Phase II Trial of Ixabepilone, an Epothilone B Analog, in Patients With Metastatic Breast Cancer Previously Untreated With Taxanes

2007 ◽  
Vol 25 (23) ◽  
pp. 3421-3427 ◽  
Author(s):  
Neelima Denduluri ◽  
Jennifer A. Low ◽  
James J. Lee ◽  
Arlene W. Berman ◽  
Janice M. Walshe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Motor Neuropathy ◽  
P53 Expression ◽  
Epothilone B ◽  
Grade 3 ◽  
Experienced Grade

Purpose Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer. Patients and Methods Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m2/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated α-tubulin, tau-1, and p53 expression when possible. Results Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor α-tubulin acetylation after treatment. Baseline or cycle 2 acetylated α-tubulin, tau-1, or p53 expression did not correlate with clinical response. Conclusion Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.

scholarly journals Grade 3 Hepatotoxicity following Fulvestrant, Palbociclib, and Erdafitinib Therapy in a Patient with ER-Positive/PR-Negative/HER2-Negative Metastatic Breast Cancer: A Case Report

2020 ◽  
Vol 13 (1) ◽  
pp. 304-308 ◽  
Author(s):  
Alyssa Schlotman ◽  
Adam Stater ◽  
Kyle Schuler ◽  
Judd Heideman ◽  
Vandana Abramson
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Case Report ◽  
Metastatic Breast ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Hepatotoxic Effect ◽  
Er Positive ◽  
Grade 3 ◽  
Experienced Grade

A 49-year-old woman with ER-positive/PR-negative/HER2-negative metastatic breast cancer experienced Grade 3 hepatotoxicity following initiation of a clinical trial of fulvestrant, palbociclib, and erdafitinib. Fulvestrant was determined to be the drug most likely responsible for this hepatotoxic effect. This case report details the timing and nature of this drug-induced liver injury, adding support to an area that has yet to be described adequately in the existing literature.

Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer

2006 ◽  
Vol 25 (1) ◽  
pp. 63-67 ◽  
Author(s):  
Neelima Denduluri ◽  
James J. Lee ◽  
Janice Walshe ◽  
Arlene W. Berman ◽  
Ujala Vatas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Metastatic Breast ◽  
Epothilone B

A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer.

1990 ◽  
Vol 8 (11) ◽  
pp. 1782-1788 ◽  
Author(s):  
R Wallerstein ◽  
G Spitzer ◽  
F Dunphy ◽  
S Huan ◽  
G Hortobagyi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Poor Response ◽  
High Dose ◽  
Significant Activity ◽  
Heavily Pretreated ◽  
Grade 3

To further improve the effect of high-dose chemotherapy in the treatment of locally advanced and metastatic breast cancer, we sought to develop a second active high-dose noncross-resistant regimen to use in tandem with our customary high-dose regimen of cyclophosphamide, etoposide, and cisplatin (CVP). We performed a phase II trial of high-dose mitoxantrone 30 mg/m2, etoposide 200 mg/m2 every 12 hours x 6, and thiotepa 250 mg/m2 x 3 days (MVT) in 31 patients with heavily pretreated metastatic breast cancer and one with locally advanced chemotherapy-refractory breast cancer. These patients were ineligible for high-dose CVP chemotherapy because of the amount of prior treatment and poor-response status. Of the 32 patients, 14 responded to cycle 1, did not experience any grade 4 toxicity, and received a second cycle of MVT. Overall, seven of 31 patients achieved a complete response (CR; 23%). Four of the 14, who were partial responders to the first cycle, achieved a CR after the second cycle. The overall response rate was 19 of 31 (61%) with an overall median freedom from progression of 4 to 5 months and an overall median survival of 9 months. Toxicity consisted primarily of mucositis (grade 3 or 4 in 69%). The results indicate that high-dose MVT produces significant activity, even in heavily pretreated patients. Administration of a second cycle of high-dose therapy with MVT increased the CR rate, and the morbidity and mortality from the second cycle were not greater than that for the first cycle. Because of the high incidence of grade 3 or 4 mucositis with this regimen, we are currently completing a follow-up study of high-dose mitoxantrone and thiotepa alone.

Combination of paclitaxel and two schedules of gefitinib in patients with metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10599-10599 ◽  
Author(s):  
S. Cresta ◽  
A. Perotti ◽  
L. Merlini ◽  
M. Mansutti ◽  
A. Marchianã ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Antitumor Activity ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Response Duration ◽  
Skin Toxicity ◽  
Median Response ◽  
Grade 3

10599 Background: The epidermal growth factor receptor (EGFR) may be overexpressed in breast cancer. Inhibition of EGFR signaling by gefitinib (Iressa) enhances the in vitro antitumor activity of many cytotoxic drugs including paclitaxel. Methods: In this phase II study patients (pts) with measurable metastatic breast cancer and maximum prior exposure to two chemotherapies were randomized to paclitaxel (100 mg/m2 on days 1, 8 q21) and continuous gefitinib, 250 mg daily for 21 days (arm A); or paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib 250 mg daily from day 1 to 15 (arm B). Therapy continued for at least 4 cycles after best response. After 6 cycles, responding pts continued with gefitinib monotherapy until progression or unacceptable toxicity. Results: 16 pts in arm A and 17 in arm B were enrolled; 25 had visceral disease (12 in arm A and 13 in arm B). Median age was 53 years (range 29–70). All but one pt received prior anthracyclines and 9 also prior taxanes. Overall 17 pts responded to therapy (intent to treat analysis; arm A: 62.5%, 95% CI: 35.4–84.8%; arm B: 41.2%, 95% CI: 18.4–67.1%). Disease control (CR+PR+SD) was achieved in 81.3% of pts in arm A and 76.5% in arm B, with 10 and 6 pts who continued with gefitinib monotherapy after completing the combination schedule. Median time to progression was 250 (arm A) and 204 days (arm B), while median response duration was 212 (arm A) and 285 days (arm B). Tolerability was good with either schedule of gefitinib. Diarrhea was frequent (68.8% and 64.7%) and of grade 3–4 severity in 6% of pts in arm A and in arm B. Grade 3–4 neutropenia affected 6% and 12% of pts respectively, and 6% of pts in both arms had a grade 3–4 increase of AST and ALT. Other grade 1–2 adverse events included acneiform rash (100% in arm A and 58.8% in arm B), sensory neuropathy (68.8% and 58.8%), anemia (50.0% and 52.9%), neutropenia (25.0% and 17.6%) and myalgia (37.5% and 41.2%). Conclusions: The combination of paclitaxel with gefitinib given continuously or for 2 out of every 3 weeks is feasible and well tolerated. The discontinuous schedule caused less skin toxicity. The good antitumor activity deserves further studies to identify sensitive subgroups and mechanisms of sensitivity. IRESSA is a trademark of the AstraZeneca group of companies. [Table: see text]

Phase II clinical trial of ixabepilone in metastatic breast cancer (MBC) patients previously untreated with taxanes

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 651-651 ◽  
Author(s):  
N. Denduluri ◽  
J. J. Lee ◽  
J. M. Walshe ◽  
S. X. Yang ◽  
U. Vatas ◽  
...  
Keyword(s):  
Imaging System ◽  
Metastatic Breast ◽  
Sensory Neuropathy ◽  
Hematologic Toxicity ◽  
Motor Neuropathy ◽  
P53 Expression ◽  
P53 Antibodies ◽  
Best Response ◽  
Duration Of Response ◽  
Grade 3

651 Background: Ixabepilone, an epothilone B analog, stabilizes microtubules by binding to tubulin. The response rate (RR) in taxane-pretreated patients at our institution was 22%. Methods: Patients (pts) were eligible if they had MBC previously untreated with taxanes and measurable disease by RECIST criteria. Ixabepilone was given at 6mg/m2/d intravenously days 1–5 every 3 weeks until unacceptable toxicity or disease progression. Primary objectives included RR and toxicity. Pts underwent pre and/or post treatment tumor biopsies for correlative studies. Acetylated α-tubulin, Tau-1, and p53 were stained with anti-acetylated α-tubulin, anti-Tau-1, and anti-p53 antibodies in samples from 13 pts. Staining was scored quantitatively using the Automated Cellular Imaging System. Results: Twenty-three pts received 197 cycles (C). Median of 7C (range 2–22) per pt were administered. Median age was 55 (range 22–79). Seven pts received 1 prior metastatic chemotherapy regimen. Ten of 23 or 43% (exact 95% confidence interval: 23.2% to 65.5%) pts had partial responses (PR), 9 (39%) stable disease (SD) (2 unconfirmed PRs), and 4 (17%) progressive disease (PD). Median time to progression was 5.3 months; median duration of response was 5.4 months from date of best response. Four pts required dose reductions for neutropenia, neuropathy or fatigue. Grade 3/4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), infection without neutropenia (9%), motor neuropathy (4%), and muscle weakness (4%). No grade 3/4 sensory neuropathy was seen, but 35% and 13% of pts had grades 1 and 2 neuropathy respectively. Median acetylated α-tubulin at baseline was 0.2 in responders and 17.6 in non-responders (p=0.069). There were no differences in response according to Tau-1 or p53 expression at baseline. Conclusion: Ixabepilone is an effective treatment for MBC with a 43% RR in 23 pts previously untreated with taxanes. There was minimal hematologic toxicity and no grade 3 sensory neuropathy. The use of baseline level of acetylated α-tubulin to predict response may warrant further study. No significant financial relationships to disclose.

First-line treatment of metastatic breast cancer with weekly abraxane (nab-paclitaxel: a 130 nm albumin-bound paclitaxel particle): A preliminary analysis of the phase II international oncology network ION-04–012 study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10707-10707 ◽  
Author(s):  
B. Mirtsching ◽  
T. Chidiac ◽  
T. Cosgriff
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Preliminary Analysis ◽  
Metastatic Breast ◽  
Line Treatment ◽  
First Line ◽  
Grade 3 ◽  
First Line Treatment ◽  
Patient Accrual

10707 Background: Abraxane (paclitaxel protein-bound particles) by intravenous weekly administration schedule has been demonstrated to be active and well tolerated in patients with metastatic breast cancer (MBC) refractory to prior taxane therapy. The purpose of this Phase II, open-label, non-randomized study is to evaluate the efficacy and safety of Abraxane administered weekly to patients with locally-advanced unresectable breast cancer (LABC) or MBC as first-line treatment. Methods: Patients ≥ 18 years with histologically confirmed LABC or MBC received Abraxane (125 mg/m2) by 30 minute IV infusion on days 1, 8, and 15 for the first 3 weeks of each 4-week cycle. HER2-positive patients received concurrent Herceptin given weekly throughout therapy, 4 mg/kg on week 1, and 2 mg/kg on subsequent weeks. Results: From March 11, 2005 to January 4, 2006, 28 patients were enrolled and 27 received study medication (included in this preliminary analysis). Patient accrual continues. Patient characteristics included: gender (M/F) 0/27, median age 60.5 years (range 36–83), ECOG performance status (0–1) 13/14, and HER2 status (±/missing) 6/18/3. A total of 285 cycles have been administered (median 3 [range 1–8]) with a median dose of 125 mg/m2 (range 0–130 mg/m2) and 6 dose modifications have occurred due to toxicity. Eighteen patients are still on study. CTC hematologic toxicities were grade 3 leukopenia (3.7% of patients) and grade 3 neutropenia (7.4%). Grade 3 nonhematologic toxicities were gastritis (3.7%), peripheral sensory neuropathy (7.4%), arthralgia (3.7%), and bone pain (3.7%). No grade 4 nonhematologic toxicities occurred. Conclusions: Preliminary data show that Abraxane given weekly at 125 mg/m2 (with or without Herceptin) for first-line treatment of MBC is well tolerated. Patient accrual continues in this study. Updated analysis of this study will be provided at the meeting. No significant financial relationships to disclose.

Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11529-e11529
Author(s):  
Jasmeet Chadha Singh ◽  
Stacy Stein ◽  
Matthew Volm ◽  
Julia Anne Smith ◽  
Yelena Novik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Clinical Benefit ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Grade 3 ◽  
Platinum Agents

e11529 Background: Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of RAD001 (oral mTOR inhibitor) and Carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study was to estimate the clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD) >6 months) and the toxicity of this combination in women with triple negative metastatic breast cancer who have had 0-3 prior chemotherapy regimens for metastatic disease. 25 subjects were to be entered into a single stage open label Phase II study. Prior Carboplatin is allowed. Treated brain metastasis are eligible. The null hypothesis that the clinical benefit rate is ≤10% could be rejected if number of CR/PR/SD >6 months was ≥6. Originally, intravenous Carboplatin AUC 6 was to be administered every 3 weeks along with daily 5mg of RAD001 with a 3 patient run-in and then 10 mg daily. Due to a surprising amount of thrombocytopenia with this combination, the dose of Carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001. Results: 18 patients have been recruited thus far. Median age is 59. There have been 1 CR, 4 PR’s and 2 SD's lasting > 6 months. One SD was achieved in a patient progressing on single agent Carboplatin at study entry. Median duration of CR+ SD +PR thus far is 13 weeks (range: 6-60 weeks). 5 patients had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). However, since amendment of Carboplatin dose to AUC 4 the regimen has been well tolerated. 1 patient suffered from grade 3 dehydration. The estimated clinical benefit rate is 50% (95% C.I.: 24%, 76%). Median time to progression or death is 87.5 days from start of treatment; there is only 1 death to date on this study. Conclusions: The study has achieved it’s primary objective of demonstrating clinical benefit of RAD 001-Carboplatin combination in triple negative metastatic breast cancer. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment.

Phase I Study of a Novel Capecitabine Schedule Based on the Norton-Simon Mathematical Model in Patients With Metastatic Breast Cancer

2008 ◽  
Vol 26 (11) ◽  
pp. 1797-1802 ◽  
Author(s):  
Tiffany A. Traina ◽  
Maria Theodoulou ◽  
Kimberly Feigin ◽  
Sujata Patil ◽  
K. Lee Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Flat Dose ◽  
Drug Scheduling ◽  
Hand Foot Syndrome ◽  
Delayed Toxicity ◽  
Grade 3 ◽  
Experienced Grade

PurposeThis study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling.Patients and MethodsEligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks.ResultsTwenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily.ConclusionAs predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.

Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Metastatic and Locally Advanced Breast Cancer

2005 ◽  
Vol 23 (12) ◽  
pp. 2726-2734 ◽  
Author(s):  
Jennifer A. Low ◽  
Suparna B. Wedam ◽  
James J. Lee ◽  
Arlene W. Berman ◽  
Adam Brufsky ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Sensory Neuropathy ◽  
Microtubule Stabilization ◽  
Epothilone B ◽  
Grade 3 ◽  
Tumor Biopsies

Purpose Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Patients and Methods Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated α-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Results Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated α-tubulin were increased in tumor biopsies performed after ixabepilone therapy. Conclusion An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.

Multicenter Phase II Trial of Weekly Paclitaxel in Women With Metastatic Breast Cancer

2001 ◽  
Vol 19 (22) ◽  
pp. 4216-4223 ◽  
Author(s):  
Edith A. Perez ◽  
Charles L. Vogel ◽  
David H. Irwin ◽  
Jeffrey J. Kirshner ◽  
Ravi Patel
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Metastatic Breast ◽  
Weekly Paclitaxel ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Prior Chemotherapy ◽  
Grade 3

PURPOSE: We evaluated the safety and efficacy of weekly paclitaxel therapy in women with metastatic breast cancer in a phase II multicenter trial. Entry criteria were relatively liberal to reflect the heterogeneity of metastatic breast cancer in clinical practice. PATIENTS AND METHODS: Patients had histologically confirmed and measurable metastatic breast cancer. Up to two prior chemotherapy regimens for metastatic disease, including prior therapy with anthracyclines and taxanes and prior high-dose therapy, were allowed. Paclitaxel 80 mg/m2 was administered weekly for 4 weeks per 4-week cycle. RESULTS: We enrolled 212 patients; 211 were assessable for toxicity and 177 were assessable for response. Ninety percent of patients had received prior chemotherapy (adjuvant, metastatic, or both), 46% of patients had three or more involved metastatic sites, and 60% of patients had visceral-dominant disease. Responses were documented on two occasions and were independently reviewed. The overall response rate (complete plus partial response) was 21.5% (95% confidence interval, 15.4% to 27.5%), with 41.8% of patients having disease stabilization. Median time to progression was 4.7 months, and overall survival in all 212 patients enrolled was 12.8 months. Therapy was well tolerated, with a 15% incidence of grade 3/4 hematologic toxicity and a 9% incidence of grade 3 neurotoxicity; other serious toxicities were rare. The response rate and toxicity profile in the 34% of patients ≥ 65 years of age were similar to that of younger patients. CONCLUSION: Weekly paclitaxel therapy was well tolerated and demonstrated reasonable activity in this relatively heavily pretreated population with advanced disease. Further study of weekly paclitaxel in combination therapy is warranted.

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