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Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Linda T. Vahdat, MD Medical Director, Breast Cancer Research Program Weill Cornell Medical College New York Presbyterian Hospital New York, NY Program Goals • Review data on new anti-microtubule agents (nabpaclitaxel and ixabepilone) – Background – Mechanism of action – Pharmacology – Pre-clinical data – Clinical data Why Target Microtubules? • Perform multiple basic cellular functions • Fill the area from nucleus to plasma membrane • At least 3 distinct binding sites for tubulin-targeting drugs • Disruption of microtubule cytoskeleton leads to mitotic arrest and cell death Microtubule Structure and Assembly + b a – - Slide courtesy of Dr. Paraskevi (Evi) Giannakakou Mitosis and Microtubules • Microtubules – Make up the mitotic spindle – Critical to separation of chromosomes in mitosis Slide courtesy of Dr. Paraskevi (Evi) Giannakakou Microtubule-Stabilizing Agents Derived From Natural Products Agent Source Latin Name Pacific yew Taxus brevifolia Myxobacteria Sorangium cellulosum Discodermolide Sponge Discodermia dissoluta Eleutherobin Corals Eleutherobin aurea Sarcodictyins Corals Sarcodictyon roseum Taccalonolide Plant Tacca plantagine/chantrieri Paclitaxel Epothilones Laulimalide Sponge Fasciospongia rimosa Cacospongia mycofijiensis Partial Listing of Drugs That Target Microtubules • Vinca alkaloids • Taxanes • Epothilones nab-paclitaxel nab-paclitaxel • Paclitaxel bound to albumin • Advantages: – No premeds – Cremophor free – Shorter infusion time • Might make use of gp60-albumin mediated receptor transport across endothelial cells nab-platform Utilizes Endogenous Albumin Pathways of Endothelial Transcytosis (gp60) and Intratumoral Binding of SPARC Albumin-Bound Drug Tumor endothelial cell gp60 receptor Red Blood cell Gp60 Receptor Albumin-drug complex TUMOR BLOOD VESSEL gp60/Alb-drug complex Caveolae TUMOR SPARC on Tumor INTERSTITIUM cell surface Alb-drug complex transcytosed by gp60 Surface SPARC bound to Alb-drug complex SPARC Internalized SPARC/Alb-drug complex Tumor cells Albumin-Drug Accumulation A Pharmacokinetic Comparison of nab-paclitaxel and Paclitaxel PK Comparison-linearity Total Paclitaxel nab-paclitaxel: 30 min infusion Linear, predictable PK Dose Cmax (mg/m2) %δ 135 175 CL (ng*hr/ml) %δ (L/h/m2) %δ ---- 3071 ---- 8604 ---- 15.9 ---- 30 5202 70 15048 75 11.6 25 (ng/ml) %δ AUC Paclitaxel: 3 hr infusion Non-linear, less-predictable PK Clinical PK Comparison of Total Paclitaxel Study C008-0 [Paclitaxel], ng/ml 15000 nab-paclitaxel (dose-adjusted to 175 mg/m2) 10000 paclitaxel (175 mg/m2) 5000 0 0 5 Hours 10 Clinical Studies nab-paclitaxel No. pts Setting Schedule RR (%) Med TTP (wks) Ibrahim1 63 No limit 300 mg/m2 Q3w 48 27 Mirtschung2 23 1st line 125 mg/m2 QW (3 out of 4 wks) 57 NR 460 1st line 260 mg/m2 vs. 175 mg/m2 Q 3W 33 vs 19 23 vs 17 Trial Gradishar3 nab-paclitaxel vs paclitaxel Significant differences in Bold; RR= response rate, TTP= time to progression; NR= not reported 1Ibrahim, JCO 2005; 2Mirtschung Breast Ca Res Treat Suppl 2006; 3Gradishar JCO 2005 Phase II Study nab-paclitaxel vs. Docetaxel first-line metastatic breast cancer patients randomized to 4 arms: Comparisons (N=300) nab-paclitaxel vs. docetaxel (A, B, C vs. D) weekly vs. every-3weeks nab-paclitaxel (B, C vs. A) Arm A: nab-paclitaxel 300 mg/m2 q3w R A N Arm B: nab-paclitaxel 100 mg/m2 weekly 3 out of 4 D O M Arm C: nab-paclitaxel 150 mg/m2 weekly 3 out of 4 I low vs. high dose weekly nab-paclitaxel (B vs. C) Z E Arm D: docetaxel 100 mg/m2 q3w Arms A, C and D administered at the MTD Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46. Phase II Study nab-paclitaxel vs. Docetaxel ABX 300 mg/m2 every 3 wks (N = 76) MBC and no previous chemotherapy for metastatic disease (N = 300) ABX 100 mg/m2 wkly for 3 of 4 wks (N = 76) ABX 150 mg/m2 wkly for 3 of 4 wks (N = 74) Docetaxel 100 mg/m2 every 3 wks (N = 74) Gradishar W, et al. ASCO 2007. Abstract 1032. Comparison of Investigator and Independent Radiology Review Response Assessments Response Rate (%) 80% 70% Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507 60% Investigator 70% IRR 62% 50% 40% 30% 45% 43% 47% 38% 35% 28% 20% 10% 0% 300 mg/m2 q3w (A: N = 76) 100 mg/m2 qw 3/4 (B: N = 76) nab-paclitaxel 150 mg/m2 qw 3/4 (C: N = 74) docetaxel 100 mg/m2 q3w (D: N = 74) Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46. Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d) P = .002 100 90 Response Rate (%) ABX 300 mg/m2 q3w ABX 100 mg/m2 qw3/4 ABX 150 mg/m2 qw3/4 Docetaxel 100 mg/m2 q3w P = .007 80 P = .003 P = .016 70 70 62 60 50 43 38 40 30 20 10 0 n= 76 76 74 74 Treatment Gradishar W, et al. ASCO 2007. Abstract 1032. • • • • PFS statistically superior with 150 mg/m2 (P = .002) and 300 mg/m2 nabpaclitaxel (P = .046) compared with docetaxel in MBC PFS statistically superior with 150 mg/m2 nab-paclitaxel compared with 100 mg/m2 nab-paclitaxel (P = .009) Lower incidence of neutropenia and fatigue with all schedules of nabpaclitaxel compared with docetaxel Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 in MBC planned Proportion Not Improved Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d) Progression-free Survival Investigator Assessments 1.0 A B C D 0.75 0.50 0.25 75% of patients off-study 0.0 0 3 6 9 12 Months 15 18 Gradishar W, et al. ASCO 2007. Abstract 1032. nab-paclitaxel: Grade 3/4 Toxicity in MBC Grade 3/4 Neutropenia 19-37% 100 80 300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW 60 40 20 N eu tr op en i a 0 Docetaxel 100 mg/m2 q3w 21-74% nab-paclitaxel: Grade 3/4 Toxicity in MBC Febrile Neutropenia 1% 100 80 300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW 60 40 20 0 i n e p ro t eu N a FN Docetaxel 100 mg/m2 q3w 7% nab-paclitaxel: Grade 3/4 Toxicity in MBC Peripheral neuropathy 7-14 % 100 80 300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW 60 40 20 N eu tr PN FN op en i a 0 100 mg/m² QW least neuropathy compared to two other nab-paclitaxel arms Docetaxel 100 mg/m2 q3w 5% Time to Improvement in Peripheral Neuropathy Proportion Not Improved 1.00 nab-paclitaxel 300 mg/m2 q3w (N = 13) nab-paclitaxel 100 mg/m2 weekly (N = 7) nab-paclitaxel 150 mg/m2 weekly (N = 12) Docetaxel 100 mg/m2 ( N = 8) 0.75 A) Median, 16 days, 95% CI, 12 to 24 B) Median, 22 days, 95% CI, 14 to 25 C) Median, 23 days, 95% CI, 12 to 31 D) Median, 41 days, 95% CI, 37 to 44 0.50 0.25 0.00 0 20 60 40 80 100 Days Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46. nab-paclitaxel: Grade 3/4 Toxicity in MBC Fatigue 0-4 % 100 80 300mg/m2 Q3w 100mg/m2 QW 150mg/m2 QW 60 40 20 PN FN Fa tig ue N eu tr op en i a 0 100 mg/m2 QW least neuropathy compared to two other nab-paclitaxel arms Docetaxel 100 mg/m2 q3w 15% Conclusions • The response rates of q3w nab-paclitaxel and docetaxel were comparable • For each regimen of nab-paclitaxel compared to docetaxel – Grade 4 neutropenia, febrile neutropenia and mucositis were less frequent – There were no statistical differences between the rates of peripheral neuropathy Case: Taxane-naïve First-line Metastatic Breast Cancer • 54 y.o. woman diagnosed with Stage II BC in 1999 (T= 2.5 cm N = 1/15, ER/PR pos. HER2neu = 0) • AC Q3W x 4 followed by Tamoxifen • 2006: increased abdominal fullness • Mild elevation of transaminases EOD: liver metastases • Biopsy: c/w prior BC ER/PR positive and HER2-neu non-amplified by FISH Case: Taxane-naïve First-line Metastatic Breast Cancer Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Case: Taxane-naïve First-line Metastatic Breast Cancer Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Recommended Approach: • nab-paclitaxel Ixabepilone Epothilones • Derived from sorangium Cellulosum along the Zambezi River • Myxobacteria • Secondary metabolites (epothilones/fungicides) Epothilones • Macrolide lactones – Epothilone A, B, E, F (epoxides) – Epothilone C,D (olefins) Goodin et al JCO 2004 Epothilones: Mechanism of Action • Induce microtubule stabilization – Bind to b-tubulin – Compete with same binding site as paclitaxel and neuronal tau protein on b-tubulin – Binding mode different from above – Accumulate in G2/M Effect of Epothilone B on Tumor Cells Microtubule bundling Control cells displaying normal interphase microtubules . Right: Cells treated with 10 nM epothilone B for 24 h displaying extensive microtubule bundling. Altmann et al Biochim Biophys Acta 2000 Epothilones: Mechanism of Action • Induces conformational changes in Bax (pro-apoptotic protein) • Bcl-2- dependent • Potential for synergism with Bcl-2 inhibitors Pharmacologic Considerations • Epothilone A and B – High in vitro tumor activity – Modest in vivo activity – Metabolic instability – Unfavorable PK – Narrow therapeutic window • Analogs developed to optimize product Class-specific Advantages • Low susceptibility to tumor resistance mechanisms – MRP-1 and P-gp efflux pumps – b (III) tubulin overexpression – b-tubulin mutations Pharmacology ixabepilone Ixabepilone: Pharmacology • Excreted in the feces (75%) and urine (25%) • Metabolized via P450 (CYP3A4) • Linear (AUC increases with dose) – Linear relationship between microtubule bundle formation in PBMC and plasma concentration • T1/2: 39 hours (range:17-50 hrs) Data: BMS data on file Ixabepilone: Pharmacology Daily x 5Q21d Daily x 3 Q21d Weekly Once Q21 d 1 1 0.5-1 1 Range 1.5 -8 8-10 1-30 32-65 MTD 6 8 25 50 Infusion duration (hr) Dose (mg/m2/day) DLT Neutropenia, neuropathy MTD: maximum tolerated dose; DLT: dose-limiting toxicity; Q: every Goodin et al, J Clin Oncol 22:2015, 2004 Pre-clinical Data IC50 of Various Epothilones Against MCF-7 Cell Lines 6.9 7 6 5 4 3.26 3 2.31 2.04 2 1 0.7 0.29 0 Paclitaxel 1 1Watkins Epo A Epo B 1 Epo D 1 Epo F 1 1 ZK-EPO 1 2 EB et al, Current Phamaceutical Design, 2005; 2Hoffman J Breast Cancer Res Treat Abstract 1103, 2006 IC50 Values (nM) for Net Growth Inhibition of Human Carcinoma Cell Lines by Epothilones A and B in Comparison to Paclitaxel Altmann et al Biochim Biophys Acta 2000 Ixabepilone: Phase II Data in Breast Cancer 45 42 ORR (%) 30 22 19 15 18 pCR 12 0 Roché1 After adjuvant anthra Low2 Conte3 Thomas4 Baselga5 Taxane-pretreated Taxane-resistant Multiresistant Neoadjuvant MBC MBC (anthra / tax / cape) T2-4, N0-3, MBC M0 1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol 2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660. 5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305. Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 60 40 20 0 Grade 3/4 neutropenia 35 to 58% Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 60 40 20 FN N eu tr op en i a 0 Febrile neutropenia 3-14% with 14 % on NCI0229 Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 60 40 20 0 Sensory neuropathy ranged from 3-22% Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 60 40 20 0 Severe myalgias range from 3-26% Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 60 NCI 0229 BMS 010 40 BMS 081 20 BMS 031 0 Fatigue variable at 6 to 34% Ixabepilone: Grade 3/4 Toxicity in MBC 100 80 BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 60 40 20 D ia rrh ea Fa tig ue ya lg ia s M PN FN N eu tro pe ni a 0 Diarrhea at 1 to 11% Case: Early Relapse After Adjuvant ACT • 53 y.o. woman with a h/o of a stage IIIB breast cancer – Left lumpectomy and AND T= 3.5 cm N= 6/25 ER/PR= pos/neg and HER2-neu negative by FISH – Received AC followed by paclitaxel Q2w – Received chest wall RT followed by anastrozole • Relapse in CW, lungs and liver 8 months after completing adjuvant therapy Case: Early Relapse After Adjuvant ACT Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Ixabepilone Case: Early Relapse After Adjuvant ACT Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Ixabepilone Recommended Approach: • Ixabepilone ± capecitabine Phase III Data A Multicenter Phase III Clinical Trial Comparing Ixabepilone plus Capecitabine with Capecitabine Alone in Patients with Metastatic Breast Cancer Previously Treated with or Resistant to Anthracycline and Resistant to Taxanes Linda T. Vahdat, MD Weill Cornell Medical College New York, New York On Behalf of the 046 Study Investigators Study Design: International, Randomized, Open-label, Phase III Trial Ixabepilone (40 mg/m2 IV over 3 hr d1 q3wk) + Capecitabine Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N = 752 Stratification • Visceral metastases • Prior chemotherapy for MBC (2000 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 375 Capecitabine (2500 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 377 •Anthracycline resistance •Study site Resistance to Prior Therapy Strict definition: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes Setting Anthracycline Taxane Metastatic ≤3 months of last dose ≤4 months of last dose Neo/adjuvant ≤6 months of last dose ≤12 months of last dose Minimum cumulative dose Any Doxorubicin: 240 mg/m2 Epirubicin: 360 mg/m2 Patient Eligibility Criteria Inclusion Criteria Exclusion Criteria • Women ≥18 years • Locally advanced or MBC • >3 prior chemo regimens (adjuvant and metastatic) • Anthracycline-resistant or minimum cumulative dose • ≥G2 motor/sensory neuropathy • Taxane-resistant • Reduced hematologic/ renal function • KPS 70–100 • Life expectancy ≥12 wk • ≥G2 liver function tests* • CNS metastases *Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G2 liver function tests) had been enrolled before amendment Progression-free Survival by Independent Radiologic Review Proportion Progression Free 1.0 0.8 Median 95% CI Ixabepilone + Capecitabine 5.8 mo (5.5–7.0) Capecitabine 4.2 mo (3.8–4.5) 0.6 HR: 0.75 (0.64–0.88) P=0.0003 0.4 0.2 0 0 4 8 12 16 20 Months 24 28 32 36 Response Rate Investigator % Response ORR (CR + PR) IRR Ixabepilone + Capecitabine N=375 Capecitabine Capecitabine N=377 Ixabepilone + Capecitabine N=375 42 23 35 14 P<0.0001 N=377 P<0.0001 Stable disease 36 38 41 46 Progressive disease 14 29 15 27 Unable to determine 8 10 9 12 Grade 3/4 Non-hematologic Toxicities 80 Ixabepilone + Capecitabine (N = 369) % of Patients Capecitabine (N = 368) 60 40 23 18 17 20 9 0 0 8 3 6 0.3 9 4 2 3 2 3 2 3 0 Epothilones in Development • • • Patupilone (epothilone B): – Phase I trials in breast cancer in combination with other cytotoxics – In preliminary efficacy data, toxicity included significant gastrointestinal effects – New formulation appears to reduce toxicity KOS-862 (epothilone D): – Phase II trial in anthracycline- and taxane-pretreated metastatic breast cancer – Of the 41 evaluable patients, 5 achieved a PR and 3 had SD – Grade 3 neurotoxicity in 43 evaluable patients: neuropathy (12%) and ataxia (9%) – Phase I trial combined with trastuzumab: • Unconfirmed response: 3/13 • Grade 3 neurotoxicity: 2/13 ZK-EPO: – First fully synthetic third-generation epothilone – Not recognized by efflux pumps; efficacy in preclinical models in taxane-resistant disease Cortes et al. J Clin Oncol 2006; 24(suppl):86s (abstract 2028). Buzdar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S69 (abstract 1087).Klar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S64 (abstract 1072). Case: Refractory Triple Negative Breast Cancer • 46 y.o. woman with a h/o stage I BC (T = 1.8 cm N = 0 ER/PR/HER 2 neu: negative diagnosed in 2000 • RLE and SLNB • AC x 4 Q3w followed by right breast RT • Did well until 2005 when developed soft tissue mass adjacent to sternum – Biopsy c/w recurrent BC ( ER/PR/HER2 neu negative) • Capecitabine: Initial response followed by POD in bone • Docetaxel: Initial response followed by POD in lungs and mediastinal LNs Case: Refractory Triple Negative Breast Cancer Which treatment option would you recommend? nab-paclitaxel Gemcitabine Vinorelbine Ixabepilone Case: Refractory Triple Negative Breast Cancer Which treatment option would you recommend? nab-paclitaxel Gemcitabine Vinorelbine Ixabepilone Recommended Approach: • Ixabepilone Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Closing Remarks