activity of epothilones in breast cancer and other tumor types

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

Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer

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)


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


Antitumor Activity: Taxane-Resistant 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.

Modified from data on file, Bristol-Myers Squibb

Med

ian

Tu

mo

r W

t. (

mg

)

Days Post-Tumor Implant

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)

1000

Days Post-Tumor Implant

10

100

40 50 60 70 80 90M

edia

n T

um

or

Wt.

(m

g)

10

100

1000

40 70 100 130 16070 100


Ixabepilone (BMS-247550)

Epothilone B

Ixabepilone

Epothilone B: Natural macrolide produced by myxobacterium Sorangium cellulosum

Ixabepilone: Semisynthetic epothilone B analog (aza-epothilone B)


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.

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


Ixabepilone in Metastatic and Locally Advanced Breast Cancer (NCI-0229)

Post-treatment biopsy

Baseline biopsy

Cycle 1 (3 weeks) Cycle 2 Cycle 3

Phase II trial Daily x 5 schedule (6 mg/m2 per day)

– Patients previously treated with a taxane

– Taxane-naive patients

Daily x 5Daily x 5 Daily x 5


Phase II Clinical Trial of Ixabepilonein Breast Cancer (NCI-0229)

Outcome, n (%) Prior Taxane(n = 37)

Complete response 1 (3)

Partial response 7 (19)

Stable disease 13 (38)

Progressive disease 16 (43)

43% partial response in taxane-naive patients

Low JA et al. J Clin Oncol. 2005;23:2726-2734.


Baseline After 11 cycles

Complete Response: Taxane-Treated Group


Phase II Ixabepilone Trial (NCI-0229): Grade 3/4 Toxicity

Toxicity (%)Taxane-Treated

(n = 37)

Neutropenia 16

Thrombocytopenia 8

Myalgia 3

Febrile neutropenia 14

Diarrhea 11

Fatigue 13



Phase II Ixabepilone Trial (NCI-0229): Peripheral Neuropathy Neurologic function evaluated before ixabepilone treatment

PatientsCTC Toxicity Grade, %

1 2 3

Taxane-treated (n = 37) 29 22 3


CTC, Common Toxicity Criteria.


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)


Phase II Ixabepilone Trial (NCI-0229): Neurologic Function


Microtubule Stability: Acetylated Tubulin

At Baseline Cycle 2

PartialResponse

ProgressiveDisease

Tumor Stromal staining



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


Phase II Ixabepilone Clinical Trials in Metastatic Breast Cancer

Outcome, n (%)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%)*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.


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 Schedule Dose (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


Neoadjuvant Ixabepilone Trial (CA 163080)

Llombart Cussac et al. ASCO 2005. Abstract 586

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


Planned and Ongoing Trials of Ixabepilone in

Metastatic Breast Cancer


Phase III Clinical Trials ofIxabepilone + Capecitabine

Ixabepilone 40 mg/m2 every 3 wks plus Capecitabine 1000 mg/m2 bid x 14 days

Capecitabine 1250 mg/m2 bid x 14 daysPatients with metastatic or

locally advanced

breast cancer

Trial Inclusion Criteria Endpoints

CA163046 Anthracycline-pretreated/resistantTaxane-resistantMeasurable tumor

TTP (primary)OSRR

CA163048 Prior anthracycline/taxaneMeasurable/nonmeasurable tumor

OS (primary)TTPRR


Ixabepilone + Pegylated Liposomal Doxorubicin: Metastatic Breast Cancer

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

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


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


Trastuzumab, Ixabepilone, and Carboplatin in HER2+ MBC

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

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


Phase I/II Ixabepilone Studies: Other Tumor Types


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.


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


Other Epothilones Under Development


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.


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 cancerOvermoyer B et al. ASCO 2005. Abstract 778.Yee L,et al. ASCO 2005. Abstract 7127.


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

activity of epothilones in breast cancer and other tumor types

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