Epothilones in Breast Cancer

Sandra M. Swain, MD

December 7, 2005

      

Sandra Swain, MD

No financial relationships with any commercial interest

• Microtubule-stabilizing agents• Epothilones• Ixabepilone (BMS-247550) trial at NCI

– Clinical outcome– Evaluation of neurotoxicity– Translational study

• Other ixabepilone trials in breast cancer

Recent Advances in the Development of Microtubule-Stabilizing Agents

Sorangium cellulosum

• Myxobacteria– Secondary metabolites

(epothilones/fungicides)

Zambezi river

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

Paclitaxel Epothilone A

Nettles. Science. 2004;305:866-869.

Epothilones Are Strong Promoters of Tubulin Polymerization

• Epothilone B has tubulin polymerizing activity 2-10 times stronger than paclitaxel

Kowalski. J Biol Chem. 1997;272:2534.

1, Paclitaxel; 2, EpoA; 3, EpoB

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.

PAT-7MDR/MRP

(Ovarian Ca)

Lo

g c

ell

kill

at

MT

D

1.3

4.5

HCT/VM46MDR

(Colon Ca)

0.4

3.1

0

1

2

3

4

5

6 Paclitaxel

Ixabepilone (epothilone B analog)

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

Epothilones

IISchering AGEpothilone BZK-EPO

IBristol-Myers

SquibbEpothilone BBMS-310705

IIINovartisEpothilone BPatupilone

IIKosan/RocheEpothilone DKOS-862

IIIBristol-Myers

SquibbEpothilone BIxabepilone

PHASEDEVELOPERDerivativeNAME

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

Antitumor Activity in Taxane-Resistant PAT-21 Breast Cancer

Xenografts

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.

Me

dia

n t

um

or

wt.

(m

g)

10

100

1000

40 70 100 130 160Days posttumor implantation

ControlIxabepilone (10 mg/kg, MTD)Paclitaxel (36 mg/kg, MTD)

ControlIxabepilone (13 mg/kg, MTD)Docetaxel (20 mg/kg, MTD)Vinorelbine (9 mg/kg, MTD)

Days posttumor implantation

10

100

1000

40 50 60 70 80 90

Me

dia

n t

um

or

wt.

(m

g)

Data on file, Bristol-Myers Squibb Company.

Ixabepilone Pharmacology

Daily x 5 q21d

Daily x 3 q21d

WeeklyOnce q21d

Infusion duration, hr

1 1 0.5-1 1

Dose (mg/m2), range

1.5-8 8-10 1-30 32-65

MTD (mg/m2)

6 8 25 50

DLT Neutropenia, neuropathy

Goodin. J Clin Oncol. 2004;22:2015-2025.

MTD=maximum tolerated dose; DLT=dose-limiting toxicity; q=every.

Abraham. J Clin Oncol. 2003;21:1866-1873; Mani. Clin Cancer Res. 2004;10:1289-1298; Zhuang. Cancer. 2005;103:1932-1938.

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

Ixabepilone in Metastatic and Locally Advanced Breast Cancer Phase II Trial NCI-0229

6 mg/m2/day

Post-treatment biopsy

Baseline biopsy

Cycle 1 (3 weeks) Cycle 2 Cycle 3…

Daily x 5Daily x 5 Daily x 5

Taxane Naïve and Prior Taxane Treated Group

Clinical Response to Ixabepilone NCI-0229

Prior Taxane

Total 37

Complete Response 1 (3%)

Partial Response 7 (19%)

Stable Disease 13 (38%)

Progressive Disease

16 (43%)

Low. J Clin Oncol. 2005;23:2726-34.

Case StudyComplete Response

Baseline After 11 Cycles

Ixabepilone Phase II Trial NCI-0229: Grade 3/4 Toxicities

Toxicity, %Prior Taxanes(N=37)

Neutropenia, 16

Thrombocytopenia 8

Myalgia 3

Febrile neutropenia 14

Diarrhea 11

Fatigue 13

Low. J Clin Oncol. 2005;23:2726-34.

Incidence of Peripheral Neuropathy During Ixabepilone Treatment: NCI 0229

CTC Toxicity Grade

0 1 2 3 4

Prior Taxane (N=37)

46 % 29 % 22% 3% –

Tools for Neurotoxicity Assessment

Semmes Weinstein Filaments

Grooved Peg Board Test

Jebsen Test of Hand Function

• In addition:– Questionnaire

(intensity and frequency of symptoms)

– Balance Testing (Tandem Stance and Modified Romberg)

– Nerve Conduction Studies

– Physical exam – CTC grading

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

Test Baseline Onset of Grade 2

Difference Between Baseline and Onset

Grooved peg board (dominant hand) 8* 25** 11

Jebsen Test of Hand Function (non-dominant hand)

1.7 6.1 7.9**

Median Difference Between Matched Subjects

*P < 0.05; **P < 0.01

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

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

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

NCI-0229*

(N=37)

CA-163010†

(N=61)

CA-163009‡

(N=49)CR 1 (3%) - -

PR 7 (19%) 27 (44%) 6 (12%)

SD 13 (35%) 21 (34%) 19 (39%)

PD 16 (43%) 12 (20%) 23 (47%)

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.

Incidence of Peripheral Neuropathy With Ixabepilone

Phase II Trial ScheduleCTC Toxicity Grade %

0 1 2 3 4

NCI-0229 (N=56)

6 mg/m2 over 1 hr qd (x5) q3wk

48 28 20 4 0

CA 163010 (N=65)

40 mg/m2 over 3 hr q3wk

N/A N/A N/A 22 0

CA 163009(N=49)

40 mg/m2 over 3 hr Q3wk

N/A N/A 33 12 0

Eng et al.(N=25)

40 mg/m2 over 3 hr q3wk

48 28 4 20 0

Incidence of Sensory Neuropathy With Microtubule-Stabilizing Agents

Agents ScheduleDose

(mg/m2)Incidence of Gr ≥ 3

Sensory PN (%)

Paclitaxel 1 wk 80-100 10-19

3 wk 135-250 0-33

Docetaxel 1 wk 35-40 0-3

3 wk 60-160 1-14

Ixabepilone 3 wk 6 (qd x5) 3

3 wk 40 7-22

ABI-007 1 wk 100 4

3 wk 175-300 0-10

Phase III Clinical Trials ofIxabepilone Plus Capecitabine

Ixabepilone 40 mg/m2 q3wk plus Capecitabine 1000 mg/m2 bid x 14 days

Capecitabine 1250 mg/m2 bid x 14 days

Trial Inclusion Criteria End Points

CA163046 • Anthracycline-resistant or minimum cumulative dose

• Taxane-resistant

• Measurable tumor

TTP (primary)OSRR

CA163048 • Anthracycline- and taxane-pretreated

• Measurable/nonmeasurable tumor

OS (primary)TTPRR

Randomized

Ixabepilone Shows Synergy With Trastuzumab In Vivo

Lee. ASCO 2005. Abstract 561

Ixabepilone + Pegylated Liposomal Doxorubicin: Metastatic Breast

Cancer

http://www.clinicaltrials.gov/ct/show/NCT00182767

• 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

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 ratehttp://www.clinicaltrials.gov/ct/gui/show/NCT00079326

Trastuzumab, Ixabepilone and Carboplatin in HER2+ MBC

http://www.clinicaltrials.gov/ct/gui/show/NCT00077376

• 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

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

Barlow. J Cell Sci. 2002;115:3469.

Status of Microtubule Assembly May Dictate Drug Sensitivity (Cabral Model)

Sensitive to Stabilizing Agents

Resistant to Stabilizing Agents

Increased Microtubule Assembly

Decreased Microtubule Assembly

Functional Microtubules

Post-translational Modifications of α-Tubulin

• These modifications occur in α-tubulins in MTs (not free form), and are correlated with stable microtubules.

H2NAc

40GEEY

Acetylation

Detyrosination

α-Tubulin H2N GEEY

H2N GEE

= Tumor

= Stromal Staining

Baseline Cycle 2

Patient 1(PR)

Patient 5(PD)

Ixabepilone May Enhance Microtubule Stability Preferentially in Tumor Cells

Acetylated Tubulin

0

2000

4000

6000

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10000

12000

14000

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18000

20000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

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Sensitive ResistantCell lines

Sen

siti

vity

mar

kers

Res

ista

nce

mar

kers

High

Low

Exp

ress

ion

le

vel

Genes Identified That Correlated With Ixabepilone Sensitivity

Lee. ASCO 2005.

Novel Agents

Kinase Inhibitors Involved With Mitosis

IOnconovaPolo-like Kinase

ON01910

IICytokinetics/

GSKKinesin Spindle Protein (KSP)

SB-715992

ICytokineticsKSPSB-743921

IVertexAurora KinaseVX-680

PHASEDEVELOPERTARGETNAME

Epidermal Growth Factor Receptor Family

INovartisEGFR, HER2, and VEGFR

AEE788

IIPfizer, NCIEGFR and

HER2CI-1033

IIIAbgenix/AmgenEGFRPantimimumab

IIGlaxoSmithKlineEGFR and

HER2Lapatinib

PHASEDEVELOPERTARGETNAME

CONTROL - No Therapy

C1

AZD2171 30 mg qd

DOCETAXEL 75mg/m2 DOXORUBICIN 50mg/m2

CYCLOPHOSPHAMIDE 600mg/m2

FILGRASTIM 300 mcg Days 2-11or PEGFILGRASTIM 6mg Day 2

C2 C3 C4 C5 C6 C7

Surgery, XRT and hormonal therapy as indicated

AZD2171 Neoadjuvant NCI Trial

Accrual Goal: 30 patients

Cycle 1: 7 days Cycles 2-7: Every three weeks

N=20

N=10

DYNAMIC MRI

TUMOR BIOPSIES, SERUM STUDIES

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

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

Miscellaneous Agents

Preclinical/I (1Q 06)

ProLXPI-3-Kinase

InhibitorPX886

IINovartisPan-kinase

inhibitorPKC412

I/IINovartismTORRAD-001

IIINovartisVEGF-R inhibitor

PTK-787

IIPfizer/SutentPan-kinase

inhibitorSU-11248

PHASEDEVELOPERTARGETNAME

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

Acknowledgments

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

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