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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

5 Mitosis and 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
Source Latin Name Paclitaxel Pacific yew Taxus brevifolia Epothilones Myxobacteria Sorangium cellulosum Discodermolide Sponge Discodermia dissoluta Eleutherobin Corals Eleutherobin aurea Sarcodictyins Sarcodictyon roseum Taccalonolide Plant Tacca plantagine/chantrieri Laulimalide Fasciospongia rimosa Cacospongia mycofijiensis

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

8 nab-paclitaxel

9 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

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

11 A Pharmacokinetic Comparison of nab-paclitaxel and Paclitaxel

12 PK Comparison-linearity Total Paclitaxel
nab-paclitaxel: 30 min infusion Linear, predictable PK Dose Cmax AUC CL (mg/m2) % δ (ng/ml) (ng*hr/ml) (L/h/m2) 135 ---- 3071 8604 15.9 175 30 5202 70 15048 75 11.6 25 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/m2) paclitaxel (175 mg/m2)

14 Clinical Studies

15 nab-paclitaxel Trial 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 Gradishar3 nab-paclitaxel vs paclitaxel 460 260 mg/m2 vs. 175 mg/m2 Q 3W 33 vs 19 23 vs 17 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

16 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-3-weeks nab-paclitaxel (B, C vs. A) low vs. high dose weekly nab-paclitaxel (B vs. C) R A N D O M I Z E Arm A: nab-paclitaxel 300 mg/m2 q3w Arm B: nab-paclitaxel 100 mg/m2 weekly 3 out of 4 Arm C: nab-paclitaxel 150 mg/m2 weekly 3 out of 4 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.

17 Phase II Study nab-paclitaxel vs. Docetaxel
ABX 300 mg/m2 every 3 wks (N = 76) ABX 100 mg/m2 wkly for 3 of 4 wks (N = 76) MBC and no previous chemotherapy for metastatic disease (N = 300) 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 Abstract 1032. 17

18 Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507
Comparison of Investigator and Independent Radiology Review Response Assessments Response Rate (%) 300 mg/m2 100 mg/m mg/m2 docetaxel q3w qw 3/4 qw 3/4 100 mg/m2 q3w (A: N = 76) (B: N = 76) (C: N = 74) (D: N = 74) nab-paclitaxel Pearson Correlation Coefficient (Investigator vs. IRR) = 0.507 Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.

19 Phase II Study Evaluating Various Doses of nab-paclitaxel vs
Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d) ABX 300 mg/m2 q3w ABX 100 mg/m2 qw3/4 ABX 150 mg/m2 qw3/4 Docetaxel 100 mg/m2 q3w 100 P = .002 90 P = .007 P = .003 80 P = .016 70 70 62 60 Response Rate (%) 50 43 38 40 30 20 10 n = 76 76 74 74 Treatment Gradishar W, et al. ASCO Abstract 1032. 19

20 Phase II Study Evaluating Various Doses of nab-paclitaxel vs
Phase II Study Evaluating Various Doses of nab-paclitaxel vs. Docetaxel (cont’d) PFS statistically superior with 150 mg/m2 (P = .002) and 300 mg/m2 nab-paclitaxel (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 nab-paclitaxel compared with docetaxel Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 in MBC planned Progression-free Survival Investigator Assessments 1.0 A B C D 0.75 Proportion Not Improved 0.50 0.25 75% of patients off-study 0.0 3 6 9 12 15 18 Months Gradishar W, et al. ASCO Abstract 1032.

21 nab-paclitaxel: Grade 3/4 Toxicity in MBC
Grade 3/4 Neutropenia 19-37% Docetaxel 100 mg/m2 q3w 21-74%

22 nab-paclitaxel: Grade 3/4 Toxicity in MBC
Febrile Neutropenia 1% Docetaxel 100 mg/m2 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/m2 q3w 5%

24 Time to Improvement in Peripheral Neuropathy
Proportion Not Improved 0.00 0.25 0.50 0.75 1.00 Days 20 40 60 80 100 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) 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/m2 QW least neuropathy compared to two other nab-paclitaxel arms Docetaxel 100 mg/m2 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 (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:

30 Ixabepilone

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

32 Epothilones 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
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

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 T1/2: 39 hours (range:17-50 hrs) Data: BMS data on file

40 Ixabepilone: Pharmacology
Daily x 5Q21d Daily x 3 Q21d Weekly Once Q21 d Infusion duration (hr) 1 0.5-1 Dose (mg/m2/day) Range 1.5 -8 8-10 1-30 32-65 MTD 6 8 25 50 DLT Neutropenia, 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 1 1 1 2 1 1 1Watkins EB et al, Current Phamaceutical Design, 2005; 2Hoffman J Breast Cancer Res Treat Abstract 1103, 2006

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
45 42 30 22 ORR (%) 19 18 pCR 15 12 Roché1 After adjuvant anthra Low2 Taxane-pretreated MBC Conte3 Taxane-resistant MBC Thomas4 Multiresistant (anthra / tax / cape) MBC Baselga5 Neoadjuvant T2-4, N0-3, M0 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.

45 Ixabepilone: Grade 3/4 Toxicity in MBC
100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 Neutropenia Grade 3/4 neutropenia 35 to 58%

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

47 Ixabepilone: Grade 3/4 Toxicity in MBC
100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 FN PN Neutropenia Sensory neuropathy ranged from 3-22%

48 Ixabepilone: Grade 3/4 Toxicity in MBC
100 80 BMS 009 NCI 0229 60 BMS 010 40 BMS 081 20 BMS 031 FN PN Myalgias Neutropenia Severe myalgias range from 3-26%

49 Ixabepilone: Grade 3/4 Toxicity in MBC
20 40 60 80 100 Neutropenia FN PN Myalgias Fatigue BMS 009 NCI 0229 BMS 010 BMS 081 BMS 031 Fatigue variable at 6 to 34%

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 Study Design: International, Randomized, Open-label, Phase III Trial
Ixabepilone (40 mg/m2 IV over 3 hr d1 q3wk) + Capecitabine (2000 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 375 Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes N = 752 Capecitabine (2500 mg/m2/day PO 2 divided doses d1-d14 q3wk) N = 377 Stratification Visceral metastases Prior chemotherapy for MBC 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 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 Any Minimum cumulative dose Doxorubicin: 240 mg/m2 Epirubicin: 360 mg/m2

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 Progression-free Survival by Independent Radiologic Review
1.0 0.8 0.6 0.4 0.2 Median 95% CI Ixabepilone + Capecitabine 5.8 mo (5.5–7.0) Capecitabine 4.2 mo (3.8–4.5) Proportion Progression Free HR: 0.75 (0.64–0.88) P=0.0003 Months

60 Ixabepilone + Capecitabine N=375
Response Rate % Response Investigator IRR Ixabepilone + Capecitabine N=375 Capecitabine N=377 Capecitabine N=377 ORR (CR + PR) 42 23 35 14 P<0.0001 Stable disease 36 38 41 46 Progressive disease 29 15 27 Unable to determine 8 10 9 12

61 Grade 3/4 Non-hematologic Toxicities
% of Patients Ixabepilone + Capecitabine (N = 369) Capecitabine (N = 368) 20 40 60 80 Peripheral neuropathy 23 Myalgia 8 0.3 Hand-foot syndrome 18 17 Diarrhea 6 9 Mucositis 3 2 Vomiting 4 2 Fatigue 9 3 Nausea Arthralgia

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:

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


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