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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5165-5171 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.5345 Phase II Trial of Bevacizumab in Persistent or Recurrent Epithelial Ovarian Cancer or Primary Peritoneal Cancer: A Gynecologic Oncology Group Study
From the University of California, Irvine, Orange, CA; GOG Statistical and Data Center, Roswell Park Cancer Institute; Department of Biostatistics, University at Buffalo, Buffalo, NY; University of Washington, Seattle, WA; and the University of Iowa, Iowa City, IA Address reprint requests to Robert A. Burger, MD, University of California, Irvine Medical Center, Building 56, Room 264, 101 The City Dr, Orange, CA 92868; e-mail: raburger{at}uci.edu
Purpose Vascular endothelial growth factor (VEGF) seems to be a promoter of tumor progression for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). We conducted a phase II trial to assess the efficacy and tolerability of single-agent bevacizumab, an anti-VEGF monoclonal antibody. Patients and Methods Eligible patients had persistent or recurrent EOC/PPC after one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of at least 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. Results The study consisted of 62 eligible and assessable patients, median age 57 years, 41 (66.1%) having received two prior regimens and 26 (41.9%) considered platinum resistant. Grade 3 adverse events at least possibly related to bevacizumab were hematologic (1), GI (3), hypertension (6), thromboembolism (1), allergy (2), hepatic (1), pain (3), coagulation (1), constitutional (1), and dyspnea (1). Grade 4 adverse events included pulmonary embolus (1), vomiting and constipation (1), and proteinuria (1). Thirteen patients (21.0%) experienced clinical responses (two complete, 11 partial; median response duration, 10 months), and 25 (40.3%) survived progression free for at least 6 months. Median PFS and overall survival were 4.7 and 17 months, respectively. There was no significant association of prior platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance status with the hazard of progression or death. Conclusion Bevacizumab seems to be well tolerated and active in the second- and third-line treatment of patients with EOC/PPC and merits phase III investigation.
Epithelial ovarian cancer (EOC), along with primary peritoneal cancer (PPC), represents the fourth leading cause of female cancer mortality, with approximately 15,000 deaths annually in the United States.1 This mortality rate has been attributed largely to limitations in cytotoxic therapy, including intrinsic and acquired drug resistance and the lack of specificity for mechanisms of disease progression. Development of targeted therapeutics is considered critical to improve outcomes. The rationale for targeting vascular endothelial growth factor (VEGF) in the treatment of EOC/PPC stems from both human and preclinical studies. The former have demonstrated VEGF overexpression2 and its association with tumor angiogenesis, ascites formation, malignant progression2-4 and early recurrence and death from disease, often independent of known prognostic factors.5-8 The latter have established that anti-VEGF therapy may impede tumor progression,9 clear malignant effusions,9 and enhance the activity of cytotoxic agents.10-12
We conducted a phase II trial of single agent bevacizumab (humanized anti-VEGF monoclonal antibody) in patients with persistent or recurrent EOC/PPC. The primary objective was to evaluate efficacy in terms of both the probability of surviving progression free for at least 6 months (progression-free survival [PFS]
Eligibility criteria included measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) parameters13; one or two prior cytotoxic regimens, at least the first platinum-based, with a second platinum-based regimen required if the initial platinum-free interval (PFI) was at least 12 months; Gynecologic Oncology Group (GOG) performance status (PS) of 0 or 1, with PS 2 allowed in patients having received only one prior cytotoxic regimen; and adequate hematologic (absolute neutrophil count [ANC]  1,500/µL and platelets 100,000/µL), renal (serum creatinine  1.5x the institutional upper limit of normal [ULN]; if higher, then creatinine clearance > 60 mL/min was required), hepatic (serum bilirubin 1.5x ULN, and both AST and alkaline phosphatase 2.5x ULN), and coagulation (prothrombin time [PT] such that international normalized ratio [INR] 1.5 or between 2.0 and 3.0 for patients receiving stable doses of therapeutic anticoagulants; and partial thromboplastin time [PTT] < 1.2x control) laboratory values.
Patients with other malignancies evident within 5 years, prior noncytotoxic therapy (ie, immunologic, biologic targeted, or hormonal therapy) for management of recurrent or persistent EOC/PPC, nonhealing wounds, infection requiring antibiotics, active bleeding, coagulopathy or CNS disease (primary brain tumor history, brain metastases, uncontrolled seizure disorder, or cerebral-vascular accident within 6 months), were ineligible. Patients were also excluded for significant cardiovascular disease (uncontrolled hypertension, myocardial infarction, or angina within 6 months, New York Heart Association
Enrolled subjects were to receive bevacizumab at 15 mg/kg intravenously every 21 days with no dose modification except for at least a 10% change in body weight. Toxicity was monitored with history, physical examination, and laboratory assessment before each treatment cycle, with adverse events defined and graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0.14 Bevacizumab was to be held for grade 3 nonhematologic toxicity for a maximum of 3 weeks to allow resolution to grade 1 or less. Treatment was discontinued for any grade 4 nonhematologic toxicity. Specific guidelines were implemented for modifying the treatment regimen in the event of hypertension, proteinuria, or a thromboembolic event. In the event of hypertension, antihypertensive medications were implemented at the discretion of the investigator according to standard clinical practice. Bevacizumab was continued for controlled hypertension (systolic blood pressure [BP] Activity of bevacizumab was assessed according to RECIST criteria15 either by palpation before each cycle for peripheral lesions or by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, before cycle 4 and then before every other cycle for (1) the measurement of target lesions, (2) the classification of clinical response, and (3) the determination of disease progression. Serum CA-125 levels were not utilized in the assessment of antitumor activity except for the requirement of CA-125 normalization, in addition to total resolution of disease by imaging and physical examination, to define a response as complete. Therapy was discontinued for disease progression, unacceptable toxicity, receipt of other anticancer therapy, or voluntary withdrawal.
The study was initially designed to evaluate efficacy strictly on PFS
The operating characteristics of this bivariate outcome design are listed in Tables 2 and 3 when the two primary outcomes are considered independent or dependent, respectively.
For secondary analyses within this study, the potential impact of the prognostic variables (initial performance status, platinum sensitivity, number of prior regimens, age) on the hazard of progression or death were assessed with a Cox proportional hazards model.
Patient Characteristics From April of 2002 through August 2004, 64 patients were enrolled, of whom two were excluded, one for uterine primary site, the other for no documentation of treatment. Thus, the study population consisted of 62 patients with median age of 57 years (range, 18 to 79 years), 58 (93.5%) of whom were white, and 45 (72.6%) of whom had GOG PS 0 (the remaining 17 had PS 1). Disease characteristics of the study population are shown in Table 4.
A total of 672 cycles of bevacizumab were administered, with a median of 7 cycles per patient (range, one to 35 cycles). Thus far, 58 patients have discontinued therapy, 53 for disease progression (one had not been determined to have progressed at the time of analysis). The remaining five patients discontinued therapy for other reasons: one for simultaneous deep vein thrombosis (DVT) and pulmonary embolus (PE; in this case disease progression was documented within 2 weeks of treatment discontinuation); one because of grade 4 proteinuria; one who underwent surgery for an incarcerated hernia; one with stable disease incorrectly classified as having progressed; and another because of CA-125 level doubling without documentation of progressive disease by RECIST criteria. Four patients were still undergoing treatment at the time of this analysis.
Adverse Events
Activity of Bevacizumab The activity of bevacizumab was analyzed in 62 patients (Table 6). Two complete responses and 11 partial responses were observed, for a clinical response rate of 21% (90% binomial confidence limits on the probability of responding, 12.9% to 31.3%), with median response duration of 10.3 months. An additional 32 (51.6%) had stable disease. Twenty-five of the 62 patients, or 40.3% (90% confidence limits, 29.8% to 53.6%), were progression-free for at least 6 months. Six-month PFS data are missing in one patient (exclusion time is approximately 1 month; she is conservatively considered to have experienced treatment failure). Fig 1 indicates that the median PFS in the study population was 4.7 months (first and third quartiles were 2.7 and 12.9 months, respectively), whereas the median OS was approximately 16.9 months (first and third quartiles were 9.1 and 32.4 months, respectively).
Of the 13 patients who responded, the median time to response was 2.6 months. The estimated third quartile for the distribution of the time until observing a response was 4.4 months. There was one patient with an unusually long period before a response was observed. This patient had stable disease until a partial response was documented 21 months after study entry and continues on protocol at the time this article was written. Five patients have received study drug for 30 to 35 cycles, translating into PFS of at least 20 months. An exploratory analysis of prognostic factors for PFS was performed using Cox proportional hazards regression. As shown in Table 7, the analysis demonstrated no statistically significant association among PS, platinum sensitivity, age, or number of prior regimens on the hazard of progression.
On the basis of historical controls for inactive cytotoxic regimens investigated in previous GOG phase II trials, bevacizumab is worthy of further investigation based on both PFS and clinical response: 13 clinical responses (21%) were observed, exceeding the 10 required by design rules, and 25 (40.3%) patients survived progression-free for at least 6 months, exceeding the 13-patient threshold. For an agent such as bevacizumab, which traditionally has been thought to exert principally an antiangiogenic effect in tumor endothelium, the observation of clinical activity in the current trial of both disease stabilization and tumor regression suggests the possibility of multiple antineoplastic mechanisms. It has been recently demonstrated that a subset of human tumors express functionally important VEGF receptors.17-21 Hypothetically, a combined blockade of VEGF activity on endothelial cells as well as on tumor cells might explain the objective clinical responses in this trial. Cox regression analysis demonstrated no apparent relationship between prognostic factors (eg, previous platinum-based chemotherapy PFI, PS, age and number of prior regimens) on PFS. Translational studies will examine tumor biopsies (quantitative immunohistochemistry for CD 31, CD 105, thrombospondin-1 and p53), serum and plasma samples (enzyme-linked immunosorbent assays for VEGF and angiogenin) and contrast-enhanced magnetic resonance images (pharmacokinetic parameters associated with microvessel permeability and volume) obtained pre- and post-treatment from patients enrolled onto this trial for the potential to distinguish tumors that progress rapidly from those with prolonged stabilization. Conclusions may be called into question when the design is changed after efficacy information becomes available. To help counter this concern, an alternative approach is put forward with a Bonferroni correction. If the original study design was based on a type I error rate of 10%, each hypothesis can be tested at the 5% level of significance. The one-sided P value for response and 6-month PFS against the null hypothesis as stated above are 0.00757 and 1.2 x 10–6 respectively. The results of this phase II trial also demonstrate that in the second- and third-line treatment setting for patients with recurrent EOC or PPC, single-agent intravenous bevacizumab therapy seems to be well tolerated at the dose and schedule of 15 mg/kg every 21 days. It is encouraging that several patients received treatment with bevacizumab for 30 to 35 cycles without unacceptable toxicity and that only two patients discontinued therapy because of adverse effects. Although difficult to extrapolate from a single phase II trial to the body of knowledge on potential adverse effects, the spectrum and extent of toxicity of bevacizumab observed in the current trial seem to be consistent with expectations, particularly with respect to pathophysiologic effects of anti-VEGF agents on the vasculature. However, these effects (hypertension, grade 1 in 12.9% and grade 3 in 9.7%; proteinuria, grade 1 to 2 in 30.6%; hemorrhage, grade 1 in 22.6%) were manageable and mild in the majority of cases. The exception was one patient who developed grade 4 proteinuria, requiring withdrawal from study therapy but resolving on discontinuation of bevacizumab. Thromboembolic complications occurred in only two patients, with both of these events venous in origin. Although the potential for a relationship between bevacizumab therapy and the development of DVT/PE exists, patients with advanced EOC and PPC share an intrinsically elevated risk for this complication when compared with the general population. Recent large-scale data from placebo-controlled phase III trials suggest an increased hazard of arterial, but not of venous, thromboembolic events; therefore, appropriate precautions should continue to be exercised in patient selection both within and outside of clinical trials to prevent coronary, cerebral, or peripheral arterial events. Although no GI perforation events were observed in the current trial, this complication is of potential concern in patients with EOC/PPC. GI perforation is estimated to occur in 2.4% of patients with solid tumors treated with bevacizumab.22 In October 2005, the NCI released an Investigational New Drug Action Letter in response to discontinuation of a single-agent industry trial (Genentech AVF 2949) because of five events in 44 enrolled subjects.23 Although the current and AVF 2949 trials are similar in design and treatment regimen, it may be useful to consider the disparity in GI perforation events as a function of eligibility differences. AVF 2949 enrolled only patients considered either primarily or secondarily platinum resistant and who received two or three previous cytotoxic regimens. These differences in eligibility ultimately translated into a higher level of platinum resistance, a greater number of prior regimens, and a slightly worse performance status profile in the AVF 2949 population. When adverse event data from all ovarian cancer studies in registered trials are considered, an overall incidence rate of 4.8% has been observed in 188 patients.23 The placebo-controlled design and prospective collection of potential risk factor data in a recently activated phase III trial within the GOG will allow this concern to be appropriately addressed. The 15-mg/kg-every-3-weeks dose and schedule of bevacizumab was selected because of the average 21-day half-life of the drug when administered systemically, a dose-density similar to that utilized in active phase II trials in other disease sites, and the potential for combining bevacizumab with standard primary cytotoxic therapy regimens in future phase III trials for patients with EOC/PPC. Because doses of bevacizumab as low as 0.3 mg/kg every 2 weeks have been reported to reduce unbound serum VEGF to undetectable levels,24 it is possible that lower dose intensities could have yielded equivalent efficacy in this trial with reduced toxicity. This would be an important question to address in future studies. Four phase III trials with positive results have demonstrated statistically significant improvement in OS for patients with metastatic colorectal25,26 and non–small-cell lung27 cancer and in PFS for patients with metastatic breast cancer.28 To date, the only published reports suggesting activity of bevacizumab monotherapy in patients with recurrent EOC/PPC are in the form of retrospective case reviews of patients who experienced failure with multiple lines of prior cytotoxic therapy.29-34 On the basis of the results of the current phase II trial, the GOG has recently activated a front-line placebo-controlled phase III trial in patients with stage III or IV EOC/PPC, of which the primary objective is to determine whether the addition of bevacizumab to standard cytotoxic therapy, when administered concurrently, or concurrently with extension to 15 months total treatment time, will produce an improvement in OS.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Robert Burger, Genentech Research Funds: Michael W. Sill, Genentech Testimony: N/A Other: N/A
Conception and design: Robert A. Burger, Michael W. Sill, Bradley J. Monk Provision of study materials or patients: Robert A. Burger, Benjamin E. Greer, Joel I. Sorosky Collection and assembly of data: Robert A. Burger, Bradley J. Monk Data analysis and interpretation: Robert A. Burger, Michael W. Sill, Bradley J. Monk, Joel I. Sorosky Manuscript writing: Robert A. Burger, Michael W. Sill, Benjamin E. Greer, Joel I. Sorosky Final approval of manuscript: Robert A. Burger, Michael W. Sill, Bradley J. Monk, Joel I. Sorosky
The following Gynecologic Oncology Group member institutions participated in this study: University of Washington/Puget Sound Oncology; Johns Hopkins Oncology Center; North Shore University Hospital; University of Iowa Hospitals and Clinics; St. Vincent Hospital and Health Care Center; University of California Medical Center at Irvine; University of Alabama at Birmingham; Washington Hospital Center; Franklin Square Hospital Center; Methodist Cancer Center; UCSF - Stanford Health Systems; University of Kansas Medical Center; Columbus Cancer Council/Ohio State; Rapid City Regional Oncology Group; Kaiser Permanente, Los Angeles Medical Group; British Columbia Cancer Agency; Mount Carmel Health Center; University of California at Los Angeles (UCLA); and Cancer Center of Santa Barbara.
We thank Sandra Dascomb, GOG Statistical and Data Center (SDC), Buffalo, NY, for her support in data abstraction; and Anne Reardon, GOG SDC, and the GOG Publications Subcommittee for their assistance in manuscript preparation and review, respectively.
Supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the GOG Statistical and Data Center (CA 37517), as well as a National Institutes of Health K-23 grant (R.A.B.); also funded by the GOG to conduct clinical research through protocols established by the GOG: GOG is supported by a 5-year grant from the National Cancer Institute (B.E.G.). Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Hollingsworth HC, Kohn EC, Steinberg SM, et al: Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 147:33-41, 1995[Abstract] 8. Paley PJ, Staskus KA, Gebhard K, et al: Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80:98-106, 1997[CrossRef][Medline] 9. Byrne AT, Ross L, Holash J, et al: Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9:5721-5728, 2003 10. Gorski DH, Beckett MA, Jaskowiak NT, et al: Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59:3374-3378, 1999 11. Hu L, Hofmann J, Zaloudek C, et al: Vascular endothelial growth factor immunoneutralization plus paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol 161:1917-1924, 2002 12. Lee CG, Heijn M, di Tomaso E, et al: Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565-5570, 2000 13. Pentecost MJ, Criqui MH, Dorros G, et al: Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and lower extremity vessels: A statement for health professionals from a special writing group of the Councils on Cardiovascular Radiology, Arteriosclerosis, Cardio-Thoracic and Vasc Surg, Clinical Cardiology, and Epidemiology and Prevention, the American Heart Association. Circulation 89:511-531, 1994 14. Common Terminology Criteria for Adverse Events v2.0. http://ctep.cancer.gov/reporting/ctc.html 15. 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. 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Numnum TM, Rocconi RP, Whitworth J, et al: The use of bevacizumab to palliate symptomatic ascites in patients with refractory ovarian carcinoma. Gynecol Oncol 102:425-428, 2006[CrossRef][Medline] 31. Monk BJ, Han E, Josephs-Cowan CA, et al: Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol 102:140-144, 2006[CrossRef][Medline] 32. Wright JD, Hagemann A, Rader JS, et al: Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis. Cancer 107:83-89, 2006[CrossRef][Medline] 33. Bidus MA, Webb JC, Seidman JD, et al: Sustained response to bevacizumab in refractory well-differentiated ovarian neoplasms. Gynecol Oncol 102:5-7, 2006[CrossRef][Medline] 34. Cohn DE, Valmadre S, Resnick KE, et al: Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecol Oncol 102:134-139, 2006[CrossRef][Medline] Submitted March 2, 2007; accepted August 1, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
and ß) with both end points being used to evaluate efficacy. The null hypothesis was H0: 
R 
