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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,

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Presentation on theme: "Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Linda T. Vahdat, MD Medical Director,"— Presentation transcript:

1 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

2 Program Goals Review data on new anti-microtubule agents (nab- paclitaxel and ixabepilone) –Background –Mechanism of action –Pharmacology –Pre-clinical data –Clinical data

3 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

4 Microtubule Structure and Assembly - Slide courtesy of Dr. Paraskevi (Evi) Giannakakou a b + –

5 Mitosis and Microtubules Microtubules –Make up the mitotic spindle –Critical to separation of chromosomes in mitosis Slide courtesy of Dr. Paraskevi (Evi) Giannakakou

6 Microtubule-Stabilizing Agents Derived From Natural Products AgentSourceLatin Name PaclitaxelPacific yewTaxus brevifolia EpothilonesMyxobacteriaSorangium cellulosum DiscodermolideSpongeDiscodermia dissoluta EleutherobinCoralsEleutherobin aurea SarcodictyinsCoralsSarcodictyon roseum TaccalonolidePlantTacca plantagine/chantrieri LaulimalideSponge Fasciospongia rimosa Cacospongia mycofijiensis

7 Partial Listing of Drugs That Target Microtubules Vinca alkaloids Taxanes Epothilones

8 nab-paclitaxel

9 Paclitaxel bound to albumin Advantages: –No premeds –Cremophor free –Shorter infusion time Might make use of gp60-albumin mediated receptor transport across endothelial cells

10 CaveolaeSPARC Albumin-Drug Accumulation Albumin-Bound Drug Gp60 Receptor nab-platform Utilizes Endogenous Albumin Pathways of Endothelial Transcytosis (gp60) and Intratumoral Binding of SPARC

11 A Pharmacokinetic Comparison of nab-paclitaxel and Paclitaxel

12 PK Comparison-linearity Total Paclitaxel nab-paclitaxel: 30 min infusion Linear, predictable PK DoseCmaxAUCCL (mg/m 2 )% δ(ng/ml)% δ(ng*hr/ml)% δ(L/h/m 2 )% δ Paclitaxel: 3 hr infusion Non-linear, less-predictable PK

13 Clinical PK Comparison of Total Paclitaxel Study C008-0 nab-paclitaxel (dose-adjusted to 175 mg/m 2 ) paclitaxel (175 mg/m 2 )

14 Clinical Studies

15 nab-paclitaxel TrialNo. ptsSettingScheduleRR (%) Med TTP (wks) Ibrahim 1 63No limit300 mg/m 2 Q3w4827 Mirtschung 2 231st line 125 mg/m 2 QW (3 out of 4 wks) 57NR Gradishar 3 nab-paclitaxel vs paclitaxel 4601st line 260 mg/m 2 vs. 175 mg/m 2 Q 3W 33 vs 1923 vs 17 Significant differences in Bold; RR= response rate, TTP= time to progression; NR= not reported 1 Ibrahim, JCO 2005; 2 Mirtschung Breast Ca Res Treat Suppl 2006; 3 Gradishar JCO 2005

16 Phase II Study nab-paclitaxel vs. Docetaxel Comparisons (N=300) nab-paclitaxel vs. docetaxel (A, B, C vs. D) weekly vs. every-3- weeks nab-paclitaxel (B, C vs. A) low vs. high dose weekly nab-paclitaxel (B vs. C) Arm A: nab-paclitaxel 300 mg/m 2 q3w Arm B: nab-paclitaxel 100 mg/m 2 weekly 3 out of 4 Arm C: nab-paclitaxel 150 mg/m 2 weekly 3 out of 4 Arm D: docetaxel 100 mg/m 2 q3w RANDOMIZE first-line metastatic breast cancer patients randomized to 4 arms: Arms A, C and D administered at the MTD Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.

17 Phase II Study nab-paclitaxel vs. Docetaxel MBC and no previous chemotherapy for metastatic disease (N = 300) ABX 300 mg/m 2 every 3 wks (N = 76) ABX 100 mg/m 2 wkly for 3 of 4 wks (N = 76) Docetaxel 100 mg/m 2 every 3 wks (N = 74) ABX 150 mg/m 2 wkly for 3 of 4 wks (N = 74) Gradishar W, et al. ASCO Abstract 1032.

18 Comparison of Investigator and Independent Radiology Review Response Assessments Response Rate (%) 300 mg/m mg/m mg/m 2 docetaxel q3wqw 3/4qw 3/4100 mg/m 2 q3w (A: N = 76)(B: N = 76)(C: N = 74)(D: N = 74) nab-paclitaxel Pearson Correlation Coefficient (Investigator vs. IRR) = Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.

19 Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (contd) ABX 300 mg/m 2 q3w ABX 100 mg/m 2 qw3/4 ABX 150 mg/m 2 qw3/4 Docetaxel 100 mg/m 2 q3w P =.016 P =.007 P =.003 P = Response Rate (%) Treatment n = Gradishar W, et al. ASCO Abstract 1032.

20 Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (contd) Months Progression-free Survival Investigator Assessments Proportion Not Improved % of patients off-study 0.75 ABCDABCD Gradishar W, et al. ASCO Abstract PFS statistically superior with 150 mg/m 2 (P =.002) and 300 mg/m 2 nab- paclitaxel (P =.046) compared with docetaxel in MBC PFS statistically superior with 150 mg/m 2 nab-paclitaxel compared with 100 mg/m 2 nab-paclitaxel (P =.009) Lower incidence of neutropenia and fatigue with all schedules of nab- paclitaxel compared with docetaxel Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m 2 vs. docetaxel 100 mg/m 2 in MBC planned

21 nab-paclitaxel: Grade 3/4 Toxicity in MBC Grade 3/4 Neutropenia 19-37% Docetaxel 100 mg/m 2 q3w 21-74%

22 nab-paclitaxel: Grade 3/4 Toxicity in MBC Febrile Neutropenia 1% Docetaxel 100 mg/m 2 q3w 7%

23 nab-paclitaxel: Grade 3/4 Toxicity in MBC Peripheral neuropathy 7-14 % 100 mg/m² QW least neuropathy compared to two other nab-paclitaxel arms Docetaxel 100 mg/m 2 q3w 5%

24 Time to Improvement in Peripheral Neuropathy Proportion Not Improved Days nab-paclitaxel 300 mg/m 2 q3w (N = 13) nab-paclitaxel 100 mg/m 2 weekly (N = 7) nab-paclitaxel 150 mg/m 2 weekly (N = 12) Docetaxel 100 mg/m 2 ( N = 8) 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 Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.

25 nab-paclitaxel: Grade 3/4 Toxicity in MBC Fatigue 0-4 % 100 mg/m 2 QW least neuropathy compared to two other nab-paclitaxel arms Docetaxel 100 mg/m 2 q3w 15%

26 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

27 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

28 Case: Taxane-naïve First-line Metastatic Breast Cancer Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine

29 Case: Taxane-naïve First-line Metastatic Breast Cancer Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Recommended Approach: nab-paclitaxel

30 Ixabepilone

31 Derived from sorangium Cellulosum along the Zambezi River Myxobacteria Secondary metabolites (epothilones/fungicides) Epothilones

32 Macrolide lactones –Epothilone A, B, E, F (epoxides) –Epothilone C,D (olefins) Goodin et al JCO 2004

33 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

34 Effect of Epothilone B on Tumor Cells 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 Microtubule bundling

35 Epothilones: Mechanism of Action Induces conformational changes in Bax (pro-apoptotic protein) Bcl-2- dependent Potential for synergism with Bcl-2 inhibitors

36 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

37 Class-specific Advantages Low susceptibility to tumor resistance mechanisms – MRP-1 and P-gp efflux pumps – b (III) tubulin overexpression – b-tubulin mutations

38 Pharmacology ixabepilone

39 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 T 1/2 : 39 hours (range:17-50 hrs) Data: BMS data on file

40 Ixabepilone: Pharmacology Daily x 5Q21dDaily x 3 Q21dWeeklyOnce Q21 d Infusion duration (hr) Dose (mg/m 2 /day) Range MTD DLTNeutropenia, neuropathy MTD: maximum tolerated dose; DLT: dose-limiting toxicity; Q: every Goodin et al, J Clin Oncol 22:2015, 2004

41 Pre-clinical Data

42 IC50 of Various Epothilones Against MCF-7 Cell Lines 1 Watkins EB et al, Current Phamaceutical Design, 2005; 2 Hoffman J Breast Cancer Res Treat Abstract 1103,

43 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

44 Ixabepilone: Phase II Data in Breast Cancer 1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr Low et al. J Clin Oncol 2005;23:2726– Conte P et al. J Clin Oncol 2006;24(18S):abstr Thomas E et al. J Clin Oncol 2006;24(18S):abstr Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305. Roché 1 After adjuvant anthra ORR (%) Low 2 Taxane-pretreated MBC Conte 3 Taxane-resistant MBC Thomas 4 Multiresistant (anthra / tax / cape) MBC Baselga 5 Neoadjuvant T2-4, N0-3, M pCR

45 Ixabepilone: Grade 3/4 Toxicity in MBC Grade 3/4 neutropenia 35 to 58% Neutropenia BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031

46 Ixabepilone: Grade 3/4 Toxicity in MBC Febrile neutropenia 3-14% with 14 % on NCI0229

47 Ixabepilone: Grade 3/4 Toxicity in MBC Sensory neuropathy ranged from 3-22% Neutropenia FN PN BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031

48 Ixabepilone: Grade 3/4 Toxicity in MBC Severe myalgias range from 3-26% Neutropenia FN PN Myalgias BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031

49 Ixabepilone: Grade 3/4 Toxicity in MBC Fatigue variable at 6 to 34% Neutropenia FN PN Myalgias Fatigue BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031

50 Ixabepilone: Grade 3/4 Toxicity in MBC Diarrhea at 1 to 11%

51 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

52 Case: Early Relapse After Adjuvant ACT Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Ixabepilone

53 Case: Early Relapse After Adjuvant ACT Which treatment option would you recommend? nab-paclitaxel Docetaxel Capecitabine Vinorelbine Ixabepilone Recommended Approach: Ixabepilone ± capecitabine

54 Phase III Data

55 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

56 Ixabepilone (40 mg/m 2 IV over 3 hr d1 q3wk) + Capecitabine (2000 mg/m 2 /day PO 2 divided doses d1-d14 q3wk) N = 375 Capecitabine (2500 mg/m 2 /day PO 2 divided doses d1-d14 q3wk) N = 377 Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N = 752 Stratification Visceral metastases Prior chemotherapy for MBC Study Design: International, Randomized, Open-label, Phase III Trial Anthracycline resistance Study site

57 Resistance to Prior Therapy Strict definition: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes SettingAnthracyclineTaxane Metastatic3 months of last dose4 months of last dose Neo/adjuvant6 months of last dose12 months of last dose Any Minimum cumulative dose Doxorubicin: 240 mg/m 2 Epirubicin: 360 mg/m 2

58 Patient Eligibility Criteria Inclusion Criteria Women 18 years Locally advanced or MBC Anthracycline-resistant or minimum cumulative dose Taxane-resistant KPS 70–100 Life expectancy 12 wk Exclusion Criteria >3 prior chemo regimens (adjuvant and metastatic) G2 motor/sensory neuropathy Reduced hematologic/ renal function 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

59 Median95% CI Ixabepilone + Capecitabine5.8 mo(5.5–7.0) Capecitabine4.2 mo(3.8–4.5) Progression-free Survival by Independent Radiologic Review P= HR: 0.75 (0.64–0.88) Proportion Progression Free Months

60 Response Rate % Response InvestigatorIRR Ixabepilone + Capecitabine N=375 Capecitabine N=377 Ixabepilone + Capecitabine N=375 Capecitabine N=377 ORR (CR + PR) P< Stable disease Progressive disease Unable to determine

61 Grade 3/4 Non-hematologic Toxicities Peripheral neuropathy 23 0 Myalgia Hand-foot syndrome Diarrhea 6 9 Mucositis 3 2 Vomiting 4 2 Fatigue 9 3 Nausea 3 2 Arthralgia % of Patients Ixabepilone + Capecitabine (N = 369) Capecitabine (N = 368)

62 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).

63 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

64 Case: Refractory Triple Negative Breast Cancer Which treatment option would you recommend? nab-paclitaxel Gemcitabine Vinorelbine Ixabepilone

65 Case: Refractory Triple Negative Breast Cancer Which treatment option would you recommend? nab-paclitaxel Gemcitabine Vinorelbine Ixabepilone Recommended Approach: Ixabepilone

66 Integration of Treatment Advances into Clinical Practice: Novel Microtubule-Targeting Agents in Metastatic Breast Cancer Closing Remarks


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