in Mice after Single 20mg/kg IV Dose

Table 3.  Brain/Plasma TPI-287 Concentration Ratios in Mice After a Single 20 mg/kg IV Dose

	Brain/Plasma Concentration Ratio
Time  (hr)	Mice  replicate  1	Mice  replicate  2	Mice  replicate  3	Mice  replicate  4	Mean	SD
0.083	1.586	1.233	0.984	1.044	1.212	0.271
0.25	2.968	2.176	1.584	2.537	2.316	0.586
2.0	2.032	3.869	3.624	3.511	3.259	0.831
8.0	13.707	3.857	3.893	3.000	6.114	5.079
24.0	16.163	10.743	6.445	7.107	10.115	4.453
32.0	11.754	13.095	15.169	7.181	11.800	3.384
48.0	90.601	32.147	35.674	12.142	42.641	33.611
72.0	71.597	109.392	17.686	25.426	56.025	42.805
96.0	48.579	105.511	22.377	78.702	63.792	36.099

Figure 3. U251 Orthotopic Xenograft Study

U251 Orthotopic Xenograft Study

Table 4. TPI 287 Increases Survival in the U251 Orthotopic (Intracranial) Xenograft Study

Group		Increased		#
Number		Life Span		Survivors
(N=10)	Treatment	(ILS)		(Day 100)	P values
1	Control	0		0	NA
2	TPI 287 20mg/kg,	60	%	0	1 vs.2,
	iv. QD1,5,9				P= 0.000
3	TPI 287 12mg/kg,	45	%	0	1 vs. 3,
	iv. QD1,5,9				P= 0.000
4	TMZ 80mg/kg, po.	380	%	1	2 vs. 3,
	QD1,5,9				P= 0.450
5	TMZ 80mg/kg, po.	575	%	1	4 vs. 5,
	+ TPI 287 20mg/kg				P= 0.683
	iv. QD1,5,9
6	TMZ 80mg/kg, po.	650	%	3	4 vs. 6,
	+ TPI 287 12mg/kg				P=0.046
	iv. QD1,5,9				5 vs. 6,
					P=0.108

Figure 4. Oral and IV Efficacy of TPI 287 in
Glioblastoma Xenograft Model

Figure 5. TPI 287 is More Active Than Other
Taxanes in the Multidrug Resistant Neuroblastoma
Xenograft Model

Conclusions

TPI 287 crosses the blood brain barrier in rodents with long tissue residence time.

In U251 ic. tumor model TPI 287 shows single agent and combination antitumor efficacy.

When dosed iv. or po. TPI 287 has comparable antitumor activity in U251 subcutaneous tumors.

TPI 287 outperforms other taxanes in SK-N-FI neuroblastoma xenograft which is inherently resistant to chemotherapy.

TPI 287 may have utility in brain cancer.

References

(1).Fomchenko, E. I., Holland, E. C. Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res. 2006; 12:5288-5297.

(2).Gallo, J. M., Li, S., Guo, P., Reed, K., Ma, J. The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice. Cancer Res. 2003; 63:5114-5117.

(3).Schabel, F., Griswold, D., Laster, W., Corbett, T., Lloyd, H. Quantative evaluation of anticancer agent activity in experimental animals. Pharmac Ther. A. 1977; 1:411-435.

(4).Emerson, D. L., Bell, C., Jones, M.E., Scheimann, B., Tapolsky, G.  Oral bioavailability and antitumor activity of TPI 287 — a new taxane analog with greater activity against tumor cells with mutant tubulin.  2006, AACR Annual Meeting Abstract/Poster 493.

(5).Jones, M. E., Bell, C., Schiemann, B., McChesney, J. D., Emerson, D. L.  Biological Characterization of TPI 287 — A Novel Third Generation Taxane Analog.  2005, Molecular Targets and Cancer Therapeutics Meeting, AACR-NCI-EORTC, Abstract/Poster B232.

(6).Helson, L., Jones, M. E., Carnathan, C., Pilia, P. A., McChesney, J. D.  Preclinical Assessment of TPI 287 — A novel third generation taxane analog.  2005, AACR Annual Meeting, Abstract/Poster 341.

(7).Helson, L., Ferrara, J., Jones, M., McChesney, J.  NBT-287 (TPI 287), a third generation taxane analog, and paclitaxel resistance due to MDR-1 and mutant tubulin.  Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings; 22 (14S): Abstract 3114.