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Activity of Epothilones in Breast Cancer and Other Tumor Types

Activity of Epothilones in Breast Cancer and Other Tumor Types. Sandra M. Swain, MD

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Activity of Epothilones in Breast Cancer and Other Tumor Types

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  1. Activity of Epothilones in Breast Cancer and Other Tumor Types Sandra M. Swain, MD Professor of Medicine Uniformed Services University of Health Sciences Chief, Cancer Therapeutics Branch Center for Cancer Research National Cancer Institute Bethesda, Maryland

  2. Novel Microtubule-Stabilizing Agents Under Evaluation • Ixabepilone (BMS-247550) • Current NCI translational study • Clinical outcome • Evaluation of neurotoxicity • Other ixabepilone trials in breast cancer • Phase I/II trials in other cancer types • Epothilone B (Patupilone, EPO906) • Epothilone D (KOS-862)

  3. 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

  4. Antitumor Activity: Taxane-Resistant Breast Cancer Xenografts Control Control • PAT-21 breast cancer xenografts are derived from a patient with MBC who received 10 cycles of CMF, then 4 cycles of paclitaxel. 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 10 100 40 70 70 100 130 160 40 50 60 70 80 90 Days Post-Tumor Implant Days Post-Tumor Implant Modified from data on file, Bristol-Myers Squibb

  5. Ixabepilone (BMS-247550) • Epothilone B: Natural macrolide produced by myxobacterium Sorangium cellulosum • Ixabepilone: Semisynthetic epothilone B analog (aza-epothilone B) Epothilone B Ixabepilone

  6. 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-naive, 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 et al.J Clin Oncol. 2003;21:1866-1873. Mani S et al. Clin Cancer Res. 2004;10:1289-1298. Zhuang SH et al. Cancer. 2005;103:1932-1938.

  7. Ixabepilone in Metastatic and Locally Advanced Breast Cancer (NCI-0229) • Phase II trial • Daily x 5 schedule (6 mg/m2 per day) • Patients previously treated with a taxane • Taxane-naive patients Cycle 1 (3 weeks) Cycle 2 Cycle 3 Daily x 5 Daily x 5 Daily x 5 Post-treatment biopsy Baseline biopsy

  8. Phase II Clinical Trial of Ixabepilonein Breast Cancer (NCI-0229) • 43% partial response in taxane-naive patients Low JA et al. J Clin Oncol. 2005;23:2726-2734.

  9. Complete Response: Taxane-Treated Group Baseline After 11 cycles

  10. Phase II Ixabepilone Trial (NCI-0229): Grade 3/4 Toxicity Low JA et al. J Clin Oncol. 2005;23:2726-2734.

  11. Phase II Ixabepilone Trial (NCI-0229): Peripheral Neuropathy • Neurologic function evaluated before ixabepilone treatment CTC, Common Toxicity Criteria. Low JA et al. J Clin Oncol. 2005;23:2726-2734.

  12. Phase II Ixabepilone Trial (NCI-0229): Neurologic Function • Baseline evaluation prior to treatment • Neurologic function tests included • Balance test • Semmes-Weinstein monofilaments • Jebsen Test of Hand Function (JTH) • Grooved Peg Board Test (PEG) Low JA et al. J Clin Oncol. 2005;23:2726-2734.

  13. Microtubule Stability: Acetylated Tubulin Cycle 2 At Baseline Tumor Stromal staining Partial Response Progressive Disease Low JA et al. J Clin Oncol. 2005;23:2726-2734.

  14. Phase II Ixabepilone Trial (NCI-0229): Summary • Good clinical activity in heavily pretreated breast cancer patients (RR = 22%) • Grade 3/4 sensory peripheral neuropathy in 3% of patients • Baseline neurologic function tests may predict grade ≥ 2 peripheral neuropathy • Acetylation of tubulin may predict response

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

  16. Incidence of Peripheral Neuropathy With Ixabepilone

  17. Incidence of Sensory Neuropathy With Microtubule-Stabilizing Agents

  18. Neoadjuvant Ixabepilone Trial (CA 163080) • Primary endpoint: pharmacogenomic markers • Eligibility: Stage IIA and IIIB breast cancer • Treatment: 4 cycles 40 mg/m2 IV over 3 hrs every 3 wks • Preliminary report in 96 patients • 19% pathologic CR in breast • 13% pathologic CR in breast and nodes Llombart Cussac et al. ASCO 2005. Abstract 586

  19. Planned and Ongoing Trials of Ixabepilone in Metastatic Breast Cancer

  20. Phase III Clinical Trials ofIxabepilone + Capecitabine Patients with metastatic or locally advanced breast cancer Capecitabine 1250 mg/m2 bid x 14 days Ixabepilone 40 mg/m2 every 3 wks plus Capecitabine 1000 mg/m2 bid x 14 days

  21. Ixabepilone + Pegylated Liposomal Doxorubicin: Metastatic Breast Cancer • Phase I/II study, currently enrolling (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

  22. 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

  23. Trastuzumab, Ixabepilone, and Carboplatin in HER2+ MBC • Phase II trial (Study chair: 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

  24. Phase I/II Ixabepilone Studies: Other Tumor Types

  25. Colorectal + Prostate Cancer Studies • Patients (N = 23) with advanced progressive colorectal cancer after IFL1 • Ixabepilone 40 mg/m2 IV over 3 hours every 3 weeks • 13 patients (56%) achieved SD after 2 cycles • Grade 3/4 peripheral neuropathy, 20% • Patients (N = 92) with treatment-naive metastatic prostate cancer2 • Ixabepilone 35 mg/m2 every 3 weeks +/- oral estramustine • 32% PR rate in ixabepilone arm, 48% PR rate in ixabepilone + estramustine arm • Grade 3/4 toxicity in ixabepilone + estramustine arm: neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%) Eng C et al. Ann Oncol. 2004;15:928-932. Galsky MD et al. J Clin Oncol. 2005;23:1439-1446.

  26. Other Tumor Types • Ixabepilone currently being evaluated in phase I and II clinical trials for: • Advanced cisplatin-refractory germ cell tumors • Endometrial cancer • Metastatic, recurrent, or unresectable kidney cancer • Recurrent glioma • Relapsed/refractory lymphoproliferative disorders • Relapsed/refractory aggressive non-Hodgkin's lymphoma www.clinicaltrials.gov

  27. Other Epothilones Under Development

  28. Epothilone B (Patupilone, EPO906): Phase I Trials • Patupilone + gemcitabine • DLTs included grade 3 diarrhea (n = 3), nausea (n = 1), dizziness (n = 1) • MTD: 2.0 mg/m² • Out of 16 evaluable patients, 1 PR and 7 SD • Patupilone + estramustine • Prior taxane therapy in 13/14 patients • DLT, grade 3 diarrhea (n = 1) • MTD, 2.5 mg/m2 • Grade 3/4 adverse events: diarrhea, fatigue, vomiting (n = 8) • 1 PR and 8 SD (preliminary tumor assessment) Rinehart JJ et al. ASCO 2004. Abstract 3100.Wojtowicz M et al. ASCO 2004. Abstract 4623.

  29. Epothilone D (KOS-862) • Anthracycline- and taxane-pretreated metastatic breast cancer • Antitumor activity in 2/10 evaluable patients • Grade 3 toxicity: peripheral neuropathy and ataxia • Second-line therapy in NSCLC • Toxicity: fatigue, neurosensory (paresthesias), nausea/vomiting • 4 of first 35 patients withdrew due to toxicity • 1 PR; SD for 16 and 31 weeks seen • Phase II study ongoing in hormone-resistant prostate cancer Overmoyer B et al. ASCO 2005. Abstract 778.Yee L,et al. ASCO 2005. Abstract 7127.

  30. Summary • Ixabepilone • Novel microtubule-stabilizing agent • Non–cross-resistant with taxanes • May have favorable efficacy and safety vs paclitaxel • Being evaluated alone and in combination in phase II/III trials of breast cancer, other cancers • Patupilone and KOS-862 also under evaluation in phase I trials

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