YGYNO-975830; No. of pages: 9; 4C: Gynecologic Oncology xxx (2015) xxx–xxx

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

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 Dana M. Roque 1, Elena S. Ratner, Dan-Arin Silasi, Masoud Azodi, Thomas J. Rutherford, Peter E. Schwartz, Wendelin K. Nelson, Alessandro D. Santin ⁎ Yale University, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, P.O. Box 208063, New Haven, CT 06511, USA

H I G H L I G H T S • Ixabepilone is a microtubule-stabilizing agent with activity in taxane-resistant disease • Weekly ixabepilone ± biweekly bevacizumab shows activity in uterine/ovarian cancers • This therapeutic combination warrants further prospective study

a r t i c l e

i n f o

Article history: Received 29 August 2014 Accepted 7 March 2015 Available online xxxx Keywords: Epothilone Ixabepilone Bevacizumab Endometrial cancer Ovarian cancer Recurrence Taxane resistance

a b s t r a c t Objective. To describe the clinical outcome and tolerability of weekly ixabepilone (16–20 mg/m2 days 1, 8, 15 of a 28-day cycle) ± biweekly bevacizumab (10 mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. Methods. A single-institution retrospective review was performed inclusive of all patients who received ≥2 cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan–Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. Results. A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1–10) prior lines of chemotherapy. Patients completed a mean of 4.7 ± 2.9 cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7 months (range:2–30). Median PFS and OS were 5.2 and 9.6 months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0 months, p = 0.01, HR 0.2, 95% CI 0.05–0.77; 9.6 versus 4.2 months, p = 0.02, HR 0.58, 95% CI 0.04–0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. Conclusions. Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations. © 2015 Elsevier Inc. All rights reserved.

1. Introduction In 2014, there were an estimated 21,980 and 52,630 incident cases of ovarian and uterine cancer with 14,270 and 8590 projected deaths,

⁎ Corresponding author. Tel.: +1 203 737 4450; fax: +1 203 737 4399. E-mail address: [email protected] (A.D. Santin). 1 Present address: University of Maryland Medical Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 22 South Greene Street, Baltimore, MD 21201, USA.

respectively, in the United States alone [1]. Despite initial response rates as high as 80% to carboplatin/paclitaxel for advanced disease [2–4], there remains a need for effective novel therapeutic approaches in the platinum- and taxane-resistant recurrent setting. Epothilones represent a class of microtubule-stabilizing agents that putatively evade paclitaxel resistance through a variety of mechanisms, including retention of tumor binding affinity despite upregulation of class III β-tubulin and maintenance of intracellular concentrations as a non-substrate for the p-glycoprotein drug efflux pump [5,6]. Ixabepilone (Ixempra,® Bristol-Meyers-Squibb) is a second-generation semi-

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Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

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D.M. Roque et al. / Gynecologic Oncology xxx (2015) xxx–xxx

synthetic epothilone that was granted FDA approval in October 2007 (1) in combination with capecitabine for the treatment of metastatic or locally advanced breast cancer resistant to anthracyclines and taxanes, or (2) as monotherapy for the treatment of metastatic or locally advanced breast cancer resistant to anthracyclines, taxanes, and capecitabine [7]. Ixabepilone monotherapy has also been examined at the phase II level for later-line treatment of recurrent or persistent endometrial (GOG 129-P; 40 mg/m2 day 1 of a 21-day cycle) [8] and ovarian (GOG 126-M; 20 mg/m2 days 1, 8, 15 of a 28-day cycle) [9] cancers. In these studies, objective response rates (ORR) and progression free survival (PFS) ranged from 12%–14.3% and 2.9–4.4 months, respectively. Growing interest lies in novel combinations of cytotoxic and antiangiogenic therapies. One mechanism of synergy is felt to arise from improved transvascular delivery of drug secondary to resolution of interstitial hypertension caused by reduced tumor cell density concurrent with normalization of tumor vasculature [10]. In phase III clinical studies of ovarian cancer, benefit with the addition of bevacizumab to first-line therapy is statistically significant but clinically modest. Bevacizumab given with carboplatin/paclitaxel and continued for an additional 12 cycles increased PFS to 24.1 from 22.4 months (p = 0.04) in ICON-7 [11]; in GOG-218, carboplatin/paclitaxel and bevacizumab administration continued through cycle 22 yielded a PFS benefit of 3.8 months over the control arm of carboplatin/paclitaxel alone [12]. Gain may be more meaningful in the recurrent setting. Supplementation of carboplatin/gemcitabine with bevacizumab enhances PFS (12.4 versus 8.4 months, HR 0.484, 95% CI 0.388–0.605, p b 0.001) and ORR (78.5% versus 57.4%, p b 0.001) in the platinumsensitive setting (OCEANS) [13]. Similarly, the AURELIA (Avastin use in platinum-sensitive resistant epithelial ovarian cancer) trial demonstrated doubling of PFS (6.7 versus 3.4 months, respectively) and ORR (27.3% versus 11.8%, p = 0.001) with the combination of bevacizumab and cytotoxic chemotherapy compared to cytotoxic agents alone in platinum-resistant disease [14]. In vitro, ixabepilone demonstrates greater growth inhibition in concert with anti-angiogenic agents such as bevacizumab, sunitinib, and brivanib compared to paclitaxel in combination with bevacizumab [15]. A phase II study comparing the combination of carboplatin/ ixabepilone/bevacizumab versus carboplatin/paclitaxel/bevacizumab versus carboplatin/paclitaxel/temsirolimus in stage III/IV or recurrent endometrial cancer (GOG 86P) [16] is currently closed to accrual as of January 2012, with results still maturing. The combination of ixabepilone/bevacizumab is also currently under study in non-gynecologic solid malignancies such as advanced renal cell carcinoma [17]. Thus, despite quite strong biologic plausibility and emerging clinical data to suggest a bona fide role for combinatorial strategies to exploit synergism of anti-angiogenic agents and epothilones for taxaneresistant disease, there are currently no existing publications that describe patient outcomes with the addition of bevacizumab to weekly ixabepilone monotherapy in gynecologic malignancies. We herein report our institutional experience with this regimen. 2. Methods After approval of the institutional review board, a retrospective chart review was performed inclusive of all patients with recurrent or persistent uterine or ovarian/fallopian tube/primary peritoneal cancers who had received at least one prior line of chemotherapy and were treated off-protocol at Yale University using ixabepilone 16 or 20 mg/m2 intravenously days 1, 8, 15 with or without bevacizumab 10 mg/kg intravenously days 1 and 15 of a 28-day cycle beginning January 01, 2010 to June 15, 2014. This dosing scheme was chosen based upon on our preliminary institutional experience supporting tolerability and promising activity and durabililty of the regimen [18]. All patients were fully counseled and aware of the investigational nature of these regimens for use in gynecologic malignancies. National Comprehensive Cancer Network guidelines currently regard use of bevacizumab as

acceptable in instances of recurrent ovarian and endometrial cancer [19,20]; the use of ixabepilone in this work was entirely off-label. Therefore, as required by the Yale Cancer Center and consistent with the informed consent process established by the American Society of Clinical Oncology's Ethics/Quality of Care joint working group [21], all patients reported in this review provided informed written consent for receipt of these agents. In instances of initial denial by insurance, coverage for the regimen could successfully be obtained by providing documentation of the existing phase II experiences with ixabepilone and bevaziumab monotherapy for use in uterine or ovarian cancers, and on-going prospective study of the combination of carboplatin, ixabepilone and bevacizumab in endometrial cancers [8,9,16]. Notably, one uterine cancer patient had to be excluded from this analysis given receipt of only one cycle of ixabepilone after insurance denied further coverage of ixabepilone. Another patient received ixabepilone monotherapy because of a lack of coverage for concurrent bevacizumab. Bevacizumab was added to the regimen either immediately or after completion of ≥ 1 cycle when appropriate based on surgical/clinical history. Bevacizumab was dosed using actual body weight regardless of body habitus and ixabepilone was dosed based on actual body weight to a maximum BSA of 2 m2 per GOG clinical guidelines. All patients who completed ≥ 2 cycles of this regimen and had an ECOG performance status of 0–2 [22] were included in the analysis. Best response was defined by RECIST criteria if measureable disease/imaging was available [23] or CA-125 response by 50% criteria: if there is a 50% decrease in serum CA-125 levels, from two initially elevated samples, then a 50% response has occurred; the sample showing a 50% decrease must be confirmed by a fourth sample (i.e., four samples are required) [24]. Unfortunately, no patient who had received a single dose of therapy at the time of data collection had appropriate criteria to describe response as we had defined and therefore we restricted our analyses to those who received 2 or more cycles. Of the 3 patients who had only received a single cycle prior to discontinuation, reasons for cessation of therapy included lack of insurance coverage for ixabepilone (n = 1, uterine cancer), death due to pericardial tamponade (n = 1, ovarian cancer), and death due to respiratory failure (n = 1, ovarian cancer). Because the number of patients who received only one cycle was very small and none of the deaths were felt to be directly attributable to the therapeutic regimen, such methodology was unlikely to influence the conclusions. Ovarian and uterine cancers were staged according to FIGO 1988 and 2009 criteria, respectively [25,26]. Toxicities were graded by NCI CTCAE v4.0 [27]. Overall survival (OS) was defined from the interval between initiation of drug to death or last follow-up. Progression-free survival was defined as the interval between initiation of drug until date of progression or last followup, or discontinuation of regimen secondary to unacceptable toxicity. Duration of response was defined as the interval from date of first documented response to progression. For patients who received a second, non-contiguous course of ixabepilone with or without bevacizumab, only outcomes from the initial course are described here. Standard descriptive statistics were employed. Survival curves were generated using the Kaplan–Meier method and compared by log-rank. The relationship between response and taxane-free interval were calculated using the Kruskal–Wallis test. P-values were considered statistically significant if b 0.05. Statistical analyses were computed using GraphPad Prism version 6 for Mac (GraphPad Software, San Diego, California, USA). 3. Results 3.1. Patient population There were 60 patients identified for this analysis: 24 with uterine and 36 with ovarian/fallopian tube/primary peritoneal cancer. Patient, disease, and treatment characteristics are detailed in Table 1. Across

Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

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Table 1 Patient, disease, and treatment characteristics. Uterine

Patient characteristics Age, years [mean ± SD] Parity [mean (range)] BMI at diagnosis, kg/m2 [mean ± SD] Race White Black Hispanic Asian Other Medical comorbidities Hypertension prior to therapy Other cancer diagnosis History of tobacco use Disease characteristics FIGO stage I II III IV Incompletely staged/unknown Histology Serous Endometrioid Clear cell Mixed endometrioid and clear cell or mesonephric Carcinosarcoma Undifferentiated Leiomyosarcoma Low-grade serous Borderline serous Treatment characteristics Cycles of ixabepilone ± bevacizumab completed [mean ± SD] Initial chemotherapy-free interval, months [median (range)] Prior lines of chemotherapy [median (range)] Status at initial cytoreduction No residual disease b1 cm N1 cm Unspecified⁎ Staging approach Laparoscopic Open Prior radiation therapy Vaginal cuff brachytherapy Vaginal cuff brachytherapy and external beam radiation Palliative radiation to skeletal metastases Palliative radiation to cranial metastases Neoadjuvant chemotherapy

Ovarian, primary peritoneal, fallopian tube

n = 24

%

(n = 36)

61.17 ± 9.97 2 31.93 ± 13.08

(0–6)

56.71 ± 12.39 2 28.73 ± 5.60

(1–4)

19 2 2 1 0

79.17 8.33 8.33 4.17 0.00

34 1 1 0 0

94.44 2.78 2.78 0.00 0.00

10 4 8

41.67 16.67 33.33

11 4 13

30.56 11.11 36.11

10 0 2 11 1

41.67 0.00 8.33 45.83 4.17

1 2 29 4 0

2.78 5.56 80.56 11.11 0.00

9 9 1 0 2 2 1 N/A N/A

37.50 37.50 4.17 0.00 8.33 8.33 4.17 N/A N/A

18 4 2 1 1 8 0 1 1

50.00 11.11 5.56 2.78 2.78 22.22 0.00 2.78 2.78

5.4 ± 4.1 13.7 (0–84.1) 2 (1–7)

%

4.55 ± 2.50 11.8 (0–144) 5 (1–10)

19 0 3 2

79.17 0.00 12.50 8.33

21 6 4 5

58.33 16.67 11.11 13.89

5 19

20.83 79.17

3 33

8.33 91.67

14 2 2 1 1

58.33 8.33 8.33 4.17 4.17

1 0 0 0 13

2.78⁎⁎ 0.00 0.00 0.00 36.1

⁎ E.g., surgery performed at outside institution. ⁎⁎ Extensive involvement cervix by serous tumor.

all patients, mean age and body mass index at diagnosis were 58.5 ± 11.6 years and 29.8 ± 8.8 kg/m2, respectively. Roughly 35% of patients carried pre-existing diagnoses of essential hypertension. Eight patients (13.3%, 5 uterine and 3 ovarian) underwent initial staging through a minimally invasive approach. Debulking to b 1 cm residual disease was achieved in 75% (58.3% no residual disease, 16.7% military disease) of ovarian and 79% of uterine cancer cases (79% no residual disease). Approximately 92% and 54% of ovarian and uterine cancer patients, respectively, presented with advanced disease. Serous tumors represented the most common ovarian histology (50%), and were equally as common as endometrioid tumors (37.5% each) among uterine tumors. Of the stage I uterine cancers, there were six of endometrioid histology (two grade 1 tumors, one grade 2 tumor, and three grade 3 tumors), three uterine serous cancers, and one heterologous carcinosarcoma.

3.2. Treatment characteristics Prior to ixabepilone with or without bevacizumab, patients had received a median of 3.5 (range: 1–10) prior lines of chemotherapy. Among uterine cancers, radiation had been prescribed in 19 instances in the form of vaginal cuff brachytherapy alone (58.3%, 14/24), vaginal cuff brachytherapy with external beam radiation (8.3%, 2/24), and palliative radiation to skeletal (8.3%, 2/24) or cranial (4.2%, 1/24) metastases. Among ovarian cancers, vaginal cuff brachytherapy was applied in one instance of a serous tumor with extensive cervical involvement (2.8%, 1/36). Patients completed a mean of 4.7 ± 2.9 cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. Reasons for non-administration of bevacizumab included provider preference (n = 7), patient refusal (n = 1), denial by insurance (n = 1), or relative contraindication

Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

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Table 2 Recorded toxicities. Without bevacizumab

Grade 1–2 Grade ≥ 3 and/or resulting in discontinuation of agent

Uterine

Anemia Thrombocytopenia Diarrhea Fatigue Neuropathy

With bevacizumab Grade 1–2

Grade ≥ 3 and/or resulting in discontinuation of agent

Anorexia Arthralgia Constipation Diarrhea Dry skin Emesis Epistaxis Hypertension Mucositis Neuropathy Proteinuria Rhinorrhea Thrombocytopenia Mucositis Neuropathy Proteinuria Seizure

given increased risk of intra-cranial or other hemorrhage (n = 2). Biweekly maintenance bevacizumab following ixabepilone and bevacizumab therapy was administered to 2 uterine and 4 ovarian cancer patients. The two uterine cancer patients had received ixabepilone and bevacizumab for 6 (n = 1) or 9 cycles (n = 1), and were then maintained on bevacizumab thereafter at the discretion of the provider. Best responses observed prior to maintenance therapy among these 2 patients included a partial response (n = 1) and disease stabilization (n = 1). The four ovarian cancer patients had received ixabepilone and bevacizumab for 4 (n = 1), 5 (n = 1), or 6 (n = 2) cycles, and were then maintained on bevacizumab thereafter at the discretion of the provider. Best responses observed prior to maintenance therapy among these 4 patients included complete response (n = 2), partial response (n = 1), and disease stabilization (n = 1). Neuropathy contributed to the decision to discontinue ixabepilone in one instance. The initial ixabepilone dose prescription was 16 mg/m2 in most patients, though ixabepilone was prescribed at 20 mg/m2 in 25% (6/24) of uterine and 2.8% (1/36) of ovarian cancer patients. Of note, ixabepilone was also dosed at 40 mg/kg every 21 days for at least a portion of the treatment course in 4 instances (6.7%) based on provider preference. Treatment remains ongoing in 6 patients (2 uterine cancers, 4 ovarian cancers) at the time of this report. Of the uterine and ovarian cancer patients who received bevacizumab in conjunction with ixabepilone, 12.5% (2/16) and 21.2% (7/33) had received prior bevacizumab, and one patient had received therapy with an epothilone 5 years prior to initiation of ixabepilone monotherapy. Other previously administered regimens included platinum/paclitaxel ± doxorubicin, paclitaxel/ifosfamide, doxorubicin and ifosfamide or cyclophosphamide, platinum/ gemcitabine with or without bevacizumab, weekly paclitaxel with or without bevacizumab, pegylated liposomal doxorubicin with or without platinum, carboplatin with or without cyclosporine A, topotecan with or without platinum, etoposide, trastuzumab, arimidex, tamoxifen, megace, navelbine, melphalan, gemzar/ taxotere, bendamustine, and dacarbazine, as well as remote participation in various trials with immune-modulating agents and small

Ovarian, primary peritoneal, fallopian tube

n=8

n=3

1 1 1 1 1

0 0 0 0 0

Uterine n = 16

Ovarian, primary peritoneal, fallopian tube n = 33

1 1 1 0 0 1 1 2 1 3 0 1 1 0 1 0 0

0 0 0 1 1 0 1 2 0 3 1 0 0 1 1 1 1

molecule inhibitors. Chemotherapy was administered via intraperitoneal catheter in 8.3% (3/36) patients. 3.3. Toxicities Toxicities are listed in Table 2. There were no bowel perforations or treatment-related deaths. Three ovarian cancer patients eventually underwent ixabepilone dose reduction to 12 or 14 mg/m2 secondary to neuropathy; one ovarian cancer patient underwent bevacizumab dose reduction to 7.5 mg/kg secondary to mucositis. While the authors recognize that dose reductions for bevacizumab are not generally recommended [28], there is evidence that incidence of certain events such as bleeding, may be higher in patients receiving bevacizumab at 10 mg/kg every 2 weeks compared to those receiving bevacizumab 5 mg/kg every 2 weeks [29], both of which exceed that expected with chemotherapy alone [30,31]. The prescribing physician therefore chose to decrease dose in one patient. The treatment regimen was discontinued altogether due to unacceptable toxicity in 4 patients secondary to fatigue, proteinuria, neuropathy, and diarrhea/mucositis/ new-onset seizures. 3.4. Clinical outcomes The median follow-up since the time of initial diagnosis within this entire cohort is 3.66 years (range: 0.59–16.19). Clinical outcomes are detailed in Fig. 1-top. To date, there have been 22 deaths from disease and 1 death not directly attributable to disease (i.e., sepsis following scheduled joint surgery); 36 patients remain alive with disease and 1 alive with no evidence of disease. Best response did not vary by taxane-free interval for either endometrial (p = 0.60) or ovarian (p = 0.85) cancers (Fig. 1-bottom left and bottom right), though information regarding taxane-free interval was incomplete for 1 ovarian and 2 endometrial cancer patients. The objective response rate for uterine cancers was 41.7% (12.5% complete, 29.2% partial) with disease stabilization in an additional 20.3%; median duration of response or stabilization was 7 months

Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

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Fig. 1. Treatment outcomes (top). Taxane-free interval is shown according to response for endometrial (bottom-left; p = 0.60) and ovarian cancers (bottom-right; p = 0.85). CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.

(range: 2–30 months). Median PFS and OS were 5.2 and 9.63 months, respectively (Fig. 2). PFS was improved in patients who received concurrent bevacizumab (6.5 versus 3.0 months, respectively, p = 0.01; HR 0.2, 95% CI 0.05–0.77); OS was also longer (9.6 versus 4.2 months, respectively, p = 0.02, HR 0.19, 95% CI 0.05–0.74) (Fig. 3). Of note, for purposes of these survival comparisons, 3 outliers were removed given PFS/OS that exceeded more than 2 standard deviations of the mean in conjunction with atypical treatment characteristics. One of these censored patients achieved disease stabilization across 20 cycles of ixabepilone monotherapy, mostly in 3-weekly fashion, for a recurrent IIIC2 carcinosarcoma before discontinuation secondary to neuropathy. Another patient, after progressing on weekly paclitaxel, received 3 cycles of ixabepilone then 15 cycles of ixabepilone in conjunction with bevacizumab with partial response followed by prolonged bevacizumab maintenance for 15 months then re-treatment with ixabepilone. She is currently alive with disease. The last patient had presented with an advanced endometrioid tumor with mesonephric components treated primarily with pelvic radiation then debulking followed by carboplatin/paclitaxel for 6 cycles, hepatic resection for persistent disease, then post-operative ixabepilone monotherapy for 6 cycles; she remains without evidence of disease now at 3.2 years since last treatment. The overall response rate for ovarian cancers was 47.2% (11.1% complete, 36.1% partial) with disease stabilization in an additional 25.0%; median duration of response or stabilization was only 3 months (range 1–9). Median PFS and OS were not reached in the ovarian cohort (Fig. 4). At the time of this report, average follow-up since initiation of ixabepilone ± bevacizumab in the ovarian cancers has only

been 9.8 ± 9.4 months (median 5.2), compared to 11.6 ± 12.6 (median 8.2 months) in the uterine cancers. There were insufficient numbers of ovarian cancer patients who received ixabepilone monotherapy to perform comparative analyses to ixabepilone ± bevacizumab. Presently, the efficacy of re-treatment with bevacizumab or epothilones has been incompletely described in the literature. Among the 9 patients in this cohort who had received prior bevacizumab, there were 44% (n = 4) partial and 11% (n = 1) complete responses; 33% (n = 3) had progression and 11% (n = 1) demonstrated disease stabilization. The one patient who received patupilone remote to ixabepilone achieved disease stabilization. Among complete responses in addition to the patient outlined above, the second case represented a patient with stage IIIA clear cell ovarian carcinoma who progressed while on an industry-sponsored trial of firstline therapy, underwent interval debulking, then received ixabepilone and bevacizumab for 6 cycles to achieve a complete response, which was maintained for 15 months. The third individual underwent a robotic hysterectomy and bilateral salpingo-oophorectomy without staging in the setting of a clinical IIIC ovarian clear cell carcinoma, was then referred from an outside institution, received carboplatin/paclitaxel for four cycles, underwent interval debulking including bowel resection, then completed ixabepilone with eventual addition of bevacizumab with no suggestion of disease on a subsequent CT scan. Unfortunately, her CA-125 began to rise 3 months later. The fourth patient had an optimally debulked IIIC serous ovarian cancer treated with adjuvant IV/IP platinum/paclitaxel who subsequently received for recurrence carboplatin/gemcitabine/bevacizumab. She failed to tolerate two industry-sponsored protocols secondary to

Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

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Fig. 2. Progression-free (top) and overall (bottom) survival for endometrial cancers. The combination of weekly ixabepilone with bevacizumab appears to perform favorably relative to ixabepilone (GOG 129P) or bevacizumab (GOG 229E) monotherapy in this population, though comparisons to these prospective studies are difficult given the retrospective nature of the present report.

toxicities. She had a 5.7-month chemotherapy-free interval following her complete response to ixabepilone/bevacizumab before beginning another line of chemotherapy. The fifth patient was treated for recurrent IIIC ovarian cancer with carboplatin/pegylated liposomal doxorubicin then gemcitabine before ixabepilone and bevacizumab for 6 cycles. She eventually recurred on bevacizumab maintenance therapy. Re-introduction of ixabepilone was ineffective, and she is currently on treatment with another line of chemotherapy. The sixth patient had a stage IVB uterine serous carcinoma and experienced a 29.3-month disease-free interval after initial therapy. Her first two recurrences responded to carboplatin/ paclitaxel and interval debulking; she was then treated with ixabepilone and bevacizumab for her third recurrence and achieved a complete response with a duration of over 8 months. The seventh patient represented a stage IA uterine serous carcinoma who was treated for recurrence with a bowel resection and ixabepilone with bevacizumab; her response was maintained for 4 months and she is currently alive with disease on another line of chemotherapy. Consistent with existing experience [32], we found that ixabepilone monotherapy had no activity in recurrent uterine leiomyosarcoma previously treated with a taxane. 4. Discussion In this report, we present the first description of clinical outcomes using weekly ixabepilone in conjunction with biweekly bevacizumab in ovarian and uterine cancers. Our experience with 60 patients demonstrates that this combination has respectable activity with an acceptable toxicity profile in both persistent or recurrent uterine and ovarian cancers that have been previously treated with a taxane. Furthermore, consistent with previous publications, it substantiates a possible role for bevacizumab in prolongation of progression-free survival in combination with cytotoxic therapy.

Across all 60 patients, 81.7% of whom received concurrent bevacizumab, we observed an ORR of 45%. This is intermediate among analogous existing publications. Hurt and colleagues (2009) retrospectively described an ORR as high as 60% (25% CR and 35% PR) among 51 heavily pre-treated ovarian cancers, among whom 98% were platinum-resistant, using weekly paclitaxel and bevacizumab [33]. Unlike the present analysis, paclitaxel was given on days 1, 8, 15, as well as 22 of a 28-day cycle at 60–70 mg/m2 IV; bevacizumab was administered on days 1 and 15 at 10–15 mg/kg, though the authors could find no benefit to higher doses of the anti-angiogenic agent. In that series, 16% of patients had received prior bevacizumab; in our series, 18.4% (9/49) of patients who received bevacizumab had been previously treated with it. It is possible that response rate in our population might have been improved by an additional treatment on day 22, or with higher dosing of bevacizumab. Of note, toxicities were reported at a much greater frequency in that study, though this may simply reflect recording bias in the retrospective setting. In the AURELIA trial [14], a randomized controlled trial of various cytotoxic therapies (paclitaxel 80 mg/m2 intravenously (IV) on days 1, 8, 15, and 22 every 4 weeks; pegylated liposomal doxorubicin 40 mg/m2 IV on day 1 every 4 weeks; topotecan 4 mg/m2 IV on days 1, 8, and 15 every 4 weeks or 1.25 mg/m2 on days 1 to 5 every 3 weeks with or without bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) in 361 patients with platinum-resistant disease, ORR in the bevacizumab-containing arm was 32% using CA-125 criteria alone, and 27% using RECIST criteria. In that study, only 7% of patients in either arm had been previously treated with bevacizumab. ORR was only 11.8% among patients who received cytotoxic agent alone (p = 0.001). Intriguingly, in preliminary reports the conferred benefit was greatest in the subgroup receiving weekly paclitaxel [34]. In the present retrospective review, we found improvement in PFS to 6.5 from 3.0 months (p = 0.01, HR 0.2, 95% CI 0.05–0.77) and OS to

Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

D.M. Roque et al. / Gynecologic Oncology xxx (2015) xxx–xxx

9.6 months from 4.2 months (p = 0.02, HR 0.58, 95% CI 0.04–0.74), respectively, among uterine cancers with the addition of bevacizumab to weekly ixabepilone. PFS after combined treatment compares favorably to 2.9 months described in GOG-129P [8], a phase II study of ixabepilone monotherapy as second-line treatment of endometrial cancer. This also exceeds 4.2 months achieved in GOG-229E [35], a phase II trial of bevacizumab monotherapy among 52 patients with recurrent or persistent endometrial cancer. At the time of this report, median values had not yet been reached among ovarian cancers, though we predict they will compare favorably to both GOG 170D (bevacizumab at 15 mg/kg every 3 weeks as monotherapy for recurrent ovarian cancers) [36] and GOG 126 M (ixabepilone at 20 mg/m2 days 1, 8, and 15 of a 28day cycle as monotherapy for recurrent ovarian cancer) [9]. In the former study, the ORR was 21%, with a median response duration of 10 months, and median PFS/OS of 4.7/17 months; in the latter, ORR was 14.3%, with median time to progression of 4.4 months and OS of 14.8 months. Overall, these findings appear again consistent with studies of weekly paclitaxel as reported by Hurt and colleagues (2007) [33] (i.e., median PFS and OS of 7 and 12 months, respectively) and reminiscent of the AURELIA trial [14], where bevacizumab offered improvement in progression-free survival (6.7 versus 3.4 months, respectively; HR 0.48, 95% CI, 0.38 to 0.60, p b 0.001). In AURELIA, OS was not affected, however, the trial was underpowered to detect this endpoint and there was a crossover rate of 40% to single-agent bevacizumab. Similar advantages in PFS have been observed using bevacizumab in combination with paclitaxel compared to paclitaxel alone as first-line treatment for metastatic breast cancer [37]. Notably,

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PFS has been increasingly deemed an acceptable endpoint for clinical trials [38]. In the present report, use of imaging to monitor response was also at the discretion of the provider. Among ovarian cancer patients with a best response of complete/partial response or stable disease, 3/26 (12%), 6/26 (23%), and 17/26 (65%) were determined by both CA-125 and CT, CT alone, CA-125 alone, respectively. Among uterine cancer patients with a best response of complete/partial response or stable disease, 3/15 (20%), 5/15 (33%), and 7/15 (47%), were determined by both CA-125 and CT, CT alone, and CA-125 alone, respectively. Use of CT alone was indicated for instances in which CA125 was not an initial marker for disease. It is possible that the improvement in outcomes in the present cohort relative to the prospective GOG studies reflects use of less stringent response criteria. We chose to administer ixabepilone in weekly fashion for several reasons. This schedule has been associated with less toxicity, especially neutropenia, compared to every three week dosing in prospective studies [8,9,39]. Some evidence also suggests that administration of microtubule-stabilizing agents in dose-dense or metronomic compared to conventional fashion may confer survival benefit in certain subsets of ovarian (JGOG 3016) [40] and breast [41] cancer populations. Confirmatory analyses are eagerly awaited, though it appears that weekly schedules produce at least equivalent outcomes as every 3-week dosing with the benefit of improved tolerability [42,43]. Interestingly, in GOG126 N, Markman et al. (2006) found re-treatment with weekly paclitaxel at 80 mg/m2 could produce an ORR of 20.9% despite recurrence b6 months following paclitaxel delivered every 3 weeks in conjunction with carboplatin [44]. In vitro, metronomic, as opposed to maximum

Fig. 3. Progression-free (top, left) and overall (bottom, left) survival for endometrial cancers were stratified by receipt of bevacizumab (bev). PFS (top, right) and OS (bottom, right) were improved in the setting of concurrent bevacizumab (6.5 versus 3.0 months, p = 0.01, HR 0.2, 95% CI 0.05–0.77 and 9.6 versus 4.2 months, p = 0.02, HR 0.58, 95% CI 0.04–0.74, respectively).

Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008

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D.M. Roque et al. / Gynecologic Oncology xxx (2015) xxx–xxx

Fig. 4. Progression-free (top) and overall (bottom) survival for ovarian cancer have not yet been reached. This is shown in relationship to ixabepilone monotherapy (GOG 126M) or bevacizumab (GOG 170D) monotherapy in this population, though comparisons to prospective studies are difficult given the retrospective nature of the present report.

tolerated, taxane dosing schemes may induce selective toxicity to endothelial cells at much lower concentrations because frequent repetitive administration does not allow recovery of the tumor vasculature [45, 46]. It is not known at present whether these mechanistic hypotheses extrapolate to epothilones. Recurrent disease is most often classified based on platinum sensitivity, as the longer the platinum-free interval, the higher the response rate to second-line platinum-based therapy [47]. To date, this phenomenon has not translated well to other classes of chemotherapy [48]. Accordingly, in this work, longer taxane-free interval was not associated with increased probability of response. Thus, recent treatment with taxane should not influence timing of initiation of epothilone therapy, though they share overlapping mechanisms of action. This report is limited by retrospective design and heterogeneity of patient and disease characteristics/prior treatment regimens received. There might have been under-documentation of toxicities. There is no ability to eliminate bias in provider choice of administration of bevacizumab, which might have influenced PFS and OS if providers remain reluctant to administer an expensive therapy to patients who they feel would have poor outcomes regardless of therapy. Future studies should address the utility of biomarkers such as class III βtubulin to predict taxane resistance and identify tumors that may alternatively respond to epothilones, and the role of maintenance bevacizumab in this setting. We look forward to the long-term survival results of the ovarian cancer patients in this retrospective review. Another unanswered concern is the potential cost of this regimen. In instances in which disease-related symptoms are present due to recurrent ovarian cancer, integration of bevacizumab has been shown to ameliorate symptoms (e.g., discomfort due to ascites) [49]. Bevacizumab in primary therapy may not be cost-effective [50,51]. Formal costeffectiveness and quality of life analyses are grossly lacking among ovarian and endometrial cancer populations treated with cytotoxic chemotherapy in combination with bevacizumab in instances of platinum-resistant disease.

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Please cite this article as: Roque DM, et al, Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary pe..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.008