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A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer
Gynecologic Oncology 119 (2010) 32–37
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer☆ Michael Friedlander a,⁎, Kenneth C. Hancock b, Danny Rischin c, Mark J. Messing d, Claude A. Stringer e, Gemma M. Matthys f, Bo Ma f, Jeffrey P. Hodge f, Joanne J. Lager f a
Prince of Wales Hospital, Randwick, Sydney, Australia Texas Oncology, Fort Worth, TX, USA Mercy Hospital for Women, Melbourne, Australia d Texas Oncology, Bedford, TX, USA e Texas Oncology, Dallas, TX, USA f GlaxoSmithKline, Research Triangle Park, NC, USA b c
a r t i c l e
i n f o
Article history: Received 14 April 2010 Available online 27 June 2010 Keywords: Ovarian cancer CA-125 Pazopanib
a b s t r a c t Objective. The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer. Methods. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with complete CA-125 response to initial platinum-based chemotherapy and subsequent elevation of CA-125 to ≥ 42 U/mL (N 2 × ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. This Green–Dahlberg study required 2 CA-125 responses in stage I (20 patients) to proceed to stage II (15 patients). The primary endpoint was CA-125 response (≥ 50% decrease from baseline, confirmed ≥ 21 days after initial evaluation). Results. Eleven of 36 patients (31%) had a CA-125 response to pazopanib, with median time to response of 29 days and median response duration of 113 days. Overall response rate was 18% in patients with measurable disease at baseline. The most common adverse events leading to discontinuation of study drug were grade 3 ALT (8%) and AST (8%) elevation. Only 1 grade 4 toxicity (peripheral edema) was reported. Conclusions. Pazopanib monotherapy was relatively well tolerated, with toxicity similar to other smallmolecule, oral angiogenesis inhibitors, and demonstrated promising single-agent activity in patients with recurrent ovarian cancer. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing. © 2010 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer (OC) is the fourth-leading cause of cancer-related deaths among women [1]. Despite extensive effort and multiple clinical trials evaluating various chemotherapy regimens, there have been no substantive improvements in clinical outcomes for patients with advanced ovarian disease over the last decade [2–4]. Most women present with advanced disease, and undergo optimal debulking surgery followed by 6 to 8 cycles of platinum-based adjuvant
☆ Note: These data were previously presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), June 1–5, 2007, Chicago, IL (abstract 5561), and at the 33rd European Society for Medical Oncology (ESMO) Congress, September 12–16, 2008, Stockholm, Sweden (oral presentation). ⁎ Corresponding author. Prince of Wales Hospital; Level 2 High Street; Randwick, Sydney NSW 2031, Australia. Fax: +61 2 9382 2588. E-mail address: [email protected] (M. Friedlander). 0090-8258/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2010.05.033
chemotherapy [5–7]. Although most patients respond to initial treatment, up to 70% of patients with advanced-stage ovarian or primary peritoneal cancer subsequently relapse [8]. The median time to progression after primary chemotherapy is about 16 to 20 months, and the median overall survival (OS) in patients with advanced OC is 31 to 51 months [3,4,9]. An increase in serum cancer antigen (CA-125) is the first sign of disease recurrence in most patients and commonly precedes symptom onset or radiologic evidence of progressive disease (PD) by a median 4-month lead time [10]. CA-125 is commonly evaluated every 2 to 4 months for the first 2 years after completing chemotherapy and every 3 to 6 months thereafter [7,11], although the need for CA-125 surveillance has recently been challenged. There are well-established Gynecologic Cancer Intergroup (GCIG) criteria defining CA-125 progression and CA-125 response [12,13]. Retrospective analysis of progression-free survival (PFS) of patients in the experimental arms of the Taxol Intergroup Trial, assessed using either CA-125 doubling or standard Response Evaluation Criteria in
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Solid Tumors (RECIST), yielded similar results, supporting use of CA125 as a surrogate efficacy endpoint [10]. Accordingly, we elected to evaluate CA-125 response in this study as well as RECIST in patients with measurable disease. The optimal management of asymptomatic patients with a rising CA-125 is controversial. Evidence from a recently presented clinical trial suggests no benefit from commencing chemotherapy until symptomatic progression [14], and many clinicians withhold chemotherapy until patients develop symptoms, whereas others institute second-line therapy at the time of CA-125 recurrence. Although platinum-based regimens are commonly used at recurrence, clinical benefit is limited by cumulative toxicity and subsequent development of drug resistance [15]. Most patients with rising CA-125 are initially asymptomatic, have a small volume of disease, and are a good population in which to evaluate the activity of novel, targeted therapies. Multiple lines of evidence suggest that angiogenesis plays a critical role in the growth of ovarian tumors and is therefore a potentially viable therapeutic target [16–18]. For example, several studies have established an inverse correlation between angiogenesis and OS and PFS in women with advanced OC [17,19,20], and preclinical and clinical data show that antibodies targeting vascular endothelial growth factor (VEGF) inhibit ascites formation, a common finding at initial presentation and at relapse that is associated with a poor prognosis [21,22]. Pazopanib (Votrient™, GlaxoSmithKline), approved by the United States Food and Drug Administration in October 2009 for the treatment of patients with advanced renal cell carcinoma [23], is an oral angiogenesis inhibitor targeting VEGF receptor (VEGFR), plateletderived growth factor receptor (PDGFR), and c-Kit [24]. Phase I testing demonstrated a manageable toxicity profile and activity in a range of solid tumors [25]. To assess pazopanib's potential utility as maintenance therapy after chemotherapy, the current study investigated the activity of pazopanib in asymptomatic patients with recurrent OC who had GCIG-defined CA-125 progression and small-volume disease. Methods Patients Eligible patients were ≥21 years of age with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. All patients had received ≤2 prior treatment regimens, including first-line platinum-based chemotherapy for ovarian disease. Patients who had received prior adjuvant chemotherapy after first-line treatment (including tamoxifen or monoclonal antibody therapies that target CA-125 [e.g., oregovomab] if the CA125 level was rising) and neoadjuvant therapies (recorded as a single line of therapy, per protocol) were eligible. In addition, patients must have had CA-125 levels ≥42 U/mL after a complete CA-125 response (defined as a normalized CA-125 value [i.e., ≤21 U/mL]) to first-line platinum-based therapy and no evidence of disease or nonbulky disease. Inclusion was restricted to patients with small-volume disease (e.g., minimal ascites not causing abdominal distention/ mesenteric thickening or not requiring paracentesis, or lesions ≤4 cm by spiral computed tomography [CT] or magnetic resonance imaging [MRI] at baseline) to minimize the potential for bowel perforations observed in previous trials with angiogenesis inhibitors. Additional eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate bone marrow, renal, and hepatic function. Patients who had received prior therapy with pazopanib or any other angiogenesis inhibitors; patients who had major surgery, chemotherapy, hormonal therapy, biologic therapy, immunotherapy, or radiotherapy within the preceding 28 days; or patients with a previous diagnosis of leptomeningeal disease, brain metastases, or another malignancy were excluded. Additional exclusion criteria included poorly controlled hypertension; QTc prolongation (i.e., QTc interval N480 ms); previous
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Class III or IV heart failure; history of cerebrovascular accident within 6 months; history of myocardial infarction, hospitalization for unstable angina, or cardiac angioplasty or stenting within 3 months; untreated venous thrombosis; malabsorption syndrome; or any condition that interfered with oral administration of the study drug. Study design and treatment This nonrandomized, open-label, multicenter phase II trial (VEG104450; NCT00281632) had a 2-stage Green-Dahlberg design with a stopping rule to allow early termination for lack of efficacy [26]. An interim efficacy evaluation of 20 patients enrolled in stage I required at least 2 patients to have a CA-125 response as assessed by Rustin criteria [12] for continuation of the study to stage II. Patients were scheduled to receive daily oral pazopanib 800 mg over 28-day treatment cycles until clinical or radiologic evidence of PD, withdrawal from treatment because of unacceptable toxicity, or withdrawal of consent. In the event of significant hematologic and nonhematologic toxicities, including grade 3/4 anemia, neutropenia, thrombosis, and thrombocytopenia; grade ≥ 2 coagulopathy, hemorrhage, and hepatobiliary toxicity; hypertension (symptomatic or systolic blood pressure ≥170 mm Hg or diastolic blood pressure ≥110 mm Hg); and proteinuria (24-h urine protein ≥3 g), the dose of pazopanib was reduced to 400 mg and the patient was monitored for 10 to 14 days. If the toxicity did not recur or worsen, the dose was increased to 600 mg with continued monitoring for an additional 10 to 14 days. If adequately tolerated, the standard 800 mg dose was resumed. If treatment was withheld for N21 days, disease assessments (CA-125 and CT scan/MRI, if applicable) were repeated before continuation of treatment. With regard to hepatic toxicity, a more conservative approach was adopted; per protocol amendment, pazopanib was discontinued if alanine aminotransferase or aspartate aminotransferase increased N8 times the upper limit of normal, even with subsequent recovery to normal. The study protocol and amendments were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board. This study was conducted in accordance with “good clinical practice,” all applicable regulatory requirements, and the guiding principles of the Declaration of Helsinki. All patients provided written informed consent. Endpoints The primary objective of this study was to assess the best biochemical response rate (as determined by CA-125 response after daily pazopanib administration, based on modified GCIG criteria) [12,27]. CA-125 response was defined as ≥50% decrease from the baseline CA-125 level and confirmed ≥21 days after initial evaluation (baseline was defined as the higher value of 2 pretreatment CA-125 assessments). The response was further qualified as normalized (if the assessed CA-125 was ≤21 U/mL) or non-normalized. Progressive disease was defined as a CA-125 increase ≥100% from nadir (if nadir N21 U/mL) or ≥42 U/mL (if nadir ≤21 U/mL); nadir was defined as the lowest CA-125 level until current assessment. If PD was not confirmed after 21 days, it was classified as unconfirmed PD. Stable disease (SD) was defined as changes in CA-125 not qualifying as either PD or response. Secondary objectives included assessment of the overall response and SD rate based on biochemical, radiographic, and physical examination, and PFS. Modified GCIG criteria [12,27] were used to assess overall response in patients with measurable disease, based on the best response from biochemical, radiologic (defined according to RECIST) [28], and physical examinations. Progression-free survival was defined as the interval from the first dose of study drug to the date of documented PD assessed by biochemical, radiological, and clinical assessment, or to date of death by any cause.
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Assessments For all patients on treatment, clinical assessments were performed monthly and CA-125 assessments were performed at a central laboratory at baseline and monthly. Additionally, radiologic assessments were performed at baseline and every other month for patients with measurable disease at baseline. For patients without measurable disease at baseline, radiologic assessments were performed at the time of a clinical or CA-125 assessment indicating PD and at the discretion of the investigator. Plasma pazopanib concentrations were measured by tandem high-performance liquid chromatography-mass spectrometry. Adverse events (AEs) were reported in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 [29]. Adverse event and serious AE data were collected from day 1 until the patient completed the posttreatment period. Statistical assessments This study was designed to evaluate 2 prespecified hypotheses about the biochemical response (CA-125) rate. The null hypothesis (response = 10%) reflected a response rate that would be of no clinical benefit, and the alternative hypothesis (response = 30%) reflected a desired target response rate that would provide greater confidence of positive outcome in larger, confirmatory studies. Based on the planned sample size of 35 patients and a true biochemical response rate of 10%, the type I error (i.e., overall probability of falsely declaring that the treatment was effective) was b0.05. Alternately, if the true biochemical response rate was 30%, the statistical power to correctly conclude that the treatment was effective was 0.93. Biochemical response, radiologic response, and overall response rates were calculated with corresponding 95% unadjusted exact binomial confidence interval (CI). The Kaplan–Meier method was used to summarize duration of CA-125 response and PFS at 6 months. Results Patients All 36 women (100%) enrolled in this study had an elevated CA125 at baseline (≥42 U/mL) and 17 (47%) had measurable disease at baseline (Table 1). Before entering the study, 31 patients (86%) had achieved objective responses (26 patients [72%] with complete response; 5 patients [14%] with partial response) to their most recent chemotherapy regimen, with median response duration of 25 weeks. At the cutoff date for this report (April 30, 2008), 22 patients (61%) and 10 patients (28%) discontinued the study because of PD and toxicity, respectively. One patient (3%) died on study because of PD, and 3 patients (8%) remained on study. These 3 patients remained on pazopanib for 2, 2.5, and 3 years, respectively; 2 patients discontinued treatment following CA-125 progression, and 1 patient discontinued treatment because of RECIST progression. Three patients (8%) withdrew consent or stopped study treatment because of investigator decision. Efficacy Most patients enrolled in this study (25 of 29 patients for whom data were available; 86%) achieved plasma pazopanib concentrations associated with clinical and biologic activity (≥34 μM) [25]. Of the 20 patients enrolled in stage I, 9 patients (45%) had CA-125 responses. Overall, 11 of 36 patients (31%; 95% CI, 16% to 48%) had a CA-125 response to pazopanib (Table 2; Fig. 1). In addition, 20 patients (56%) had SD based on CA-125 criteria; the median duration of their SD response was 80 days (95% CI, 56 to 100 days). The median time to
Table 1 Patient baseline demographics and disease characteristics. N = 36 Age, mean years (range) Female, n (%) Weight, mean kg (range) Race, n (%) White Asian ECOG performance status 0 1 Primary tumor type Ovarian Primary peritoneal Histology Malignant serous tumor Malignant endometrioid tumor Mixed epithelial cell Undifferentiated adenocarcinoma Unknown Other Stage at initial diagnosis II IIIb IIIc IV IVa Time since initial diagnosis, median days (range) Time to relapse Relapsed b 6 months Relapsed 6 - 12 months Relapsed N 12 months Response to most recent platinum-based therapya Refractory Resistant Sensitive Disease at baseline, n (%) Measurable Number of prior therapeutic regimens, n (%) 1 2
59.9 (40–85) 36 (100) 71.8 (48–111) 34 (94) 2 (6) 33 (92) 3 (8) 33 (92) 3 (8) 25 (69) 1 (3) 1 (3) 1 (3) 1 (3) 7 (19) 1 (3) 2 (6) 29 (81) 1 (3) 3 (8) 594 (293–2060) 14 (39) 12 (33) 10 (28) 3 (8) 6 (17) 27 (75) 17 (47) 21 (58) 15 (42)
Abbreviation: ECOG, Eastern Cooperative Oncology Group. a Platinum-refractory is defined as disease that progresses during platinum-based therapy; platinum-resistant is defined as recurrence b6 months from completion of platinum-based therapy; and platinum-sensitive is defined as recurrence ≥6 months from completion of platinum-based therapy.
CA-125 response was 29 days (range, 27 to 57 days), and median duration of response was 113 days (95% CI, 58 to 190 days; Fig. 2). A lower proportion of patients who received 1 line of prior therapy (4 of Table 2 Summary of CA-125 response.
Best CA-125 response, n (%) 50% response normalizeda 50% response non-normalizedb 50% response rate (normalized + non-normalized) 95% confidence interval Stable disease Progressive disease Unconfirmed progressive disease Unknown
1 Line of prior therapy (n = 21)
2 Lines of prior therapy (n = 15)
Total (N = 36)
1 (5) 3 (14) 4 (19)
1 (7) 6 (40) 7 (47)
2 (6) 9 (25)c 11 (31)c
(5.4 - 41.9) 13 (62) 1 (5) 2 (10) 1 (5)
(21.3 - 73.4) 7 (47) 0 1 (7) 0
(16.3 - 48.1) 20 (56) 1 (3) 3 (8) 1 (3)
Abbreviation: CA-125, cancer antigen-125. a Normalized response was defined as a ≥50% decrease in CA-125 levels to ≤21 U/ mL. b Non-normalized response was defined as a ≥ 50% decrease in CA-125 levels to N21 U/mL. c Includes 1 patient who had a biochemical response per protocol definition before pazopanib dosing.
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Fig. 1. Maximum percentage reduction from baseline cancer antigen-125.
21 patients, 19%; 95% CI, 5% to 42%) had a CA-125 response compared with patients who received 2 lines of prior therapy (7 of 15 patients, 47%; 95% CI, 21% to 73%). However, no definitive conclusions can be drawn from these small subsets of patients. The overall response rate, based on CA-125 and RECIST, was 18% (95% CI, 4% to 43%) in patients with measurable disease at baseline (n = 17; Table 3) [13]. No partial or complete responses were observed in patients with measurable disease based on RECIST. In 17 patients with radiographically measurable disease, 5 patients (29%) had SD, 10 patients (59%) had PD, and the responses of 2 patients (12%) were not known. Progression-free survival at 6 months was 17% (95% CI, 6% to 33%). Safety The median duration of pazopanib monotherapy was 56 days (range, 8 to 673 days). Eleven patients (31%) required dose interruptions during the study for a median duration of 7 days. Four patients (11%) experienced AEs that required dose reduction. The dose was reduced by 1 dose level and was not escalated. The most common AE causing dose reduction was fatigue (8%). The most common AEs, regardless of causality, were diarrhea, fatigue, and nausea (47% for each; Table 4). The most common grade 3 AEs were fatigue and γ-glutamyl transpeptidase elevation (11% for both). One patient (3%) had grade 4 peripheral edema with underlying disease in the abdominal wall and concurrent hypoalbuminemia. No drug-related deaths were reported. One patient died during the study because of PD 93 days after the first dose of pazopanib. Of the 10 patients taking antihypertensive medications at baseline, 4 required an increase in their antihypertensive therapy to control blood pressure. Overall, 15 patients (42%) received antihypertensive medications during the study. Ten patients (28%) experienced 21 AEs that led to study drug discontinuation. The most common AEs leading to study drug discontinuation were alanine aminotransferase and aspartate aminotransferase elevations (8% for each). Other AEs leading to discontin-
uation included nausea (6%), fatigue (6%), and other hepatic enzyme increases (6%). Discussion Based on emerging data with other angiogenesis inhibitors demonstrating promising activity, it was reasonable to evaluate the activity of pazopanib in women with recurrent OC [30–33]. We observed evidence of activity of pazopanib with a CA-125 response in 31% of patients with recurrent disease after either 1 (n = 21) or 2 (n = 15) lines of prior chemotherapy. Pazopanib demonstrated a safety profile similar to that reported with other tyrosine kinase inhibitors [34,35]. The most common AEs leading to discontinuation of study drug were elevation of hepatic enzymes and fatigue. The majority of patients who discontinued therapy for grade 3 events were asymptomatic, with elevated hepatic enzymes. There were no deaths or incidences of bowel perforation. Clinical studies suggest that the therapeutically relevant plasma concentration of pazopanib is ≥34 μM and that this concentration is achieved by dosing with pazopanib of 800 mg daily [25]. Results of the present study demonstrate that trough plasma pazopanib concentrations ≥34 μM were achieved at a dose of 800 mg once daily in 86% of all patients and in 100% of the CA-125 responders from whom data were available. Therefore, factors other than plasma pazopanib concentration likely influence the CA-125 response, and translational studies are needed to identify which patients are most likely to benefit from treatment. The majority of patients with platinum-sensitive OC who have entered clinical trials in the past have been similar to the patient population enrolled in this study. For example, of the nearly 1000 patients enrolled in the GCIG CALYPSO study, 60% had an ECOG performance status of 0 and only 60% had measurable disease, with the majority having 1 site b5 cm [36]. Similarly, the patient population in our study also had excellent performance status and CA-125
Table 3 Summary of overall response based on modified GCIG criteria in patients with measurable disease (CA-125, RECIST).a Patients with measurable disease (n = 17) Response rate, n (%) [95% CI] Best response, n (%) Complete response Partial responseb Stable disease Progressive disease Unknown
Fig. 2. Cancer antigen-125 percentage change from baseline.
3 (18) [3.8–43.4] 0 3 (18) 3 (18) 11 (65) 0
Abbreviations: CA-125, cancer antigen-125; CI, confidence interval; GCIG, Gynecologic Cancer Intergroup; RECIST, Response Evaluation Criteria in Solid Tumors. a Described in Vergote I, et al. [13]. b Based on CA-125 only.
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Table 4 Adverse events reported overall in ≥10% of patients. Adverse event
Any adverse event Fatigue Hypertension Diarrhea ALT elevation Vomiting AST elevation Abdominal pain Nausea Arthralgia Anorexia Hair color changes GGT elevation Constipation Headache Ascites Abdominal pain, upper Pain in extremity Back pain Muscle spasms Abdominal distension Insomnia Rash Dyspepsia
CTC maximum toxicity grade n (%) Grade 2
Grade 3
Grade 4
9 (25) 7 (19) 7 (19) 6 (17) 6 (17) 6 (17) 5 (14) 4 (11) 4 (11) 3 (8) 2 (6) 2 (6) 2 (6) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 0
20 (56) 4 (11) 1 (3) 3 (8) 3 (8) 0 1 (3) 1 (3) 0 0 0 0 4 (11) 1 (3) 1 (3) 1 (3) 0 0 0 0 0 0 0 0
1 (3)a 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTC, Common Terminology Criteria; GGT, γ-glutamyl transpeptidase. a One grade 4 adverse event, peripheral edema, occurred in 1 patient.
recurrence after first- or second-line chemotherapy as defined by GCIG criteria; 53% of patients had no measurable disease by radiographic imaging. These characteristics are representative of most of the patients diagnosed with recurrent disease on the basis of rising CA-125 levels. Although CA-125 is routinely evaluated as patient follow-up after chemotherapy, the optimal management of asymptomatic patients with CA-125 progression remains a clinical dilemma, as early initiation of cytotoxic chemotherapy based on a rising CA-125 has not shown survival benefit [14]. However, it is known that a prolonged platinum-free interval, particularly greater than 12 to 18 months, is associated with an increased likelihood of response to subsequent platinum-based chemotherapy [15]. It is possible that noncytotoxic agents such as pazopanib could delay time to progression and potentially increase the platinum-free interval when administered to asymptomatic patients with recurrent OC, given that the median time to develop symptomatic progression and initiating chemotherapy is about 4 months after CA-125 progression. The use of CA-125 to measure response is controversial, although widely used in clinical practice. One recent report suggested that CA125 may not be reliable to measure response with anti-VEGF targeted therapy and may underestimate activity [37]. However, this particular study included only 14 evaluable patients with elevated CA-125 at study entry who were treated with a combination of sorafenib and bevacizumab [37]. Although 8 patients (53%) had a partial response based on CA-125 criteria, only 5 were subsequently confirmed by imaging. Similarly, of the 7 patients who achieved partial response based on imaging, 5 had concordant CA-125 outcome. Overall, the level of concordance between imaging and CA-125 criteria was 67%. Furthermore, 3 patients would have terminated therapy early if CA125 criteria alone had been used. However, based on imaging data, these patients continued on therapy and their tumor size did not change for up to 1 year after the point of progression by CA-125 criteria. Thus, CA-125 criteria alone may not reflect the true response rate. Indeed, RECIST may also underestimate response to angiogenesis inhibitors, as it is often inconsistent in assessing response in OC [38]. The criteria for PD in the current study included CA-125 progression as well as RECIST for progression. Patients were only required to
discontinue treatment if there was clinical or radiologic evidence of progression, but the treating physician and patient were not blinded to the CA-125 results. The possibility that some patients might have come off study early based on CA-125 progression cannot be excluded. However, since at this time there is insufficient data to determine the discordance between imaging and CA-125 criteria, it is reasonable to continue treatment with angiogenesis inhibitors if the treatment is well tolerated and there is no objective evidence of tumor progression. There is now evidence to support the activity of angiogenesis inhibitors in multiple tumor types, including OC [30,39–41]. Other studies have evaluated the efficacy and safety of oral tyrosine kinase inhibitors in women with recurrent OC, and a recent phase II study of cediranib reported a clinical benefit rate of 30% that included a 17% PR rate [42]. In that study, 23% of patients discontinued treatment because of toxicities before 2 cycles. Adverse events included hypertension, diarrhea, and fatigue; hepatic toxicity was not observed with this agent, indicating the subtle between-class differences in the safety profile of these agents. Other oral inhibitors of VEGF and VEGFR, such as BIBF1120, vandetanib, and sunitinib, among others, are being evaluated in recurrent OC. It remains unclear which, if any, of these agents will be optimal in this patient population, and the choice of treatment will ultimately depend on efficacy and toxicity. Additionally, a number of large, randomized clinical trials combining bevacizumab with carboplatin and paclitaxel in the first-line setting are nearing completion and will provide useful clinical insight about the optimal use of these agents. In conclusion, this study demonstrated that pazopanib monotherapy was relatively well tolerated, with a toxicity profile similar to other oral tyrosine kinase angiogenesis inhibitors, and had antitumor activity in patients with recurrent OC. A clinical trial evaluating the potential benefit of pazopanib as maintenance therapy following firstline chemotherapy for advanced OC is currently in progress. Conflict of interest statement M. Friedlander received an honorarium from GlaxoSmithKline for speaking at an investigators' meeting in June 2007 (beyond the 24-month ACCME definition of a relevant financial relationship requiring disclosure), and reports no other relevant financial relationships. D. Rischin received funding from GlaxoSmithKline for the trial reported in this manuscript. B. Ma and J.P. Hodge are employed by GlaxoSmithKline and own company stock. G.M. Matthys is also employed by GlaxoSmithKline, but reports no stock ownership. J.J. Lager reports employment relationships with GlaxoSmithKline (during authorship) and Sanofi-aventis. Authors Hancock, Messing, and Stringer report no potential conflict of interest.
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[23] U.S. Department of Health and Human Services Food & Drug Administration. Pazopanib [approval notice], published 2009. (http://www.fda.gov/AboutFDA/ CentersOffices/CDER/ucm187509.htm). [24] Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 2007;9:115–9. [25] Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009;15:4220–7. [26] Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Stat Med 1992;11:853–62. [27] Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 2004;96:487–8. [28] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [29] Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v3.0 (CTCAE), published August 2006. (http://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/ctcaev3.pdf). [30] Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2007;25:5165–71. [31] Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007;25:5180–6. [32] Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and lowdose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008;26:76–82. [33] Nimeiri HS, Oza AM, Morgan RJ, et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol 2008;110:49–55. [34] Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34. [35] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24. [36] Pujade-Lauraine E, Mahner S, Kaern J, et al. A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG). J Clin Oncol 2009;27 (15S Part I of II): 279s (abstr #LBA5509). [37] Azad NS, Annunziata CM, Steinberg SM, et al. Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy. Cancer 2008;112:1726–32. [38] Markman M. Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy [letter]. Cancer 2008;113:2832–3. [39] Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103–11. [40] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: 2335–42. [41] Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. [42] Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009;27:5601–6.
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer☆ Michael Friedlander a,⁎, Kenneth C. Hancock b, Danny Rischin c, Mark J. Messing d, Claude A. Stringer e, Gemma M. Matthys f, Bo Ma f, Jeffrey P. Hodge f, Joanne J. Lager f a
Prince of Wales Hospital, Randwick, Sydney, Australia Texas Oncology, Fort Worth, TX, USA Mercy Hospital for Women, Melbourne, Australia d Texas Oncology, Bedford, TX, USA e Texas Oncology, Dallas, TX, USA f GlaxoSmithKline, Research Triangle Park, NC, USA b c
a r t i c l e
i n f o
Article history: Received 14 April 2010 Available online 27 June 2010 Keywords: Ovarian cancer CA-125 Pazopanib
a b s t r a c t Objective. The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer. Methods. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with complete CA-125 response to initial platinum-based chemotherapy and subsequent elevation of CA-125 to ≥ 42 U/mL (N 2 × ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. This Green–Dahlberg study required 2 CA-125 responses in stage I (20 patients) to proceed to stage II (15 patients). The primary endpoint was CA-125 response (≥ 50% decrease from baseline, confirmed ≥ 21 days after initial evaluation). Results. Eleven of 36 patients (31%) had a CA-125 response to pazopanib, with median time to response of 29 days and median response duration of 113 days. Overall response rate was 18% in patients with measurable disease at baseline. The most common adverse events leading to discontinuation of study drug were grade 3 ALT (8%) and AST (8%) elevation. Only 1 grade 4 toxicity (peripheral edema) was reported. Conclusions. Pazopanib monotherapy was relatively well tolerated, with toxicity similar to other smallmolecule, oral angiogenesis inhibitors, and demonstrated promising single-agent activity in patients with recurrent ovarian cancer. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing. © 2010 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer (OC) is the fourth-leading cause of cancer-related deaths among women [1]. Despite extensive effort and multiple clinical trials evaluating various chemotherapy regimens, there have been no substantive improvements in clinical outcomes for patients with advanced ovarian disease over the last decade [2–4]. Most women present with advanced disease, and undergo optimal debulking surgery followed by 6 to 8 cycles of platinum-based adjuvant
☆ Note: These data were previously presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), June 1–5, 2007, Chicago, IL (abstract 5561), and at the 33rd European Society for Medical Oncology (ESMO) Congress, September 12–16, 2008, Stockholm, Sweden (oral presentation). ⁎ Corresponding author. Prince of Wales Hospital; Level 2 High Street; Randwick, Sydney NSW 2031, Australia. Fax: +61 2 9382 2588. E-mail address: [email protected] (M. Friedlander). 0090-8258/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2010.05.033
chemotherapy [5–7]. Although most patients respond to initial treatment, up to 70% of patients with advanced-stage ovarian or primary peritoneal cancer subsequently relapse [8]. The median time to progression after primary chemotherapy is about 16 to 20 months, and the median overall survival (OS) in patients with advanced OC is 31 to 51 months [3,4,9]. An increase in serum cancer antigen (CA-125) is the first sign of disease recurrence in most patients and commonly precedes symptom onset or radiologic evidence of progressive disease (PD) by a median 4-month lead time [10]. CA-125 is commonly evaluated every 2 to 4 months for the first 2 years after completing chemotherapy and every 3 to 6 months thereafter [7,11], although the need for CA-125 surveillance has recently been challenged. There are well-established Gynecologic Cancer Intergroup (GCIG) criteria defining CA-125 progression and CA-125 response [12,13]. Retrospective analysis of progression-free survival (PFS) of patients in the experimental arms of the Taxol Intergroup Trial, assessed using either CA-125 doubling or standard Response Evaluation Criteria in
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Solid Tumors (RECIST), yielded similar results, supporting use of CA125 as a surrogate efficacy endpoint [10]. Accordingly, we elected to evaluate CA-125 response in this study as well as RECIST in patients with measurable disease. The optimal management of asymptomatic patients with a rising CA-125 is controversial. Evidence from a recently presented clinical trial suggests no benefit from commencing chemotherapy until symptomatic progression [14], and many clinicians withhold chemotherapy until patients develop symptoms, whereas others institute second-line therapy at the time of CA-125 recurrence. Although platinum-based regimens are commonly used at recurrence, clinical benefit is limited by cumulative toxicity and subsequent development of drug resistance [15]. Most patients with rising CA-125 are initially asymptomatic, have a small volume of disease, and are a good population in which to evaluate the activity of novel, targeted therapies. Multiple lines of evidence suggest that angiogenesis plays a critical role in the growth of ovarian tumors and is therefore a potentially viable therapeutic target [16–18]. For example, several studies have established an inverse correlation between angiogenesis and OS and PFS in women with advanced OC [17,19,20], and preclinical and clinical data show that antibodies targeting vascular endothelial growth factor (VEGF) inhibit ascites formation, a common finding at initial presentation and at relapse that is associated with a poor prognosis [21,22]. Pazopanib (Votrient™, GlaxoSmithKline), approved by the United States Food and Drug Administration in October 2009 for the treatment of patients with advanced renal cell carcinoma [23], is an oral angiogenesis inhibitor targeting VEGF receptor (VEGFR), plateletderived growth factor receptor (PDGFR), and c-Kit [24]. Phase I testing demonstrated a manageable toxicity profile and activity in a range of solid tumors [25]. To assess pazopanib's potential utility as maintenance therapy after chemotherapy, the current study investigated the activity of pazopanib in asymptomatic patients with recurrent OC who had GCIG-defined CA-125 progression and small-volume disease. Methods Patients Eligible patients were ≥21 years of age with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. All patients had received ≤2 prior treatment regimens, including first-line platinum-based chemotherapy for ovarian disease. Patients who had received prior adjuvant chemotherapy after first-line treatment (including tamoxifen or monoclonal antibody therapies that target CA-125 [e.g., oregovomab] if the CA125 level was rising) and neoadjuvant therapies (recorded as a single line of therapy, per protocol) were eligible. In addition, patients must have had CA-125 levels ≥42 U/mL after a complete CA-125 response (defined as a normalized CA-125 value [i.e., ≤21 U/mL]) to first-line platinum-based therapy and no evidence of disease or nonbulky disease. Inclusion was restricted to patients with small-volume disease (e.g., minimal ascites not causing abdominal distention/ mesenteric thickening or not requiring paracentesis, or lesions ≤4 cm by spiral computed tomography [CT] or magnetic resonance imaging [MRI] at baseline) to minimize the potential for bowel perforations observed in previous trials with angiogenesis inhibitors. Additional eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate bone marrow, renal, and hepatic function. Patients who had received prior therapy with pazopanib or any other angiogenesis inhibitors; patients who had major surgery, chemotherapy, hormonal therapy, biologic therapy, immunotherapy, or radiotherapy within the preceding 28 days; or patients with a previous diagnosis of leptomeningeal disease, brain metastases, or another malignancy were excluded. Additional exclusion criteria included poorly controlled hypertension; QTc prolongation (i.e., QTc interval N480 ms); previous
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Class III or IV heart failure; history of cerebrovascular accident within 6 months; history of myocardial infarction, hospitalization for unstable angina, or cardiac angioplasty or stenting within 3 months; untreated venous thrombosis; malabsorption syndrome; or any condition that interfered with oral administration of the study drug. Study design and treatment This nonrandomized, open-label, multicenter phase II trial (VEG104450; NCT00281632) had a 2-stage Green-Dahlberg design with a stopping rule to allow early termination for lack of efficacy [26]. An interim efficacy evaluation of 20 patients enrolled in stage I required at least 2 patients to have a CA-125 response as assessed by Rustin criteria [12] for continuation of the study to stage II. Patients were scheduled to receive daily oral pazopanib 800 mg over 28-day treatment cycles until clinical or radiologic evidence of PD, withdrawal from treatment because of unacceptable toxicity, or withdrawal of consent. In the event of significant hematologic and nonhematologic toxicities, including grade 3/4 anemia, neutropenia, thrombosis, and thrombocytopenia; grade ≥ 2 coagulopathy, hemorrhage, and hepatobiliary toxicity; hypertension (symptomatic or systolic blood pressure ≥170 mm Hg or diastolic blood pressure ≥110 mm Hg); and proteinuria (24-h urine protein ≥3 g), the dose of pazopanib was reduced to 400 mg and the patient was monitored for 10 to 14 days. If the toxicity did not recur or worsen, the dose was increased to 600 mg with continued monitoring for an additional 10 to 14 days. If adequately tolerated, the standard 800 mg dose was resumed. If treatment was withheld for N21 days, disease assessments (CA-125 and CT scan/MRI, if applicable) were repeated before continuation of treatment. With regard to hepatic toxicity, a more conservative approach was adopted; per protocol amendment, pazopanib was discontinued if alanine aminotransferase or aspartate aminotransferase increased N8 times the upper limit of normal, even with subsequent recovery to normal. The study protocol and amendments were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board. This study was conducted in accordance with “good clinical practice,” all applicable regulatory requirements, and the guiding principles of the Declaration of Helsinki. All patients provided written informed consent. Endpoints The primary objective of this study was to assess the best biochemical response rate (as determined by CA-125 response after daily pazopanib administration, based on modified GCIG criteria) [12,27]. CA-125 response was defined as ≥50% decrease from the baseline CA-125 level and confirmed ≥21 days after initial evaluation (baseline was defined as the higher value of 2 pretreatment CA-125 assessments). The response was further qualified as normalized (if the assessed CA-125 was ≤21 U/mL) or non-normalized. Progressive disease was defined as a CA-125 increase ≥100% from nadir (if nadir N21 U/mL) or ≥42 U/mL (if nadir ≤21 U/mL); nadir was defined as the lowest CA-125 level until current assessment. If PD was not confirmed after 21 days, it was classified as unconfirmed PD. Stable disease (SD) was defined as changes in CA-125 not qualifying as either PD or response. Secondary objectives included assessment of the overall response and SD rate based on biochemical, radiographic, and physical examination, and PFS. Modified GCIG criteria [12,27] were used to assess overall response in patients with measurable disease, based on the best response from biochemical, radiologic (defined according to RECIST) [28], and physical examinations. Progression-free survival was defined as the interval from the first dose of study drug to the date of documented PD assessed by biochemical, radiological, and clinical assessment, or to date of death by any cause.
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Assessments For all patients on treatment, clinical assessments were performed monthly and CA-125 assessments were performed at a central laboratory at baseline and monthly. Additionally, radiologic assessments were performed at baseline and every other month for patients with measurable disease at baseline. For patients without measurable disease at baseline, radiologic assessments were performed at the time of a clinical or CA-125 assessment indicating PD and at the discretion of the investigator. Plasma pazopanib concentrations were measured by tandem high-performance liquid chromatography-mass spectrometry. Adverse events (AEs) were reported in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 [29]. Adverse event and serious AE data were collected from day 1 until the patient completed the posttreatment period. Statistical assessments This study was designed to evaluate 2 prespecified hypotheses about the biochemical response (CA-125) rate. The null hypothesis (response = 10%) reflected a response rate that would be of no clinical benefit, and the alternative hypothesis (response = 30%) reflected a desired target response rate that would provide greater confidence of positive outcome in larger, confirmatory studies. Based on the planned sample size of 35 patients and a true biochemical response rate of 10%, the type I error (i.e., overall probability of falsely declaring that the treatment was effective) was b0.05. Alternately, if the true biochemical response rate was 30%, the statistical power to correctly conclude that the treatment was effective was 0.93. Biochemical response, radiologic response, and overall response rates were calculated with corresponding 95% unadjusted exact binomial confidence interval (CI). The Kaplan–Meier method was used to summarize duration of CA-125 response and PFS at 6 months. Results Patients All 36 women (100%) enrolled in this study had an elevated CA125 at baseline (≥42 U/mL) and 17 (47%) had measurable disease at baseline (Table 1). Before entering the study, 31 patients (86%) had achieved objective responses (26 patients [72%] with complete response; 5 patients [14%] with partial response) to their most recent chemotherapy regimen, with median response duration of 25 weeks. At the cutoff date for this report (April 30, 2008), 22 patients (61%) and 10 patients (28%) discontinued the study because of PD and toxicity, respectively. One patient (3%) died on study because of PD, and 3 patients (8%) remained on study. These 3 patients remained on pazopanib for 2, 2.5, and 3 years, respectively; 2 patients discontinued treatment following CA-125 progression, and 1 patient discontinued treatment because of RECIST progression. Three patients (8%) withdrew consent or stopped study treatment because of investigator decision. Efficacy Most patients enrolled in this study (25 of 29 patients for whom data were available; 86%) achieved plasma pazopanib concentrations associated with clinical and biologic activity (≥34 μM) [25]. Of the 20 patients enrolled in stage I, 9 patients (45%) had CA-125 responses. Overall, 11 of 36 patients (31%; 95% CI, 16% to 48%) had a CA-125 response to pazopanib (Table 2; Fig. 1). In addition, 20 patients (56%) had SD based on CA-125 criteria; the median duration of their SD response was 80 days (95% CI, 56 to 100 days). The median time to
Table 1 Patient baseline demographics and disease characteristics. N = 36 Age, mean years (range) Female, n (%) Weight, mean kg (range) Race, n (%) White Asian ECOG performance status 0 1 Primary tumor type Ovarian Primary peritoneal Histology Malignant serous tumor Malignant endometrioid tumor Mixed epithelial cell Undifferentiated adenocarcinoma Unknown Other Stage at initial diagnosis II IIIb IIIc IV IVa Time since initial diagnosis, median days (range) Time to relapse Relapsed b 6 months Relapsed 6 - 12 months Relapsed N 12 months Response to most recent platinum-based therapya Refractory Resistant Sensitive Disease at baseline, n (%) Measurable Number of prior therapeutic regimens, n (%) 1 2
59.9 (40–85) 36 (100) 71.8 (48–111) 34 (94) 2 (6) 33 (92) 3 (8) 33 (92) 3 (8) 25 (69) 1 (3) 1 (3) 1 (3) 1 (3) 7 (19) 1 (3) 2 (6) 29 (81) 1 (3) 3 (8) 594 (293–2060) 14 (39) 12 (33) 10 (28) 3 (8) 6 (17) 27 (75) 17 (47) 21 (58) 15 (42)
Abbreviation: ECOG, Eastern Cooperative Oncology Group. a Platinum-refractory is defined as disease that progresses during platinum-based therapy; platinum-resistant is defined as recurrence b6 months from completion of platinum-based therapy; and platinum-sensitive is defined as recurrence ≥6 months from completion of platinum-based therapy.
CA-125 response was 29 days (range, 27 to 57 days), and median duration of response was 113 days (95% CI, 58 to 190 days; Fig. 2). A lower proportion of patients who received 1 line of prior therapy (4 of Table 2 Summary of CA-125 response.
Best CA-125 response, n (%) 50% response normalizeda 50% response non-normalizedb 50% response rate (normalized + non-normalized) 95% confidence interval Stable disease Progressive disease Unconfirmed progressive disease Unknown
1 Line of prior therapy (n = 21)
2 Lines of prior therapy (n = 15)
Total (N = 36)
1 (5) 3 (14) 4 (19)
1 (7) 6 (40) 7 (47)
2 (6) 9 (25)c 11 (31)c
(5.4 - 41.9) 13 (62) 1 (5) 2 (10) 1 (5)
(21.3 - 73.4) 7 (47) 0 1 (7) 0
(16.3 - 48.1) 20 (56) 1 (3) 3 (8) 1 (3)
Abbreviation: CA-125, cancer antigen-125. a Normalized response was defined as a ≥50% decrease in CA-125 levels to ≤21 U/ mL. b Non-normalized response was defined as a ≥ 50% decrease in CA-125 levels to N21 U/mL. c Includes 1 patient who had a biochemical response per protocol definition before pazopanib dosing.
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Fig. 1. Maximum percentage reduction from baseline cancer antigen-125.
21 patients, 19%; 95% CI, 5% to 42%) had a CA-125 response compared with patients who received 2 lines of prior therapy (7 of 15 patients, 47%; 95% CI, 21% to 73%). However, no definitive conclusions can be drawn from these small subsets of patients. The overall response rate, based on CA-125 and RECIST, was 18% (95% CI, 4% to 43%) in patients with measurable disease at baseline (n = 17; Table 3) [13]. No partial or complete responses were observed in patients with measurable disease based on RECIST. In 17 patients with radiographically measurable disease, 5 patients (29%) had SD, 10 patients (59%) had PD, and the responses of 2 patients (12%) were not known. Progression-free survival at 6 months was 17% (95% CI, 6% to 33%). Safety The median duration of pazopanib monotherapy was 56 days (range, 8 to 673 days). Eleven patients (31%) required dose interruptions during the study for a median duration of 7 days. Four patients (11%) experienced AEs that required dose reduction. The dose was reduced by 1 dose level and was not escalated. The most common AE causing dose reduction was fatigue (8%). The most common AEs, regardless of causality, were diarrhea, fatigue, and nausea (47% for each; Table 4). The most common grade 3 AEs were fatigue and γ-glutamyl transpeptidase elevation (11% for both). One patient (3%) had grade 4 peripheral edema with underlying disease in the abdominal wall and concurrent hypoalbuminemia. No drug-related deaths were reported. One patient died during the study because of PD 93 days after the first dose of pazopanib. Of the 10 patients taking antihypertensive medications at baseline, 4 required an increase in their antihypertensive therapy to control blood pressure. Overall, 15 patients (42%) received antihypertensive medications during the study. Ten patients (28%) experienced 21 AEs that led to study drug discontinuation. The most common AEs leading to study drug discontinuation were alanine aminotransferase and aspartate aminotransferase elevations (8% for each). Other AEs leading to discontin-
uation included nausea (6%), fatigue (6%), and other hepatic enzyme increases (6%). Discussion Based on emerging data with other angiogenesis inhibitors demonstrating promising activity, it was reasonable to evaluate the activity of pazopanib in women with recurrent OC [30–33]. We observed evidence of activity of pazopanib with a CA-125 response in 31% of patients with recurrent disease after either 1 (n = 21) or 2 (n = 15) lines of prior chemotherapy. Pazopanib demonstrated a safety profile similar to that reported with other tyrosine kinase inhibitors [34,35]. The most common AEs leading to discontinuation of study drug were elevation of hepatic enzymes and fatigue. The majority of patients who discontinued therapy for grade 3 events were asymptomatic, with elevated hepatic enzymes. There were no deaths or incidences of bowel perforation. Clinical studies suggest that the therapeutically relevant plasma concentration of pazopanib is ≥34 μM and that this concentration is achieved by dosing with pazopanib of 800 mg daily [25]. Results of the present study demonstrate that trough plasma pazopanib concentrations ≥34 μM were achieved at a dose of 800 mg once daily in 86% of all patients and in 100% of the CA-125 responders from whom data were available. Therefore, factors other than plasma pazopanib concentration likely influence the CA-125 response, and translational studies are needed to identify which patients are most likely to benefit from treatment. The majority of patients with platinum-sensitive OC who have entered clinical trials in the past have been similar to the patient population enrolled in this study. For example, of the nearly 1000 patients enrolled in the GCIG CALYPSO study, 60% had an ECOG performance status of 0 and only 60% had measurable disease, with the majority having 1 site b5 cm [36]. Similarly, the patient population in our study also had excellent performance status and CA-125
Table 3 Summary of overall response based on modified GCIG criteria in patients with measurable disease (CA-125, RECIST).a Patients with measurable disease (n = 17) Response rate, n (%) [95% CI] Best response, n (%) Complete response Partial responseb Stable disease Progressive disease Unknown
Fig. 2. Cancer antigen-125 percentage change from baseline.
3 (18) [3.8–43.4] 0 3 (18) 3 (18) 11 (65) 0
Abbreviations: CA-125, cancer antigen-125; CI, confidence interval; GCIG, Gynecologic Cancer Intergroup; RECIST, Response Evaluation Criteria in Solid Tumors. a Described in Vergote I, et al. [13]. b Based on CA-125 only.
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Table 4 Adverse events reported overall in ≥10% of patients. Adverse event
Any adverse event Fatigue Hypertension Diarrhea ALT elevation Vomiting AST elevation Abdominal pain Nausea Arthralgia Anorexia Hair color changes GGT elevation Constipation Headache Ascites Abdominal pain, upper Pain in extremity Back pain Muscle spasms Abdominal distension Insomnia Rash Dyspepsia
CTC maximum toxicity grade n (%) Grade 2
Grade 3
Grade 4
9 (25) 7 (19) 7 (19) 6 (17) 6 (17) 6 (17) 5 (14) 4 (11) 4 (11) 3 (8) 2 (6) 2 (6) 2 (6) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 0
20 (56) 4 (11) 1 (3) 3 (8) 3 (8) 0 1 (3) 1 (3) 0 0 0 0 4 (11) 1 (3) 1 (3) 1 (3) 0 0 0 0 0 0 0 0
1 (3)a 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTC, Common Terminology Criteria; GGT, γ-glutamyl transpeptidase. a One grade 4 adverse event, peripheral edema, occurred in 1 patient.
recurrence after first- or second-line chemotherapy as defined by GCIG criteria; 53% of patients had no measurable disease by radiographic imaging. These characteristics are representative of most of the patients diagnosed with recurrent disease on the basis of rising CA-125 levels. Although CA-125 is routinely evaluated as patient follow-up after chemotherapy, the optimal management of asymptomatic patients with CA-125 progression remains a clinical dilemma, as early initiation of cytotoxic chemotherapy based on a rising CA-125 has not shown survival benefit [14]. However, it is known that a prolonged platinum-free interval, particularly greater than 12 to 18 months, is associated with an increased likelihood of response to subsequent platinum-based chemotherapy [15]. It is possible that noncytotoxic agents such as pazopanib could delay time to progression and potentially increase the platinum-free interval when administered to asymptomatic patients with recurrent OC, given that the median time to develop symptomatic progression and initiating chemotherapy is about 4 months after CA-125 progression. The use of CA-125 to measure response is controversial, although widely used in clinical practice. One recent report suggested that CA125 may not be reliable to measure response with anti-VEGF targeted therapy and may underestimate activity [37]. However, this particular study included only 14 evaluable patients with elevated CA-125 at study entry who were treated with a combination of sorafenib and bevacizumab [37]. Although 8 patients (53%) had a partial response based on CA-125 criteria, only 5 were subsequently confirmed by imaging. Similarly, of the 7 patients who achieved partial response based on imaging, 5 had concordant CA-125 outcome. Overall, the level of concordance between imaging and CA-125 criteria was 67%. Furthermore, 3 patients would have terminated therapy early if CA125 criteria alone had been used. However, based on imaging data, these patients continued on therapy and their tumor size did not change for up to 1 year after the point of progression by CA-125 criteria. Thus, CA-125 criteria alone may not reflect the true response rate. Indeed, RECIST may also underestimate response to angiogenesis inhibitors, as it is often inconsistent in assessing response in OC [38]. The criteria for PD in the current study included CA-125 progression as well as RECIST for progression. Patients were only required to
discontinue treatment if there was clinical or radiologic evidence of progression, but the treating physician and patient were not blinded to the CA-125 results. The possibility that some patients might have come off study early based on CA-125 progression cannot be excluded. However, since at this time there is insufficient data to determine the discordance between imaging and CA-125 criteria, it is reasonable to continue treatment with angiogenesis inhibitors if the treatment is well tolerated and there is no objective evidence of tumor progression. There is now evidence to support the activity of angiogenesis inhibitors in multiple tumor types, including OC [30,39–41]. Other studies have evaluated the efficacy and safety of oral tyrosine kinase inhibitors in women with recurrent OC, and a recent phase II study of cediranib reported a clinical benefit rate of 30% that included a 17% PR rate [42]. In that study, 23% of patients discontinued treatment because of toxicities before 2 cycles. Adverse events included hypertension, diarrhea, and fatigue; hepatic toxicity was not observed with this agent, indicating the subtle between-class differences in the safety profile of these agents. Other oral inhibitors of VEGF and VEGFR, such as BIBF1120, vandetanib, and sunitinib, among others, are being evaluated in recurrent OC. It remains unclear which, if any, of these agents will be optimal in this patient population, and the choice of treatment will ultimately depend on efficacy and toxicity. Additionally, a number of large, randomized clinical trials combining bevacizumab with carboplatin and paclitaxel in the first-line setting are nearing completion and will provide useful clinical insight about the optimal use of these agents. In conclusion, this study demonstrated that pazopanib monotherapy was relatively well tolerated, with a toxicity profile similar to other oral tyrosine kinase angiogenesis inhibitors, and had antitumor activity in patients with recurrent OC. A clinical trial evaluating the potential benefit of pazopanib as maintenance therapy following firstline chemotherapy for advanced OC is currently in progress. Conflict of interest statement M. Friedlander received an honorarium from GlaxoSmithKline for speaking at an investigators' meeting in June 2007 (beyond the 24-month ACCME definition of a relevant financial relationship requiring disclosure), and reports no other relevant financial relationships. D. Rischin received funding from GlaxoSmithKline for the trial reported in this manuscript. B. Ma and J.P. Hodge are employed by GlaxoSmithKline and own company stock. G.M. Matthys is also employed by GlaxoSmithKline, but reports no stock ownership. J.J. Lager reports employment relationships with GlaxoSmithKline (during authorship) and Sanofi-aventis. Authors Hancock, Messing, and Stringer report no potential conflict of interest.
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