Combination Of Ixabepilone Research Articles

Therapy options for metastatic triple negative breast cancer

Metastatic triple-negative breast cancer remains the most unfavourable among all breast cancer subtypes from the prognostic point of view. Despite the active introduction into practice of combinations of cytostatics with immunotherapeutic agents, as well as PARP inhibitors, sequential lines of chemotherapy with the median overall survival which does not exceed 15 months remains the main method of treating patients in this group. This breast cancer subtype is characterized by a rapid development of drug resistance at the early stages of systemic treatment and a predominantly visceral progression, which determines a low life expectancy in patients. The combination of capecitabine and ixabepilone has proved to be effective in the treatment of tumours that are resistant to taxanes and anthracyclines. The use of this combination is characterized by an acceptable and controlled toxicity profile. This article presents a clinical case of therapy with a combination of ixabepilone and capecitabine of a patient with breast cancer progression during the previous therapy of taxanes, a platinum-based doublet chemotherapy and eribulin. This approach, together with symptomatic laparocentesis and pleurodesis, allowed for overall survival exceeding 45 months with the preservation of a satisfactory functional status of the patient.

Preclinical Evaluation of Ixabepilone in Combination with VEGF Receptor and PARP Inhibitors in Taxane-Sensitive and Taxane-Resistant MDA-MB-231 Breast Cancer Cells

Long-term use of cytotoxic agents promotes drug-resistance in triple-negative breast cancer (TNBC). The identification of new drug combinations with efficacy against drug-resistant TNBC cells in vitro is valuable in developing new clinical strategies to produce further cancer remissions. We undertook combination analysis of the cytotoxic agent ixabepilone with small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and poly (ADP-ribose) polymerase (PARP) in taxane-sensitive (231C) and taxane-resistant (TXT) MDA-MB-231-derived cells. As single agents, the VEGFR inhibitors cediranib and bosutinib decreased both 231C and TXT cell viability, but four other VEGFR inhibitors and two PARP inhibitors were less effective. Combinations of ixabepilone with either cediranib or bosutinib synergistically decreased 231C cell viability. However, only the ixabepilone/cediranib combination was synergistic in TXT cells, with predicted 15.3-fold and 1.65-fold clinical dose reductions for ixabepilone and cediranib, respectively. Flow cytometry and immunoblotting were used to further evaluate the loss of cell viability. Thus, TXT cell killing by ixabepilone/cediranib was enhanced over ixabepilone alone, and expression of proapoptotic cleaved caspase-3 and the Bak/Bcl-2 protein ratio were increased. These findings suggest that the synergistic activity of the ixabepilone/cediranib combination in taxane-sensitive and taxane-resistant cells may warrant clinical evaluation in TNBC patients.

Combination of Ixabepilone and Capecitabine in Metastatic Triple Negative Breast Cancer. Clinical case

Combination of Ixabepilone and Capecitabine in Metastatic Triple Negative Breast Cancer. Clinical case

Systematic review of ixabepilone for treating metastatic breast cancer.

Ixabepilone is now a Food and Drug Administration-approved therapeutic option for patients with metastatic breast cancer (MBC) whose disease has progressed despite prior anthracycline and taxane therapy. We conducted a systematic review and meta-analysis to systematically evaluate the efficacy and safety of ixabepilone for treating metastatic breast cancer. A systematic review and meta-analysis were conducted. Randomized controlled studies applying ixabepilone for treating MBC were included. The primary outcome was Overall Survival (OS). The authors of primary articles were contacted and methodological quality was evaluated. Subgroups were drawn based on intervention measures; heterogeneity and bias were discussed. Eight studies with 5247 patients were included. Compared with a weekly schedule, a triweekly schedule of ixabepilone was better at improving overall response rate (ORR), while there were no differences in improving OS and progression-free survival (PFS). Ixabepilone plus capecitabine was superior to capecitabine monotherapy in improving OS, PFS and ORR. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. There was no difference in the improvement of ORR, clinical benefit rate (CBR) and disease control rate (DCR) between ixabepilone and eribulin. Current evidence suggests that a triweekly schedule of ixabepilone is more effective than weekly dosing in improving ORR. Use of ixabepilone in combination with capecitabine possesses superior clinical efficacy to the use of capecitabine alone. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. The efficacy and safety between ixabepilone and eribulin were identical.

Abstract B113: Phase I and pharmacokinetic study of ixabepilone and temsirolimus in adult patients with advanced solid tumors

Abstract Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been identified as a synergistic combination in preclinical models. Additional studies have further evaluated the impact of treatment sequence with paclitaxel and rapamycin where administration of rapamycin after paclitaxel was associated with synergy. In our preclinical studies, apoptosis was greater with the combination of ixabepilone and temsirolimus than with either single agent. Thus, a Phase I study of the combination of Ixabepilone (IXB) and Temsirolimus (TEM) was performed to determine the maximum tolerated dose (MTD), describe the toxicity profile and characterize the pharmacokinetics of each agent in patients with advanced cancer. Methods: Eligible patients included adults with a histologically confirmed solid tumor malignancy that was metastatic or unresectable who have received ≤ 2 chemotherapy regimens and had ECOG PS ≤ 2 with adequate bone marrow, renal and hepatic function. Using a standard 3+3 design, patients were treated with IXB IV over 3 hours on day 1 and TEM IV over 0.5 hours on days 2 and 9 (schedule A) or days 1 and 8 (schedule B) every 21 days. Pharmacokinetics (PK) was performed in patients on schedule B. Results: 22 evaluable patients were enrolled between August 24, 2011 and November 7, 2014. The final 7 patients were treated on schedule B. Patients were treated at 3 dose levels of IXB (mg/m2)/TEM (mg): DL1- 24/15 (A- 6 pts, B- 2 pts); DL2- 32/15 (A- 3 pts, B- 5 pts); DL3- 32/20 (A- 6 pts). One patient had DLT (grade 3 hypophosphatemia) and 1 patient expired due to disease progression in DL1A. No DLTs were seen in DL2A. The dose was escalated to DL3 and 1 patient had DLT (grade 3 hypokalemia). Following a change to schedule B, 5 patients were enrolled to DL2B and 1 experienced DLT (grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 sepsis). The dose was reduced to DL1B and 2 more patients were enrolled, both of whom experienced DLTs (grade 5 bronchopulmonary hemorrhage and grade 4 neutropenia). Grade 4 events considered at least possibly related to treatment occurred in 6 of 22 patients (27%) and included cardiac arrest, dyspnea, hypokalemia, hypoxia, multi-organ failure, decreased platelets, acute renal failure, neutropenia, neutropenic fever, sepsis, and decreased WBCs. Patients received a median of 4 cycles (range, 1-10+). Partial response was noted in 1 patient and stable disease was noted in 11 patients. One patient remains on treatment after 11 cycles. IXB (plasma), TEM (whole blood) and sirolimus (whole blood) concentrations were measured by a sensitive, specific lc/ms/ms assay. A 24 and 32 mg/m2 IXB dose yields Cmax of 159 and 312 ng/ml, respectively. The IXB CLp and t1/2 values were 31 L/h and 76 h, respectively. The Cmax, Cl and t1/2 values after a 15 mg TEM dose were 518 ng/ml, 6.4 L/h and 11 h, respectively. The Cmax and t1/2 values of sirolimus after a 15 mg TEM dose were 37.6 ng/ml and 49 h, respectively. The PK of IXB and TEM in combination were similar to those reported for each drug alone. Conclusions: The reasons for the unpredictable, severe toxicity of the IXB/TEM combination are unclear. The MTD could not be determined, and enrollment was discontinued. This trial exemplifies challenges associated with development of drug combinations with mTOR inhibitors. Supported in part by UM1 CA186686 and P30 CA15083. Clinical trial information: NCT01375829 Citation Format: Joel M. Reid, Michael E. Menefee, Felix Boakye-Agyeman, Chad A. Walden, Charles Erlichman, Keith C. Bible. Phase I and pharmacokinetic study of ixabepilone and temsirolimus in adult patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B113.

Ixabepilone Alone or With Cetuximab as First-Line Treatment for Advanced/Metastatic Triple-Negative Breast Cancer

BackgroundDespite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced nonresectable and/or metastatic breast cancer. Patients and MethodsWomen were randomly assigned to receive either ixabepilone (40 mg/m2) every 21 days (n = 40), or ixabepilone (40 mg/m2) every 21 days with cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2) once weekly (n = 39). The primary end point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy. ResultsOf 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6-46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2-52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events. ConclusionIxabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required to improve patient outcomes.

Ixabepilone and eribulin mesylate: two novel agents approved for the chemotherapeutic treatment of metastatic breast cancer

While the majority of breast cancer patients present with early stage disease, 40% of these patients will eventually progress to metastatic disease. Resistance to existing chemotherapeutic agents continues to pose a challenge in the management of these patients. This review will analyze the two most recently approved chemotherapy drugs for the treatment of breast cancer; ixabepilone and eribulin mesylate. Ixabepilone is a semisynthetic analog of epothilone B, and is thought to overcome taxane resistance via disruption to microtubule homeostasis. Two Phase III studies, one by Rugo et al. and the other by Thomas et al., showed improvement in progression-free survival with the combination of ixabepilone and capecitabine to approximately 6 months compared with 4.2 months in the capecitabine-alone group in both trials. These resulted in ixabepilone being approved for use alone or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer after failure of an anthracycline and a taxane in either the adjuvant or the metastatic setting. The drug has been shown to have activity even in heavily pretreated patients who have received at least two prior chemotherapy regimens for the treatments of metastatic disease. The main adverse events were noted to be fatigue, cytopenias and peripheral sensory neuropathy, all of which were manageable and reversible. Eribulin mesylate is another novel agent that has been approved for the treatment of metastatic breast cancer. It functions by inhibiting mitotic-spindle formation and has demonstrated efficacy against various taxane-resistant tumor cell lines. Median progression-free survival was approximately 3 months and overall survival ranged from 9 to 13 months amongst the various trials. Eribulin mesylate is approved to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for metastatic disease, including both anthracycline- and taxane-based chemotherapy regimens. The most common toxicities observed were fatigue, nausea, cytopenias and peripheral neuropathy. In conclusion, both drugs provide additional options for patients who have progressed on other agents.

Abstract P5-20-08: Phase II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)

Abstract Background: Ixa is a novel semi-synthetic epothilone microtubule blocking agent with activity in taxane and anthracycline-resistant MBC. D is a potent small molecule tyrosine kinase inhibitor with substantial activity against SRC family non-receptor kinases, known to play multiple roles in promoting tumor growth and metastases. D inhibits cellular SRC autophosphorylation in cell lines that highly express SRC and inhibits in vivo activation in a broad array of tumors in nude mice. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. A phase I trial of the combination determined the maximally tolerated doses of ixabepilone at 20 mg/m2 weekly and dasatinib 100 mg po daily with objective responses seen. Neutropenia was the dose limiting toxicity. Methods: Multicenter single arm phase II trial. Eligibility: Measurable or evaluable disease by RECIST 1.0, ECOG PS 0–2, HER2− or HER2 refractory, no CYP 3A4 inducers or inhibitors, no H2 blockers or PPIs, no pleural/pericardial effusion, exposure to 1 or 2 prior lines of chemotherapy in the metastatic setting, peripheral neuropathy ≤ grade 1. The primary endpoint was progression-free survival (PFS). Assessment for response was performed every 8 weeks. The treatment schedule was D at 100 mg po daily starting day 1, and Ixa 20 mg/m2 Day 1, 8, 15 every 28 days (1 cycle). Results: The study met its accrual goal with 50 patients (pts) enrolled on the phase II dosing, including six from the phase I portion. As of May 21, 2012, 47 pts are evaluable. The median age was 55 (range, 34–70), 19 African-American, 46 ECOG PS 0–1, median number of metastatic sites, three. Forty pts had prior taxanes, 24 prior anthracyclines. Median PFS was 6.0 months (95% CI, 2.9–8.0), achieving pre-specified value of interest for further study of the combination. The overall unconfirmed response rate was 14.9% with a clinical benefit rate (CR+PR + stable at 24 weeks) of 25.5%. Six pts continued D monotherapy after eight cycles of Ixa + D. All-grade adverse events (AEs) occurring in >15% of pts included anemia (45%), neutropenia (32%), nausea (51%), vomiting (32%) diarrhea (51%), fatigue (53%), anorexia (25%) dysgeusia (32%), headache (28%), peripheral neuropathy (34%) cough (28%) alopecia (21%) and hypokalemia (19%). Grade 3/4 adverse events occurred in 30 patients, with only four experiencing grade 4 AEs, three neutropenia and one chest pain. No grade 3/4 febrile neutropenia occurred. Grade 3 AEs of interest included two pts with peripheral neuropathy and 1 with pleural effusion. Conclusions: The combination of Ixabepilone weekly + Dasatinib orally daily is an active and well tolerated regimen in pretreated MBC with manageable toxicity. Updated results will be reported. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-08.

A Phase I Study of Ixabepilone in Combination With Epirubicin in Patients With Metastatic Breast Cancer

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer. Patients and MethodsPatients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). ResultsForty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m2 (n = 6) in combination with 75 mg/m2 epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m2 was 30 mg/m2, and the DLT dose was 35 mg/m2 with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels. ConclusionsThe combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m2, followed by ixabepilone 30 mg/m2 every 3 weeks.

P5-19-09: Phase II Trial of Ixabepilone Plus Carboplatin in Patients with Metastatic Breast Cancer: The ECLIPSE Study.

Abstract Introduction: Ixabepilone adds to the antitumor effectiveness of capecitabine in both ER+ and triple negative (TN) breast cancer. Ixabepilone has antitumor activity in taxane-refractory patients, and novel combinations are needed in this poor prognosis population. Carboplatin combined with gemcitabine or paclitaxel has activity in metastatic breast cancer; there is also demonstrated activity of the gemcitabine/carboplatin combination in the ER+ versus TN subsets. A Phase I study of ixabepilone + carboplatin in solid tumor patients demonstrated the safety of this combination.1 We conducted a Phase II trial of ixabepilone + carboplatin at the doses and schedule used in the Phase I trial to determine its effectiveness in hormone receptor positive (HR+) and TN patients. Methods: This was a Phase II, open label, nonrandomized parallel, noncomparative study of 2 groups. Patients could have received up to 2 lines of treatment for metastatic disease. All patients received ixabepilone 20 mg/m2 on Days 1 and 8 and carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. Patients were stratified as either (HR+) (n=50) or (TN) ER-/PR-/HER2− (n=53). Patients received drug until PD or intolerable toxicity. Patients continued treatment for as long as they responded (CR, PR, or SD). The primary objective was to evaluate objective response rate (ORR). Secondary objectives included evaluation of clinical benefit rate (CBR) defined as ORR (CR+PR)+SD≥6 months, progression-free survival (PFS), overall survival (OS), duration of responses, and toxicity. Results: Based on preliminary data, 96 patients (55 [57.3%] HR+ and 40 [41.7%] TN) received study treatment, with 1 patient found ineligible. Median age was 55.2 years; all were females; baseline PS of 0/1/2 was 50/44/2; stage at diagnosis I/II/III/IV/unknown was 12/38/23/21/2, respectively. PR was 26.3% overall. There were no CRs. CBR overall was 41.1% (39), 52.7% (29) for HR+ patients, and 25.6% (10) for TN patients. Median PFS was 7.6 months, and median OS was 12.7 months. The median time to response and duration of response in patients achieving a PR was 1.7 and 6.5 months, respectively. Grade 3/4 hematological toxicities included 49% neutropenia, 10.4% anemia, and 4.2% thrombocytopenia. The most common grade 3/4 non-hematologic toxicities included fatigue (8.3%), nausea (6.3%), neuropathy (6.3%), vomiting (5.2%), and dehydration (5.2%). Of 32 deaths during the study, one was due to neutropenic sepsis, and 25 were due to PD. Conclusion: The combination of ixabepilone plus carboplatin was a tolerable and active regimen for both HR+ and TN breast cancer. In general, it had expected hematologic and manageable non-hematological toxicities. Further follow-up of the remaining 12 patients still on treatment is ongoing. 1. Plummer R, et al. Clin Cancer Res. 2008 Dec 15;14(24):8288–8294. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-09.

Abstract C24: Phase I trial of dasatinib and ixabepilone in patients with solid tumors.

Abstract Background: Ixabepilone is an epothilone B analog that stabilizes tubulin, disrupts homeostasis and induces apoptosis. Dasatinib is a potent oral tyrosine kinase inhibitor (TKI), which inhibits multiple targets including SRC. Synergistic activity has been reported when combining dasatinib with chemotherapy agents. This phase I study was conducted to determine the dose-limiting toxicities (DLTs), maximum tolerated doses (MTDs), pharmacokinetics (PK) and preliminary antitumor activity for ixabepilone and dasatinib when used in combination. Methods: Patients with metastatic or unresectable solid tumors who progressed on standard therapy received ixabepilone and dasatinib at escalating doses. An expansion cohort was formed after the MTD was reached. PK studies were performed. Results: Nineteen patients were enrolled. No DLTs were seen at dose level (DL) 1 (ixabepilone 30 mg/m2 IV Q 3 weeks, dasatinib 100 mg PO QD). At DL 2 (ixabepilone 40 mg/m2 IV Q 3 weeks, dasatinib 100 mg PO QD), the second patient had 3 DLTs (grade 3 diarrhea, grade 4 neutropenia and grade 3 febrile neutropenia), thus DL 2 was expanded to include 6 patients. No additional DLTs were seen at DL 2. At DL 3 (ixabepilone 40 mg/m2 IV Q 3 weeks, dasatinib 150 mg PO QD), the first patient developed grade 3 diarrhea during cycle 2 and the second patient had a DLT (grade 3 diarrhea) and grade 3 mucositis during cycle 2. Accrual to DL 3 was halted due to these toxicities and MTDs were designated to be ixabepilone 40 mg/m2 IV every 3 weeks and dasatinib 100 mg PO daily (DL 2). Additional 8 patients were then enrolled to DL 2. Three of these patients experienced DLTs (grade 4 neutropenia, grade 3 hyperkalemia and grade 3 fatigue). The best responses included one (5%) partial response (PR) in a lung cancer patient. Twelve (63%) patients had stable disease (SD) for at least 2 cycles. Altogether 13 (68%) patients came off study due to toxicities. Conclusion: The combination of ixabepilone and dasatinib showed modest clinical activity with doses 40 mg/m2 IV every 3 weeks and100 mg PO QD, respectively. Treatment related toxicities were seen frequently. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C24.

How do I Treat “Triple-Negative” Disease

Over the recent years, there has been an increasing recognition that triple-negative breast cancer constitutes a separate, albeit heterogeneous, entity arising from distinct oncogenic pathways. Despite its aggressive clinical behavior, triple-negative disease responds favorably to cytotoxic chemotherapy resulting in high response rates. Nonetheless, the relapse rates are high and, in the absence of targeted therapies to significantly alter its natural history, the prognosis can be poor. Most of the trials conducted in the past that led to the formulation of the current guidelines have indiscriminately lumped triple-negative disease with receptor-positive subtypes. Therefore, there are relatively scant data regarding how standard approaches specifically apply for triple-negative disease. By virtue of its chemosensitive nature and high probability of achieving a complete pathologic response, neoadjuvant chemotherapy in early-stage/operable and locally-advanced/inoperable triple-negative disease is highly recommended. The indications for adjuvant chemotherapy are the same as in receptor-positive tumors, although endocrine therapies or agents targeting Her2 signaling have no established role in triple-negative disease. The optimal chemotherapy is not entirely clear; however, by virtue of their efficacy in breast cancer in general, anthracycline-containing regimens are the most widely used. The incorporation of taxanes in the regimen is supported by retrospective analyses. There is scant evidence to recommend any particular agent in the metastatic setting, although the combination of ixabepilone with capecitabine was shown to be active specifically in triple-negative disease. Given the uncertainty in the optimal management of triple-negative disease, the shortcomings of contemporary regimens, and the strong rationale of novel therapies, participation in clinical trials should be strongly considered at any stage of the disease.

Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer.

1083 Background: Data on chemotherapy for elderly patients (pts) with metastatic breast cancer (MBC) are limited. We performed a retrospective analysis of elderly pts (≥65 years of age) enrolled into the pivotal phase III studies of ixabepilone plus capecitabine versus capecitabine alone in order to determine the efficacy and safety of these agents compared with the overall population. Methods: 1,973 pts with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase III studies to receive either ixabepilone (40 mg/m2 IV over 3h q3w) plus capecitabine (1,000 mg/m2 PO BID x 14d q3w) or capecitabine alone (1,250 mg/m2 PO BID x 14d q3w). Due to the similarity of the study populations, individual patient data from both studies were pooled. 251 randomized pts were ≥65 years of age. Results: Efficacy endpoints in the elderly population were consistent with pts <65 years of age. The combination of ixabepilone plus capecitabine was favored over capecitabine monotherapy (Table). Grade 3 or 4 hematologic adverse events (AEs) occurring in >5% of pts receiving ixabepilone plus capecitabine were similar in pts <65 and ≥65 years of age: neutropenia 21% vs 26% and febrile neutropenia 5% vs 10%. Non-hematologic AEs occurring in >5% of pts receiving ixabepilone plus capecitabine were also similar in these age groups and included: fatigue 10% vs 12%, asthenia 6% vs 14%, peripheral sensory neuropathy 14% vs 17%, and hand-foot syndrome 20% vs 19%. Conclusions: The combination of ixabepilone plus capecitabine maintains its efficacy in elderly pts with anthracycline and taxane pretreated MBC. Furthermore, the safety profile of ixabepilone plus capecitabine is similar in pts <65 and ≥65 years of age. <65 years of age ≥65 years of age Ixa + cape cape Ixa + cape cape n 751 740 104 116 ORR,* n (%) 317 (42) 194 (26) 38 (37) 22 (19) Median PFS, mo 5.6 4.2 5.5 3.9 HR (95% CI) 0.81 (0.73–0.90) 0.77 (0.59–1.02) n 868 853 116 135 Median OS, mo 14.7 13.9 13.9 12.2 HR (95% CI) 0.90 (0.81–1.01) 1.07 (0.81–1.40) * ORR and PFS were computed on all randomized pts with measurable disease strata.

Q-TWiST analysis of ixabepilone in combination with capecitabine on quality of life in patients with metastatic breast cancer

Combination therapy with ixabepilone and capecitabine (cape) is approved for use in patients with locally advanced/metastatic breast cancer that is resistant to treatment with anthracyclines or taxanes. The current study evaluated the trade-off between quality and quantity of life using quality-adjusted time without symptoms or toxicity (Q-TWiST) outcomes. Within the trial, 752 women were randomly assigned to receive either the combination of ixabepilone and cape (once every 21 days) or cape alone (on days 1-14). The area under the survival curve was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity, and recurrence (relapse [REL]). The mean time in each health state was weighted by a range of utilities and summed to estimate quality-adjusted survival (QAS). Patient-reported outcomes were also evaluated using the Functional Assessment of Cancer Therapy (FACT)-Breast Symptom Index (FBSI). A statistically significant difference between groups with regard to change from baseline FBSI scores favoring the cape group was observed (P = .0002), but no differences were observed after adjusting for deaths in the analysis. All combinations of utilities for REL and TOX resulted in an observed difference in QAS favoring combination therapy. Differences were found to be statistically significant for comparisons, with higher tolerance for TOX. QAS was found to be greater for the combination therapy group (42.2 weeks vs 38.4 weeks), assuming the base case scenario of utility equal to 0.5 for both TOX and REL (P = .0227). The Q-TWiST analysis supports a positive benefit-risk ratio for the combination of ixabepilone plus cape in patients with advanced/metastatic breast cancer that is refractory to anthracyclines and taxanes versus cape alone, despite the potential for added toxicities with combination therapy.

Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer

Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥ 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥ 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim.

Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m(2) intravenously on day 1) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14) or capecitabine alone (2,500 mg/m(2) on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death. There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible. This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.

Phase I study of ixabepilone in combination with capecitabine in Japanese patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

e13095 Background: Ixabepilone is a new class of nontaxane tubulin polymerization agents and is approved as both monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer (MBC) in the United States. Primary objective of this study was to establish the maximum tolerated dose (MTD) and the recommended dose (RD) of ixabepilone plus capecitabine in Japanese MBC patients (pts) previously treated with an anthracycline and a taxane. Methods: Ixabepilone (Ixa) was administered intravenously over 3 hours on day 1 and capecitabine (Cap) was given orally twice daily from days 1 to 14. Treatment cycles were repeated every 3 weeks. Three cohorts were planned as follows: Ixa 32 mg/m2+ Cap 1,650 mg/m2, Ixa 40 mg/m2+ Cap 1,650 mg/m2 and Ixa 40 mg/m2 + Cap 2,000 mg/m2 respectively. If no dose-limiting toxicity (DLT) was observed within 3 pts in the cohort, another 3 pts were enrolled and treated in next cohort. Results: Nine MBC pts, median age of 58 (range 30-69), with ECOG PS 0-1 received treatments at median 10 cycles (2-12). Grade (G) 3 neutropenia was observed in all pts and G4 neutropenia was seen in 5 pts; however, no febrile neutropenia was documented. Nonhematologic toxicities were mild to moderate except for G3 fatigue (2 pts) and G3 AST elevation (1 pt). No DLTs were observed, therefore the MTD, consistent with RD, was determined as ixabepilone 40 mg/m2 and capecitabine 2,000 mg/m2. Of the 9 pts, 1 had complete response, 4 had partial response, 2 had stable disease, and 2 had disease progression. All 3 pts at the maximum dose level responded (1CR, 2PR) and had long treatment duration (12 cycles). Conclusions: Ixabepilone in combination with capecitabine was well tolerated and highly active in Japanese MBC patients previously treated with both an anthracycline and a taxane. The recommended phase II dose of the combination is ixabepilone 40 mg/m2and capecitabine 2,000 mg/m2. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

To analyze the safety, efficacy, and toxicity profile of ixabepilone and capecitabine combination in metastatic breast cancer patients in Indian population.

e11513 Background: With the increasing use of anthracyclines and taxanes in the adjuvant setting, improved survival of patients with breast cancer, there is an unmet need of developing second-line chemotherapeutic agents which can be used specially in the subset of HER2-negative patients. Methods: Patients had to have histologically proven breast cancer, at least one measurable disease, age >18 years, ECOG scale 0-2. Patients with CNS metastasis deranged LFT, estimated life survival less than three months were excluded. Ixabepilone was administered as 40 mg/m2 q 3 weekly and capecitabine as 850 mg/m2 bd for 14 days. Prophylactic growth factor support was not given. Patients were evaluated before treatment and subsequently every 3 cycles until progression. The primary end point was to assess time-to-tumor progression, toxicity profile, and quality of life. Results: 25 patients were analyzed. The median number of cycles received was 5. 15 patients had partial response whereas 2 patients achieved complete response. 5 patients had stable disease whereas 3 patients had progressive disease. 3 patients could not tolerate the combination therapy and had to discontinue treatment. The median time-to-tumor progression was 5.8 months. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (33%), anorexia (22%), and neuropathy (41%). The incidence of hand foot syndrome was 30%. The most distressing symptom was neuropathy and hand foot syndrome. Conclusions: The combination of ixabepilone and capecitabine, though effective, is associated with significant neuropathy and hematological toxicity. A lot of research needs to be done to develop new chemotherapeutic agents that are equally efficacious, cost effective, and maintain a good quality of life for the patients. No significant financial relationships to disclose.

Implications of Anthracycline-Resistant and Taxane-Resistant Metastatic Breast Cancer and New Therapeutic Options

Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options. Drug resistance can occur due to various mechanisms including modification of drug efflux membrane transporters such as P-glycoprotein, as well as alterations in beta-tubulin. The novel epothilone B analog, ixabepilone, which has low susceptibility to various drug-resistance mechanisms, has demonstrated preclinical activity in drug-resistant breast cancer. The clinical activity of ixabepilone was evaluated in metastatic breast cancer patients with highly pretreated and/or resistant/refractory disease. Results were reviewed from three phase II trials in which ixabepilone was administered as monotherapy and one phase III trial that evaluated ixabepilone in combination with capecitabine. As a single agent, ixabepilone demonstrated activity in women who were heavily pretreated and resistant to an anthracycline, a taxane, and/or capecitabine. The combination of ixabepilone and capecitabine was significantly more active than capecitabine alone in patients with prior treatment or resistance to anthracyclines and taxanes. Treatment-related adverse events were generally low grade except for grade 3/4 toxicities, including neutropenia (53-54%) and reversible peripheral sensory neuropathy (14-16%). Ixabepilone has significant activity in patients with heavily pretreated metastatic breast cancer who are disease resistant or refractory to anthracyclines and taxanes. Further clinical evaluation of this agent in patients with drug-resistant breast cancer and in specific patient subsets is warranted.