activity of epothilones in breast cancer and other tumor types sandra m. swain, md professor of...
TRANSCRIPT
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)
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
Ixabepilone (BMS-247550)
Epothilone B
Ixabepilone
Epothilone B: Natural macrolide produced by myxobacterium Sorangium cellulosum
Ixabepilone: Semisynthetic epothilone B analog (aza-epothilone B)
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
Baseline After 11 cycles
Complete Response: Taxane-Treated Group
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Low JA et al. J Clin Oncol. 2005;23:2726-2734.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Low JA et al. J Clin Oncol. 2005;23:2726-2734.
CTC, Common Toxicity Criteria.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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)
Low JA et al. J Clin Oncol. 2005;23:2726-2734.
Phase II Ixabepilone Trial (NCI-0229): Neurologic Function
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
Microtubule Stability: Acetylated Tubulin
At Baseline Cycle 2
PartialResponse
ProgressiveDisease
Tumor Stromal staining
Low JA et al. J Clin Oncol. 2005;23:2726-2734.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
Planned and Ongoing Trials of Ixabepilone in
Metastatic Breast Cancer
Beyond Taxane Therapy: Emerging Role of Epothilones 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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
Phase I/II Ixabepilone Studies: Other Tumor Types
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
Other Epothilones Under Development
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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.
Beyond Taxane Therapy: Emerging Role of Epothilones in Metastatic Breast Cancer
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