Elsevier

Gynecologic Oncology

Volume 125, Issue 1, April 2012, Pages 136-140
Gynecologic Oncology

A phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California Cancer Phase II Consortia

https://doi.org/10.1016/j.ygyno.2011.11.042Get rights and content

Abstract

Objective

The aim of this multi-institutional non randomized phase II trial was to determine the efficacy and safety of single agent aflibercept (VEGF Trap), a recombinant fusion protein that blocks multiple vascular endothelial growth factor isoforms, in women with gynecologic soft tissue sarcoma.

Methods

Patients were enrolled in two cohorts each with Simon two stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, ovarian or fallopian tube origin. Eligibility criteria included ≤ 2 prior lines of chemotherapy for metastatic disease and ECOG performance status of ≤ 2. Aflibercept 4 mg/kg was administered intravenously on day 1 of a 14 day cycle. Primary endpoints were objective response and disease stabilization (Progression Free Survival (PFS) at 6 months).

Results

41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled on study. In the leiomyosarcoma cohort, eleven (27%) patients had stable disease (SD), 4 with SD lasting at least 24 weeks. The 6 month PFS was 17%, with median time to progression (TTP) of 1.8 (95% CI:1.6–2.1) months. In the carcinosarcoma cohort, two (9%) patients had SD, one lasting > 24 weeks, median TTP was 1.6 months (95%CI: 1.1–1.7) No partial responses were observed in patients from either cohort. Grade 3 or more aflibercept related toxicity was uncommon and included hypertension, fatigue, headache and abdominal pain.

Conclusions

Single agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma.

Highlights

► In this study we investigate the efficacy of the anti-angiogenic aflibercept in 2 groups of women with uterine sarcoma. ► Single agent aflibercept has minimal activity in women with recurrent or metastatic carcinosarcoma. ► Single agent aflibercept has modest activity (stable disease rate 27%) in women with metastatic or recurrent uterine leiomyosarcoma.

Introduction

Endometrial sarcomas constitute less than 10% of all uterine malignancies [1], [2]. Carcinosarcoma (CS) and leiomyosarcoma (LMS) comprise almost 90% of all endometrial sarcomas. Median survival of women with unresectable, recurrent or advanced disease is approximately 12 months in both cases and new therapeutic options are urgently required [1], [2], [3].

Carcinosarcomas are believed to be metaplastic carcinomas rather than true sarcomas [4] and hence warrant separate clinical trials to evaluate potential efficacy of new agents. Trials of agents which have previously shown benefit in other gynecologic carcinomas to treat women with CS would seem reasonable. Conventional chemotherapy has modest activity in CS but response duration is short. In a randomized phase III trial, the combination of cisplatin and ifosfamide was associated with a higher response rate (54% v 36%) and an improved median progression-free survival (PFS) compared to ifosfamide when used alone as first line therapy. This did not, however, translate into an improvement in overall survival (OS) and toxicity was significant [5]. A second study reported an improvement in OS (from 8.4 to 13.5 months) for Ifosfamide–paclitaxel–filgrastim over ifosfamide alone [6]. More recently, a phase II trial of carboplatin plus paclitaxel reported a response rate of 54% and demonstrated a similar PFS, 7.6 months, and OS, 14.7 months to the earlier, more toxic, ifosfamide combination studies [7].

Uterine LMS has a similarly poor prognosis and palliative chemotherapy with single agents such as ifosfamide, etoposide and doxorubicin produce response rates ranging from 11 to 25% [8], [9], [10]. More recently trabectedin demonstrated response rates of 16–18% with PFS at 6 months of 30–33% in retrospective [11] and pooled analyses in heavily pre treated patients [12]. The combination of docetaxel with gemcitabine produced a response rate of 35.8% as first line treatment (median PFS 4.4 months and OS 16.1 months) [13] and 27% when administered to women who had received prior chemotherapy [14]. Given the relatively poor outcomes for these two diseases, new therapeutic approaches informed by tumor biology are clearly needed.

One potential biologic target for therapy of these cancers is the vascular endothelial growth factor (VEGF) family of proteins. Increased expression of VEGF family members is associated with disease progression and poor prognosis in many gynecologic malignancies [15], [16] and VEGF pathway targeting agents have demonstrated efficacy in many tumor types. Similarly, increased levels of VEGF in uterine LMS and other soft tissue sarcomas are associated with increased risk of progressive disease [18], [19], [20]. CS are known to over express the angiogenic protein platelet-derived growth factor (PDGF) [17] suggesting the importance of angiogenesis in this malignancy.

Aflibercept, VEGF Trap, is a recombinant fusion protein combining the Fc portion of human IgG1 with the principal extracellular ligand-binging domains of human VEGF receptors 1 and 2. It is a potent inhibitor of angiogenesis acting as a high affinity soluble decoy VEGF receptor. Compared to other VEGF inhibitors it has a high VEGF-A binding affinity (approximately 1000-fold greater than bevacizumab), the ability to bind VEGF-B, as well as placental growth factors 1 and 2 (which have independent pro angiogenic effects), and a longer circulating half-life compared with other soluble receptor constructs. Aflibercept inhibits the growth of multiple tumor types, including a rhabdomyosarcoma, in mouse xenograft models [21]. In the phase I study of single agent aflibercept a minor response was seen in a heavily pre-treated patient with metastatic uterine LMS [22].

We conducted a multi-center phase II study in two separate cohorts of women: one with advanced recurrent carcinosarcoma and a second with uterine leiomyosarcoma, to determine the efficacy (objective response rate and rate of progression-free survival at 6 months) and toxicity of aflibercept in these two patient groups

Section snippets

Patients and methods

This was a single agent, multi-centre, 2 stage, phase II trial to investigate the efficacy of aflibercept in 2 cohorts of women with metastatic or recurrent gynecologic soft tissue sarcomas: women with uterine LMS and women with CS of endometrial, ovarian or fallopian tube origin, conducted by the Princess Margaret Hospital, Chicago and California Cancer Phase II Consortia. The study was conducted according to Good Clinical Practice guidelines, with full research ethics board approval at each

Results

Between January 2006 and January 2010, 63 patients, 41 with uterine leiomyosarcoma and 22 with carcinosarcoma were accrued to this phase II study at 15 participating institutions within the Princess Margaret Hospital, University of Chicago and California Cancer Phase II consortia. At the time of this analysis all patients were off study. Patients discontinued the study in the LMS cohort for documented progression (30/41), adverse events (6/41), patient choice (2/41) 4 death, two potentially

Discussion

The prognosis for women with advanced or metastatic CS and uterine LMS is poor and targeting angiogenesis an attractive therapeutic option. Given that the biology of these two diseases differs this study was designed to evaluate aflibercept in two distinct cohorts. No objective response was seen in either cohort. Since PFS at 3 and 6 months has been proposed as an end-point in soft tissue sarcoma phase II studies, together with the perception that biological agents may be more likely to induce

Conflict of interest statement

None of the authors of this manuscript have any conflict of interest to declare.

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Support: The Cancer Therapeutics Evaluation Program, US National Cancer Institute N01-CM-62203, NO1-CCM-07003-74 and NO1-CM-62209.

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