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Epothilones in Breast Cancer

Epothilones in Breast Cancer. Sandra M. Swain, MD December 7, 2005. Sandra Swain, MD. No financial relationships with any commercial interest. Recent Advances in the Development of Microtubule-Stabilizing Agents. Microtubule-stabilizing agents Epothilones

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Epothilones in Breast Cancer

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  1. Epothilones in Breast Cancer Sandra M. Swain, MD December 7, 2005

  2. Sandra Swain, MD No financial relationships with any commercial interest

  3. Recent Advances in the Development of Microtubule-Stabilizing Agents • Microtubule-stabilizing agents • Epothilones • Ixabepilone (BMS-247550) trial at NCI • Clinical outcome • Evaluation of neurotoxicity • Translational study • Other ixabepilone trials in breast cancer

  4. Sorangium cellulosum • Myxobacteria • Secondary metabolites (epothilones/fungicides) Zambezi river

  5. Paclitaxel Epothilone A Epothilones Bind Specifically and Uniquely to Beta-Tubulin • Thiazole side-chain occupies the region of binding site not occupied by taxanes • Only 1 polar contact point (C7-OH) is shared with taxanes EpoA and paclitaxel bound to beta-tubulin Nettles. Science. 2004;305:866-869.

  6. Epothilones Are Strong Promoters of Tubulin Polymerization • Epothilone B has tubulin polymerizing activity 2-10 times stronger than paclitaxel 1, Paclitaxel; 2, EpoA; 3, EpoB Kowalski. J Biol Chem. 1997;272:2534.

  7. 6 Paclitaxel Ixabepilone (epothilone B analog) 5 4.5 3.1 4 Log cell kill at MTD 3 2 0.4 1.3 1 HCT/VM46MDR (Colon Ca) 0 PAT-7MDR/MRP (Ovarian Ca) Epothilones Are Less Susceptible to MDR Than Paclitaxel • Poor substrates for MDR proteins • MDR expression not altered in epothilone- resistant cell lines Modified from Data on file, Bristol- Myers Squibb Company.

  8. Potential Advantages of Epothilones • Bind specifically and uniquely to beta-tubulin • Epothilone B has 2- to 10-fold greater polymerizing activity than paclitaxel • No steroid premedication needed • Less susceptible to multidrug resistance (MDR) • Poor substrates for MDR proteins • MDR expression not altered in epothilone-resistant cell lines

  9. Epothilones NAME Derivative DEVELOPER PHASE Ixabepilone Epothilone B Bristol-Myers Squibb III Patupilone Epothilone B Novartis III KOS-862 Kosan/Roche II Epothilone D BMS-310705 Epothilone B Bristol-Myers Squibb I ZK-EPO Epothilone B Schering AG II

  10. Ixabepilone (BMS-247550) • Epothilone B is a natural macrolide produced by the myxobacterium Sorangium cellulosum • Ixabepilone is a semisynthetic analog of epothilone B (aza-epothilone B) Epothilone B Ixabepilone

  11. Antitumor Activity in Taxane-Resistant PAT-21 Breast Cancer Xenografts Control Control Ixabepilone (13 mg/kg, MTD) Ixabepilone(10 mg/kg, MTD) Docetaxel (20 mg/kg, MTD) Paclitaxel (36 mg/kg, MTD) Vinorelbine (9 mg/kg, MTD) 1000 1000 Median tumor wt. (mg) Median tumor wt. (mg) 100 100 10 10 40 70 100 130 160 40 50 60 70 80 90 Days posttumor implantation Days posttumor implantation PAT-21 breast cancer xenografts are derived from a patient with MBC who received 10 cycles of CMF, then 4 cycles of paclitaxel. MTD=maximum tolerated dose. Data on file, Bristol-Myers Squibb Company.

  12. Ixabepilone Pharmacology MTD=maximum tolerated dose; DLT=dose-limiting toxicity; q=every. Goodin. J Clin Oncol. 2004;22:2015-2025.

  13. Phase I Trials of Ixabepilone • Ixabepilone IV over 1 hr, 5 days every 21 days (N=27) • Objective responses in patients with cervical, breast, and basal cell cancer • Ixabepilone IV over 1 hr, 1 day every 21 days (N=25) • Objective PRs in paclitaxel-refractory ovarian cancer (N=2) and breast cancer (1 taxane-naїve, 1 taxane-refractory) • Ixabepilone IV over 1 hr, 3 days every 21 days (N=26) • DLT: neutropenia • Prolonged SD in patients with mesothelioma, ovarian cancer, and renal cell carcinoma Abraham.J Clin Oncol. 2003;21:1866-1873; Mani. Clin Cancer Res. 2004;10:1289-1298; Zhuang. Cancer. 2005;103:1932-1938.

  14. Ixabepilone in Metastatic and Locally Advanced Breast Cancer Phase II Trial NCI-0229 Taxane Naïve and Prior Taxane Treated Group Cycle 1 (3 weeks) Cycle 2 Cycle 3… Daily x 5 Daily x 5 Daily x 5 Post-treatment biopsy Baseline biopsy 6 mg/m2/day

  15. Clinical Response to Ixabepilone NCI-0229 Low. J Clin Oncol. 2005;23:2726-34.

  16. Case StudyComplete Response Baseline After 11 Cycles

  17. Ixabepilone Phase II Trial NCI-0229: Grade 3/4 Toxicities Low. J Clin Oncol. 2005;23:2726-34.

  18. Incidence of Peripheral Neuropathy During Ixabepilone Treatment: NCI 0229

  19. Tools for Neurotoxicity Assessment • In addition: • Questionnaire (intensity and frequency of symptoms) • Balance Testing (Tandem Stance and Modified Romberg) • Nerve Conduction Studies • Physical exam • CTC grading Semmes Weinstein Filaments Grooved Peg Board Test Jebsen Test of Hand Function

  20. Matched Pair Study • Each patient who developed grade 2+ neuropathy was matched to a patient who did not • Patients matched by age, cumulative dose of taxane therapy, length of time on study, number of prior regimens Median Difference Between Matched Subjects *P < 0.05; **P < 0.01

  21. Exploratory Univariate Analysis • Hypothesis: Test scores above a certain cutpoint would indicate high likelihood of developing neuropathy Example: Baseline score for Jebsen Test of Hand Function using non-dominant hand For scores greater than 55, median time for neuropathy was 4 months from cycle 3

  22. Functional Tests May Predict Development of Neuropathy • Low incidence of neuropathy with ixabepilone on daily x 5 schedule • Grade 2: 24% • Grade 3: 5% • Grade 4-5: 0% • Grooved Peg Board Test and Jebsen Test of Hand Function most often correlated and predicted ixabepilone-induced grade 2-3 neuropathy

  23. Summary: NCI-0229 • Good clinical activity in heavily pretreated breast cancer patients (RR=22%) and taxane naïve patients (RR=43%) • Grade 3/4 sensory peripheral neuropathy in 3% of patients • Baseline neurologic functional tests may predict grade ≥ 2 peripheral neuropathy

  24. Ixabepilone Phase II Clinical Trials in Metastatic Breast Cancer *Taxane-pretreated. †Anthracycline-pretreated; Ixabepilone 40 mg/m2 q3wk; Roche et al. ASCO 2003;22:18. Abstract 69. ‡Taxane-refractory; Ixabepilone 40 mg/m2 q3wk; Thomas et al. ASCO. 2003;22:8. Abstract 30.

  25. Incidence of Peripheral Neuropathy With Ixabepilone

  26. Incidence of Sensory Neuropathy With Microtubule-Stabilizing Agents

  27. Phase III Clinical Trials ofIxabepilone Plus Capecitabine Capecitabine 1250 mg/m2 bid x 14 days Randomized Ixabepilone 40 mg/m2 q3wk plus Capecitabine 1000 mg/m2 bid x 14 days

  28. Ixabepilone Shows Synergy With Trastuzumab In Vivo Lee. ASCO 2005. Abstract 561

  29. Ixabepilone + Pegylated Liposomal Doxorubicin: Metastatic Breast Cancer • Phase I/II study (PI: Ellen Chuang, MD, Weill Cornell) • Previously treated metastatic breast, ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer • Ixabepilone + pegylated doxorubicin (PLD) IV Day 1 every 21 days • Phase I (dose escalation): Ixabepilone over 3 hours + PLD over 30-60 min • Phase II: Ixabepilone at MTD (determined in phase I) plus fixed phase I PLD dose • Endpoints: MTD, safety, efficacy http://www.clinicaltrials.gov/ct/show/NCT00182767

  30. Trastuzumab + Ixabepilone in HER2+ Metastatic Breast Cancer • Ongoing phase II (PI: Craig Bunnell, MD, Dana Farber) • Women with stage IV/recurrent HER2+ metastatic breast cancer (3+ by IHC or FISH+) • Prior therapy • Cohort 1: No prior treatment for metastatic breast cancer except hormone therapy • Cohort 2: Prior chemotherapy + trastuzumab • Trastuzumab + ixabepilone IV Day 1 every 21 days • Primary objective, response rate http://www.clinicaltrials.gov/ct/gui/show/NCT00079326

  31. Trastuzumab, Ixabepilone and Carboplatin in HER2+ MBC • Phase II trial (PI: Stacy L. Moulder, MD) • Patients with HER2+ metastatic breast cancer • No prior chemotherapy for metastatic disease • Primary objective, response rate • Treatment schedule • Trastuzumab IV on Days 1, 8, 15, and 22 • Ixabepilone + carboplatin IV on Days 1, 8, and 15 • Treatment every 28 days for ≤ 6 cycles in the absence of unacceptable toxicity http://www.clinicaltrials.gov/ct/gui/show/NCT00077376

  32. Can we predict which patients will respond and which are resistant?

  33. Status of Microtubule Assembly May Dictate Drug Sensitivity (Cabral Model) Sensitive to Stabilizing Agents Increased Microtubule Assembly Functional Microtubules Resistant to Stabilizing Agents Decreased Microtubule Assembly Barlow. J Cell Sci. 2002;115:3469.

  34. Post-translational Modifications of α-Tubulin Ac GEEY H2N 40 Acetylation α-Tubulin GEEY H2N Detyrosination GEE H2N • These modifications occur in α-tubulins in MTs (not free form), and are correlated with stable microtubules.

  35. Ixabepilone May Enhance Microtubule Stability Preferentially in Tumor Cells Acetylated Tubulin = Tumor = Stromal Staining Patient 1 (PR) Patient 5 (PD) Baseline Cycle 2

  36. Genes Identified That Correlated With Ixabepilone Sensitivity Sensitive Resistant Cell lines Sensitivity markers High Expression level Low Resistance markers Lee. ASCO 2005.

  37. Novel Agents

  38. Kinase Inhibitors Involved With Mitosis NAME TARGET DEVELOPER PHASE VX-680 Aurora Kinase Vertex I SB-715992 Kinesin Spindle Protein (KSP) Cytokinetics/GSK II SB-743921 KSP Cytokinetics I ON01910 Polo-like Kinase Onconova I

  39. Epidermal Growth Factor Receptor Family NAME TARGET DEVELOPER PHASE EGFR and HER2 GlaxoSmithKline Lapatinib II CI-1033 EGFR and HER2 Pfizer, NCI II AEE788 EGFR, HER2, and VEGFR Novartis I Pantimimumab EGFR Abgenix/Amgen III

  40. DYNAMIC MRI TUMOR BIOPSIES, SERUM STUDIES AZD2171 Neoadjuvant NCI Trial Accrual Goal: 30 patients Cycle 1: 7 days Cycles 2-7: Every three weeks C1 C2 C3 C4 C5 C6 C7 N=20 Surgery, XRT and hormonal therapy as indicated N=10 AZD217130 mg qd CONTROL - No Therapy DOCETAXEL 75mg/m2 DOXORUBICIN 50mg/m2 CYCLOPHOSPHAMIDE 600mg/m2 FILGRASTIM 300 mcg Days 2-11 or PEGFILGRASTIM 6mg Day 2

  41. AZD2171 Neoadjuvant NCI Trial Objectives • Pathologic CR in the breast • Changes in parameters of angiogenesis: • Phospho-VEGFR-2 in tumor • VEGF in tumor • Soluble VEGFR-2, VEGF, and circulating endothelial cells. • Vascular permeability using Dynamic Contrast Enhanced MRI

  42. PARP Inhibition • Inhibition leads to sensitization to DNA damaging agents • Radiation • Platinums, cyclophosphamide, irinotecan, temozolomide, anthracyclines • May be more potent in tumors with defective DNA repair mechanisms

  43. Miscellaneous Agents NAME TARGET DEVELOPER PHASE SU-11248 Pan-kinase inhibitor Pfizer/Sutent II RAD-001 mTOR Novartis I/II PTK-787 VEGF-R inhibitor Novartis III PKC412 Pan-kinase inhibitor Novartis II PX886 PI-3-Kinase Inhibitor ProLX Preclinical/I (1Q 06)

  44. Conclusion • Ixabepilone very active in breast cancer • Advantages • No steroid premedication • Minimal hypersensitivity reactions and nausea/ vomiting • 3%-5% Grade 3 peripheral neuropathy • Combinations in progress • Many new agents on the horizon

  45. Acknowledgments • CTEP • Jennifer A. Low, MD, PhD • Dimitrios Colevas, MD • Radiology • Catherine Chow, MD • Rehabilitation Medicine • Earllaine Croarkin • Rebecca Parks • Statistics • Seth Steinberg, PhD • Bristol-Myers Squibb Co • Ron Peck, MD Cancer Therapeutics Branch James Lee, MD, PhD Tito Fojo, MD, PhD Xiaowei Yang, MD, PhD Marianne Poruchynsky, PhD Neelima Denduluri, MD Janice Walshe, MD Suparna Bonthala, MD Arlene Berman, RN Michael Cox, PharmD Nitin Mannan Ujala Vatas

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