A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

Abstract

Background The combination of gemcitabine and docetaxel is standard first-line therapy for recurrent or metastatic uterine leiomyosarcoma. There is no standard second-line therapy. Ixabepilone is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and may be a more potent polymerizer of tubulin. We sought to determine activity of ixabepilone as a single agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy. Methods Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40 mg/m2 on day one of a 21 day cycle. Patients with prior pelvic radiation were treated without dose reduction. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT). Results Twenty-three of 26 women were evaluable (two wrong histology, one never treated) with two of 23 receiving one cycle of therapy. There were no complete or partial responses. Stable disease (SD) was seen in four patients (17.4%, median 3.4 months). Seventeen patients (73.9%) had increasing disease (PD) and two patients were inevaluable per RECIST. One patient had SD over six cycles of treatment. Median PFS for all 23 patients was 1.4 months and overall survival was 7.0 months. The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13%), grade 4 (17%), anemia grade 3 (22%). Conclusion Ixabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.

Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: A retrospective review

“…Consistent with existing experience [32], we found that ixabepilone monotherapy had no activity in recurrent uterine leiomyosarcoma previously treated with a taxane.…”

The role of adjuvant therapy in uterine leiomyosarcoma

“…Ixabepilone was studied by the NRG Oncology Group in a phase 2 trial and found not to be active as a single agent in uLMS [60]. Of 23 evaluable patients enrolled on the trial, only 4 patients (17.4%) had stable disease as best response to therapy.…”

EP4 and Class III β-Tubulin Expression in Uterine Smooth Muscle Tumors: Implications for Prognosis and Treatment

“…In the present study, class III β-tubulin was not predictive of overall survival, perhaps due to the limited number of cases examined. Interestingly, a phase II study of ixabepilone, a microtubule-stabilizing agent which putatively overcomes taxane resistance conferred by upregulation of class III β-tubulin, showed no activity as a second-line agent in this disease [19], underscoring gaps in our current understanding of the biology of this disease and the persistent need for novel approaches to therapy.…”

“…Gemcitabine plus docetaxel currently represents one of the most effective cytotoxic combinations for this disease, with an overall response rate (ORR) of 27% [13]. Ifosfamide (ORR 17%) [14], pegylated liposomal doxorubicin (ORR 16%) [15], paclitaxel (ORR 8%) [16], oral etoposide (ORR 7%) [17], cisplatin (ORR 5%) [18], and ixabepilone (0% ORR) [19] have also been evaluated in patients. Adjuvant radiation therapy does not result in improved survival [20].…”