The Experts below are selected from a list of 543 Experts worldwide ranked by ideXlab platform
Linda T Vahdat - One of the best experts on this subject based on the ideXlab platform.
-
efficacy and safety of Ixabepilone and capecitabine in patients with advanced triple negative breast cancer a pooled analysis from two large phase iii randomized clinical trials
Clinical Breast Cancer, 2018Co-Authors: Hope S Rugo, Eva Thomas, Hyun-cheol Chung, Henri Roche, Guillermo Lerzo, Igor Vasyutin, Amit Patel, Linda T VahdatAbstract:Abstract Introduction The purpose of this study was to evaluate the safety and efficacy of Ixabepilone plus capecitabine in patients with metastatic or locally advanced triple-negative breast cancer (TNBC). Patients and Methods We conducted a pooled analysis of patients with TNBC enrolled in 2 phase III trials ( NCT00080301 and NCT00082433 ), pretreated or resistant to an anthracycline and a taxane. In each study, patients were randomized to receive Ixabepilone 40 mg/m2 (3-hour intravenous infusion, day 1), plus oral capecitabine 1000 mg/m2 twice daily (days 1-14), or capecitabine alone 1250 mg/m2 twice daily (days 1-14), every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. Results In the subset of patients with TNBC (N = 443), the addition of Ixabepilone to capecitabine compared with capecitabine alone prolonged median progression-free survival from 1.7 months to 4.2 months (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52-0.78; P Conclusion Adding Ixabepilone to capecitabine is effective in prolonging progression-free survival and improving objective response rate compared with capecitabine alone in patients with advanced TNBC previously treated with anthracyclines and taxanes.
-
CLINICAL TRIAL
2016Co-Authors: Linda T Vahdat, Agustin A Garcia, Nicholas Iannotti, Prashanth Gopalakrishna, Charles Vogel, Christine Pellegrino, Deborah L. Lindquist, Joseph A SparanoAbstract:Eribulin mesylate versus Ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropath
-
eribulin mesylate versus Ixabepilone in patients with metastatic breast cancer a randomized phase ii study comparing the incidence of peripheral neuropathy
Breast Cancer Research and Treatment, 2013Co-Authors: Linda T Vahdat, Agustin A Garcia, Charles L Vogel, Christine M Pellegrino, Deborah Lindquist, Nicholas Iannotti, Prashanth Gopalakrishna, Joseph A SparanoAbstract:Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin mesylate or Ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for Ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m2, 2–5 min intravenous on days 1 and 8) or Ixabepilone (40 mg/m2, 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 Ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and Ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with Ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for Ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and Ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later.
-
maintenance of clinical efficacy after dose reduction of Ixabepilone plus capecitabine in patients with anthracycline and taxane resistant metastatic breast cancer a retrospective analysis of pooled data from 2 phase iii randomized clinical trials
Clinical Breast Cancer, 2012Co-Authors: Vicente Valero, Eva Thomas, Linda T Vahdat, Henry L Gomez, Pralay Mukhopadhyay, Linda D Bosserman, Eduard Vrdoljak, Alexey Manikhas, Carlos Medina, Diane OpattAbstract:Abstract Background This retrospective analysis aimed to determine whether early dose reduction impacts the efficacy of Ixabepilone plus capecitabine in women with metastatic breast cancer (MBC). Patients and Methods In 2 phase III trials, patients (N = 1973) with anthracycline/taxane–pretreated MBC were randomized to receive Ixabepilone 40 mg/m 2 on day 1 plus capecitabine 1000 mg/m 2 twice daily (BID) on days 1 to 14 or single-agent capecitabine 1250 mg/m 2 BID on days 1 to 14 of a 3-week course. Because of the similar design and populations, data from trials were pooled to evaluate efficacy of the combination regimen among women who did or did not undergo Ixabepilone dose reduction during the first 4 courses. To adjust for bias resulting from selecting patients with inherently better outcome based on longer treatment durations, these analyses were restricted to patients who received ≥ 4 courses of Ixabepilone. Results The pooled cohort included 566 patients with measurable disease who were evaluable for efficacy. Patients who had early dose reduction showed similar objective response rates (ORRs) and progression-free survival (PFS) as did those with no/late dose reduction. ORRs were 62.6% (95% confidence interval [CI], 55.8%-69.0%) and 55.3% (95% CI, 49.9%-60.6%), respectively; median PFS was 7.2 months (95% CI, 6.6-8.0) and 7.0 months (95% CI, 6.5-7.5), respectively (hazard ratio=0.98; 95% CI, 0.83-1.17). Conclusion These data suggest that early Ixabepilone dose reduction did not affect the overall efficacy of Ixabepilone plus capecitabine in patients with MBC who received ≥ 4 courses of treatment. By making appropriate dose reductions, Ixabepilone-related toxicities can be minimized while maintaining clinical efficacy.
-
Ixabepilone associated peripheral neuropathy data from across the phase ii and iii clinical trials
Supportive Care in Cancer, 2012Co-Authors: Linda T Vahdat, Eva Thomas, Monica Fornier, Craig A Bunnell, Henri Roche, Gabriel N Hortobagyi, Joseph A Sparano, Louise Yelle, Miguel Martin, Pralay MukhopadhyayAbstract:Purpose Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with Ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that Ixabepilone and taxanes produce a similar neurotoxicity profile.
Mario Campone - One of the best experts on this subject based on the ideXlab platform.
-
ucbg 2 08 5 year efficacy results from the unicancer pacs08 randomised phase iii trial of adjuvant treatment with fec100 and then either docetaxel or Ixabepilone in patients with early stage poor prognosis breast cancer
European Journal of Cancer, 2018Co-Authors: Mario Campone, Magali Lacroixtriki, Lise Roca, Marc Spielmann, Hans Wildiers, Paul Cottu, Pierre Kerbrat, Christelle Levy, I Desmoulins, Thomas BachelotAbstract:Abstract Purpose UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then Ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with Ixabepilone would increase 5-year disease-free survival (DFS). Patients and methods Triple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)−/HER2− BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m2) or Ixabepilone (40 mg/m2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. Results Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with Ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58–1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66–1.42; p = 0.897). TNBC patients treated with Ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53–1.11; p = 0.168). DFS was longer with Ixabepilone than docetaxel in patients with grade II–III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29–1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III–IV AEs and two ( Conclusion After adjuvant FEC, Ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of Ixabepilone in subgroups (patients with TNBC and grade II–III lymphocytic infiltration) requires further evaluation.
-
CLINICAL TRIAL
2016Co-Authors: Hope S Rugo, Pierfranco Conte, Mario Campone, Dino Amadori, Cristian Villanueva, Daniela Aldrighetti, Andrew Wardley, Michelle Melisko, M. Brent, Mchenry DavidAbstract:A randomized, phase II, three-arm study of two schedules of Ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cance
-
Ixabepilone alone or with cetuximab as first line treatment for advanced metastatic triple negative breast cancer
Clinical Breast Cancer, 2015Co-Authors: Olivier Tredan, Jacek Jassem, Mario Campone, Rostislav Vyzula, B Coudert, Carmen Pacilio, Jana Prausova, Anneclaire Hardybessard, Ana Arance, Pralay MukhopadhyayAbstract:Abstract Background Despite 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 Methods Women were randomly assigned to receive either Ixabepilone (40 mg/m 2 ) every 21 days (n = 40), or Ixabepilone (40 mg/m 2 ) every 21 days with cetuximab (400 mg/m 2 loading dose, followed by 250 mg/m 2 ) 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. Results Of 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. Conclusion Ixabepilone 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.
-
neoadjuvant doxorubicin cyclophosphamide followed by Ixabepilone or paclitaxel in early stage breast cancer and evaluation of βiii tubulin expression as a predictive marker
Oncologist, 2013Co-Authors: Cristina Saura, Mario Campone, Ling Ming Tseng, Stephen Chan, Raju Titus Chacko, Alexy Manikhas, Shona Nag, Cynthia G Leichman, Lokanatha Dasappa, Peter A FaschingAbstract:Background This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by Ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated. Patients and methods Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either Ixabepilone 40 mg/m2 (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m2 (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. βIII-Tubulin expression was assessed using immunohistochemistry. Results There was no significant difference in the rate of pCR in the Ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6-30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4-31.7). βIII-Tubulin-positive patients obtained higher pCR rates compared with βIII-tubulin-negative patients in both treatment arms; however, βIII-tubulin expression was not significantly associated with a differential response to Ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the Ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy. Conclusions Neoadjuvant treatment of early stage BC with AC followed by Ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among βIII-tubulin-positive patients.
-
a randomized phase ii three arm study of two schedules of Ixabepilone or paclitaxel plus bevacizumab as first line therapy for metastatic breast cancer
Breast Cancer Research and Treatment, 2013Co-Authors: Hope S Rugo, Pierfranco Conte, Mario Campone, Dino Amadori, D Aldrighetti, Andrew M Wardley, Cristian Villanueva, Michelle E Melisko, Brent M Mchenry, David LiuAbstract:The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of Ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naive metastatic breast cancer (MBC) were randomized 3:3:2 to Ixabepilone 16 mg/m2 weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); Ixabepilone 40 mg/m2 Q3W (reduced to 32 mg/m2 after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m2 weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, Ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of Ixabepilone may be less active than Q3W dosing, but with less neutropenia.
Eva Thomas - One of the best experts on this subject based on the ideXlab platform.
-
efficacy and safety of Ixabepilone and capecitabine in patients with advanced triple negative breast cancer a pooled analysis from two large phase iii randomized clinical trials
Clinical Breast Cancer, 2018Co-Authors: Hope S Rugo, Eva Thomas, Hyun-cheol Chung, Henri Roche, Guillermo Lerzo, Igor Vasyutin, Amit Patel, Linda T VahdatAbstract:Abstract Introduction The purpose of this study was to evaluate the safety and efficacy of Ixabepilone plus capecitabine in patients with metastatic or locally advanced triple-negative breast cancer (TNBC). Patients and Methods We conducted a pooled analysis of patients with TNBC enrolled in 2 phase III trials ( NCT00080301 and NCT00082433 ), pretreated or resistant to an anthracycline and a taxane. In each study, patients were randomized to receive Ixabepilone 40 mg/m2 (3-hour intravenous infusion, day 1), plus oral capecitabine 1000 mg/m2 twice daily (days 1-14), or capecitabine alone 1250 mg/m2 twice daily (days 1-14), every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. Results In the subset of patients with TNBC (N = 443), the addition of Ixabepilone to capecitabine compared with capecitabine alone prolonged median progression-free survival from 1.7 months to 4.2 months (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52-0.78; P Conclusion Adding Ixabepilone to capecitabine is effective in prolonging progression-free survival and improving objective response rate compared with capecitabine alone in patients with advanced TNBC previously treated with anthracyclines and taxanes.
-
maintenance of clinical efficacy after dose reduction of Ixabepilone plus capecitabine in patients with anthracycline and taxane resistant metastatic breast cancer a retrospective analysis of pooled data from 2 phase iii randomized clinical trials
Clinical Breast Cancer, 2012Co-Authors: Vicente Valero, Eva Thomas, Linda T Vahdat, Henry L Gomez, Pralay Mukhopadhyay, Linda D Bosserman, Eduard Vrdoljak, Alexey Manikhas, Carlos Medina, Diane OpattAbstract:Abstract Background This retrospective analysis aimed to determine whether early dose reduction impacts the efficacy of Ixabepilone plus capecitabine in women with metastatic breast cancer (MBC). Patients and Methods In 2 phase III trials, patients (N = 1973) with anthracycline/taxane–pretreated MBC were randomized to receive Ixabepilone 40 mg/m 2 on day 1 plus capecitabine 1000 mg/m 2 twice daily (BID) on days 1 to 14 or single-agent capecitabine 1250 mg/m 2 BID on days 1 to 14 of a 3-week course. Because of the similar design and populations, data from trials were pooled to evaluate efficacy of the combination regimen among women who did or did not undergo Ixabepilone dose reduction during the first 4 courses. To adjust for bias resulting from selecting patients with inherently better outcome based on longer treatment durations, these analyses were restricted to patients who received ≥ 4 courses of Ixabepilone. Results The pooled cohort included 566 patients with measurable disease who were evaluable for efficacy. Patients who had early dose reduction showed similar objective response rates (ORRs) and progression-free survival (PFS) as did those with no/late dose reduction. ORRs were 62.6% (95% confidence interval [CI], 55.8%-69.0%) and 55.3% (95% CI, 49.9%-60.6%), respectively; median PFS was 7.2 months (95% CI, 6.6-8.0) and 7.0 months (95% CI, 6.5-7.5), respectively (hazard ratio=0.98; 95% CI, 0.83-1.17). Conclusion These data suggest that early Ixabepilone dose reduction did not affect the overall efficacy of Ixabepilone plus capecitabine in patients with MBC who received ≥ 4 courses of treatment. By making appropriate dose reductions, Ixabepilone-related toxicities can be minimized while maintaining clinical efficacy.
-
Ixabepilone associated peripheral neuropathy data from across the phase ii and iii clinical trials
Supportive Care in Cancer, 2012Co-Authors: Linda T Vahdat, Eva Thomas, Monica Fornier, Craig A Bunnell, Henri Roche, Gabriel N Hortobagyi, Joseph A Sparano, Louise Yelle, Miguel Martin, Pralay MukhopadhyayAbstract:Purpose Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with Ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that Ixabepilone and taxanes produce a similar neurotoxicity profile.
-
phase i ii study of Ixabepilone plus capecitabine in anthracycline pretreated resistant and taxane resistant metastatic breast cancer
Clinical Breast Cancer, 2008Co-Authors: Craig A Bunnell, Linda T Vahdat, Judith Klimovsky, Ronald Peck, Valerie Poulart, Lee S Schwartzberg, Julie Gralow, Eva ThomasAbstract:Abstract Purpose The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue Ixabepilone plus capecitabine in anthracycline–pretreated/resistant and taxane-resistant metastatic breast cancer (MBC). Patients and Methods A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (Ixabepilone 40 mg/m 2 intravenously on day 1 plus capecitabine 1650-2000 mg/m 2 on days 1-14 of a 21-day cycle) or schedule B (Ixabepilone 8-10 mg/m 2 on days 1-3 plus capecitabine 1650 mg/m 2 on days 1-14 of a 21-day cycle). Results No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m 2 and 10/1650 mg/m 2 cohorts; 1 of 30 patients in the 40/1650 mg/m 2 cohort and 2 of 30 patients in the 40/2000 mg/m 2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m 2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption. Conclusion Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline–pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.
-
Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment
Journal of Clinical Oncology, 2007Co-Authors: Eva Thomas, Xavier Pivot, Hyun-cheol Chung, Jacek Jassem, Judith Klimovsky, Henry L Gomez, Rubi K Li, Luis Enrique Fein, Valorie F Chan, Fernando Hurtado De MendozaAbstract:Purpose Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare Ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxaneresistant locally advanced or metastatic breast cancer. Patients and Methods Seven hundred fifty-two patients were randomly assigned to Ixabepilone 40 mg/m 2 intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m 2 orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m 2 on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review. Results Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P .0003). Objective response rate was also increased (35% v 14%; P .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups. Conclusion Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes. J Clin Oncol 25:5210-5217. © 2007 by American Society of Clinical Oncology
Pralay Mukhopadhyay - One of the best experts on this subject based on the ideXlab platform.
-
phase iii randomized trial of second line Ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer
Gynecologic Oncology, 2015Co-Authors: Scott Mcmeekin, Pralay Mukhopadhyay, Don S Dizon, James F Barter, Giovanni Scambia, Lyudmila Manzyuk, Alla Lisyanskaya, Ana Oaknin, Sarah Ringuette, Julie RosenbergAbstract:Abstract Objective The purpose of this multicenter, open label, randomized phase III study was to determine whether Ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. Methods Patients were randomized 1:1 to Ixabepilone (40mg/m 2 ), or either paclitaxel (175mg/m 2 ) or doxorubicin (60mg/m 2 ), every 21days. Patients that had previously received an anthracycline were randomized to Ixabepilone or paclitaxel; all other patients were randomized to Ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. Results At the time of database lock, 496 patients were randomized to receive Ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0–1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. Conclusions The study did not meet its primary objective of improving OS in the Ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for Ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of Ixabepilone and control.
-
Ixabepilone alone or with cetuximab as first line treatment for advanced metastatic triple negative breast cancer
Clinical Breast Cancer, 2015Co-Authors: Olivier Tredan, Jacek Jassem, Mario Campone, Rostislav Vyzula, B Coudert, Carmen Pacilio, Jana Prausova, Anneclaire Hardybessard, Ana Arance, Pralay MukhopadhyayAbstract:Abstract Background Despite 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 Methods Women were randomly assigned to receive either Ixabepilone (40 mg/m 2 ) every 21 days (n = 40), or Ixabepilone (40 mg/m 2 ) every 21 days with cetuximab (400 mg/m 2 loading dose, followed by 250 mg/m 2 ) 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. Results Of 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. Conclusion Ixabepilone 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.
-
randomized phase ii study of Ixabepilone or paclitaxel plus carboplatin in patients with non small cell lung cancer prospectively stratified by beta 3 tubulin status
Journal of Clinical Oncology, 2013Co-Authors: Martin J Edelman, Pralay Mukhopadhyay, Clauspeter Schneider, Chunming Tsai, Heungtae Kim, Elisabeth Quoix, Alexander Luft, Remigiusz Kaleta, Ovidiu C Trifan, Laura WhitakerAbstract:Purpose Retrospective studies have reported that tumor expression of the beta-3 tubulin (3T) isoform is an unfavorable prognostic factor in non–small-cell lung cancer (NSCLC) treated with tubulininhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including 3T isoform expression in several tumor models. This randomized phase II study evaluated Ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for 3T expression. Patients and Methods Patients were stratified by 3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive Ixabepilone (32 mg/m 2 ) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m 2 ) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the 3T-positive subgroup.
-
maintenance of clinical efficacy after dose reduction of Ixabepilone plus capecitabine in patients with anthracycline and taxane resistant metastatic breast cancer a retrospective analysis of pooled data from 2 phase iii randomized clinical trials
Clinical Breast Cancer, 2012Co-Authors: Vicente Valero, Eva Thomas, Linda T Vahdat, Henry L Gomez, Pralay Mukhopadhyay, Linda D Bosserman, Eduard Vrdoljak, Alexey Manikhas, Carlos Medina, Diane OpattAbstract:Abstract Background This retrospective analysis aimed to determine whether early dose reduction impacts the efficacy of Ixabepilone plus capecitabine in women with metastatic breast cancer (MBC). Patients and Methods In 2 phase III trials, patients (N = 1973) with anthracycline/taxane–pretreated MBC were randomized to receive Ixabepilone 40 mg/m 2 on day 1 plus capecitabine 1000 mg/m 2 twice daily (BID) on days 1 to 14 or single-agent capecitabine 1250 mg/m 2 BID on days 1 to 14 of a 3-week course. Because of the similar design and populations, data from trials were pooled to evaluate efficacy of the combination regimen among women who did or did not undergo Ixabepilone dose reduction during the first 4 courses. To adjust for bias resulting from selecting patients with inherently better outcome based on longer treatment durations, these analyses were restricted to patients who received ≥ 4 courses of Ixabepilone. Results The pooled cohort included 566 patients with measurable disease who were evaluable for efficacy. Patients who had early dose reduction showed similar objective response rates (ORRs) and progression-free survival (PFS) as did those with no/late dose reduction. ORRs were 62.6% (95% confidence interval [CI], 55.8%-69.0%) and 55.3% (95% CI, 49.9%-60.6%), respectively; median PFS was 7.2 months (95% CI, 6.6-8.0) and 7.0 months (95% CI, 6.5-7.5), respectively (hazard ratio=0.98; 95% CI, 0.83-1.17). Conclusion These data suggest that early Ixabepilone dose reduction did not affect the overall efficacy of Ixabepilone plus capecitabine in patients with MBC who received ≥ 4 courses of treatment. By making appropriate dose reductions, Ixabepilone-related toxicities can be minimized while maintaining clinical efficacy.
-
Ixabepilone associated peripheral neuropathy data from across the phase ii and iii clinical trials
Supportive Care in Cancer, 2012Co-Authors: Linda T Vahdat, Eva Thomas, Monica Fornier, Craig A Bunnell, Henri Roche, Gabriel N Hortobagyi, Joseph A Sparano, Louise Yelle, Miguel Martin, Pralay MukhopadhyayAbstract:Purpose Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with Ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that Ixabepilone and taxanes produce a similar neurotoxicity profile.
Tito Fojo - One of the best experts on this subject based on the ideXlab platform.
-
a phase ii multi center study of bevacizumab in combination with Ixabepilone in subjects with advanced renal cell carcinoma
Oncologist, 2017Co-Authors: Mauricio Burotto, Maureen Edgerly, Margarita Velarde, Sanjeeve Balasubramaniam, Harry Drabkin, Juan G Gormaz, Ciara C Osullivan, Ravi A Madan, Tito FojoAbstract:LESSONS LEARNED Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. BACKGROUND Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that Ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of Ixabepilone plus bevacizumab in patients with refractory mRCC. METHODS We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with Ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 Ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination. RESULTS The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of Ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). CONCLUSION The combination of Ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.
-
phase ii clinical trial of Ixabepilone in metastatic cervical carcinoma
Oncologist, 2015Co-Authors: Mauricio Burotto, Marianne S Poruchynsky, Susan E Bates, Maureen Edgerly, Herb Kotz, Margarita Velarde, Sanjeeve Balasubramaniam, Julia Wilkerson, Tito FojoAbstract:LESSONS LEARNED Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that Ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance. BACKGROUND Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that Ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of Ixabepilone in previously treated mCC. METHODS Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with Ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. RESULTS In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naive, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. CONCLUSION Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.
-
a phase ii clinical trial of Ixabepilone ixempra bms 247550 nsc 710428 an epothilone b analog in patients with metastatic renal cell carcinoma
Clinical Cancer Research, 2010Co-Authors: Hui Huang, Marianne S Poruchynsky, Susan E Bates, Michael E Menefee, Maureen Edgerly, Sen Zhuang, Herb Kotz, Lyn M Huff, Tito FojoAbstract:Purpose: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of Ixabepilone in patients with metastatic renal cell carcinoma. Experimental Design: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m 2 Ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing. Results: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of Ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response. Conclusion: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies. Clin Cancer Res; 16(5); 1634–41
-
evidence for microtubule target engagement in tumors of patients receiving Ixabepilone
Clinical Cancer Research, 2007Co-Authors: Sen H Zhuang, Tito Fojo, Elizabeth Y Hung, Laura Hung, Robert W Robey, Dan L Sackett, Marston W Linehan, Susan E Bates, Marianne S PoruchynskyAbstract:Purpose: Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. α-Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with Ixabepilone(BMS-247550; Ixempra). Experimental Design: Levels of posttranslationally modified α-tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with Ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis. Results: In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated α-tubulin increased after microtubule stabilization induced by Ixabepilone. Ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated α-tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated α-tubulin in 11 of 12 serial biopsies obtained from patients receiving Ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after Ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined. Conclusion: Assessing the levels of detyrosinated and/or acetylated α-tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent Ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.
-
a phase i clinical trial of Ixabepilone bms 247550 an epothilone b analog administered intravenously on a daily schedule for 3 days
Cancer, 2005Co-Authors: Sen H Zhuang, Manish Agrawal, R Maureen N Edgerly, R Susan N Bakke, M Herb D Kotz, M Paul D Thambi, R Ann N Rutt, M Frank M D Balis, M Susan D Bates, Tito FojoAbstract:BACKGROUND: The epothilones are a novel class of microtubule-stabilizing agents. Ixabepilone (BMS-247550; NSC 710428) is a semisynthetic analog of the natural product epothilone B. The authors conducted a Phase I study by administering Ixabepilone to patients as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. METHODS: Twenty-six patients were enrolled and received Ixabepilone at a starting dose of 8 or 10 mg/m(2) per day for 3 consecutive days. RESULTS: One hundred and nineteen cycles were administered to 26 patients. The maximum-tolerated dose was 8 mg/m(2) per day of Ixabepilone administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. The dose-limiting toxicity (DLT) was neutropenia. Other nonhematologic Grade 3 toxicities included fatigue (3 cycles), hyponatremia (1 cycle), anorexia (1 cycle), ileus (1 cycle), stomatitis (1 cycle), and emesis (1 cycle). Prolonged disease stabilization was observed in patients with mesothelioma, ovarian carcinoma, and renal cell carcinoma. CONCLUSIONS: The recommended Phase II dose of Ixabepilone on the daily schedule for 3 days was 8-10 mg/m(2) per day. Neutropenia was the DLT. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.
