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Phase II Study of Vandetanib or Placebo in Small-Cell Lung Cancer Patients After Complete or Partial Response to Induction Chemotherapy With or Without Radiation Therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20

Andrew M. Arnold, Lesley Seymour, Michael Smylie, Keyue Ding, Yee Ung, Brian Findlay, Christopher W. Lee, Marina Djurfeldt, Marlo Whitehead, Peter Ellis, Glenwood Goss, Adrien Chan, Jacinta Meharchand, Yasmin Alam, Richard Gregg, Charles Butts, Peter Langmuir, Frances Shepherd

From the National Cancer Institute of Canada–Clinical Trials Group, Kingston, Ontario, Canada; and AstraZeneca, Wilmington, DE

Address reprint requests to Lesley Seymour, MD, PhD, NCI-Canada Clinical Trials Group, 10 Stuart St, Kingston, K7L3N6, ON, Canada; e-mail: lseymour{at}ctg.queensu.ca

	ABSTRACT

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Purpose This double-blind randomized phase II trial examined whether vandetanib, an inhibitor of vascular endothelial and epidermal growth factor receptors, could prolong progression-free survival in responding patients with small-cell lung cancer.

Patients and Methods Eligible patients with complete response (CR) or partial response (PR) to combination chemotherapy (± thoracic or prophylactic cranial radiation) received oral vandetanib 300 mg/d or matched placebo. With 100 patients and 77 events, the study had 80% power to detect an improvement in median progression-free survival from 4 to 6.5 months (one-sided, 10%-level test).

Results Between May 2003 and March 2006, 107 patients were accrued; 46 had limited disease and 61 extensive disease. There were fewer patients with a performance status of 0 (n = 11 v 20), and fewer had CR to initial therapy (n = 4 v 8) in the vandetanib arm. Vandetanib patients had more toxicity and required more dose modifications for gastrointestinal toxicity and rash. Asymptomatic Corrected QT interval (QT_C) prolongation was observed in eight vandetanib patients. Median progression-free survival for vandetanib and placebo was 2.7 and 2.8 months, respectively (hazard ratio [HR], 1.01; 80% CI, 0.75 to 1.36; one-sided P = .51). Overall survival for vandetanib was 10.6 versus 11.9 months for placebo (HR, 1.43; 80% CI, 1.00 to 2.05; one-sided P = 0.9). In planned subgroup analyses, a significant interaction was noted (P = .01): limited-stage vandetanib patients had longer overall survival (HR, 0.45; one-sided P = .07) and extensive-stage vandetanib patients shorter survival compared with placebo (HR, 2.27; one-sided P = .996).

Conclusion Vandetanib failed to demonstrate efficacy as maintenance therapy for small-cell lung cancer.

	INTRODUCTION

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Lung cancer is the most common cause of cancer-related mortality in North America, and accounts for more deaths than breast, colon, and prostate cancers combined.^1,2 Although small-cell lung cancer (SCLC) accounts for only 15% to 20% of all lung cancer cases, 60% of lung cancer patients have extrathoracic metastases at the time of diagnosis, and few of these patients survive more than 1 year after diagnosis despite response rates exceeding 60% from treatment with a platinum drug in combination with etoposide.^3,4 Trials of three- and four-drug regimens, dose intensification, or incorporating third-generation cytotoxic agents (gemcitabine, taxanes, vinorelbine, irinotecan, and topotecan) have failed to improve outcomes.⁵ The Surveillance, Epidemiology, and End Results (SEER) database has demonstrated only marginal gains in 2- and 5-year survival rates for SCLC during the last 30 years.⁶

Advances in the understanding of molecular carcinogenesis have led to the development of targeted agents for several tumor types, including c-kit receptor inhibitors for GI stromal tumors⁷ and the epidermal growth factor receptor (EGFR) antagonists⁸ and vascular endothelial growth factor (VEGF) inhibitors for non–small-cell lung cancer (NSCLC).

Almost three decades have passed since Folkman^8a first proposed the hypothesis that angiogenesis is critical for tumor growth. Evidence that angiogenesis plays an important role specifically in lung cancer has emerged more recently, although the majority of data relates to NSCLC.⁹ With respect to SCLC, Lucchi et al¹⁰ reported that high microvessel density predicted poorer outcome in univariate analyses in patients undergoing surgical resection followed by adjuvant chemotherapy. Only expression of VEGF was significant on multivariate analysis. Increased serum basic fibroblast growth factor levels also predict a poor outcome in SCLC, whereas increased interleukin-2 has been shown to confer a favorable prognosis. High expression levels of the matrix metalloproteinases MMP-3, -11, and -14 have been shown to be independent negative prognostic indicators.^11,12 Thus, there is considerable rationale for evaluating angiogenesis inhibitors in SCLC.

Although data from early trials of agents purported to have some antiangiogenesis activity such as interferon and matrix metalloproteinase inhibitors (MMPIs) have been disappointing,¹³ recent reports of thalidomide in untreated extensive-stage SCLC are encouraging.¹⁴ Vandetanib (ZD6474; Zactima; AstraZeneca, Wilmington, DE) is an orally bioavailable inhibitor of VEGF receptor-2 (VEGFR, KDR) and, to a lesser extent, EGFR.¹⁵

We report here the results of the National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG) BR.20 trial of vandetanib as maintenance therapy in patients with SCLC who have responded to chemotherapy.

	PATIENTS AND METHODS

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Patients
Patients 16 years of age or older were eligible if they had histologic or cytologic proof of SCLC (small-cell or variant; mixed histology was not permitted) and had received at least four cycles of combination chemotherapy, achieving complete response (CR) or partial response (PR). The choice of platinum-based chemotherapy regimen and any radiation were left to the discretion of the investigator.

Patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2; life expectancy of at least 12 weeks; and adequate hematology and biochemistry. They were ineligible if they had brain metastases that were untreated, or treated with persistent symptoms; necrosis; or hemorrhage; or if they required increasing doses of steroids. Other ineligible patients included those with other invasive malignancies within the preceding 5 years (excluding nonmelanomatous skin lesions); those receiving medications known to prolong corrected QT interval (QT_C) or inhibit/induce cytochrome P450 3A4 (cyp3A4); patients who had significant cardiovascular conditions, bleeding diatheses, recent major surgery or bleeding, and severe infections or medical conditions; and pregnant or nursing women. The protocol was approved by an Ethics Review Board at each institution; all patients provided written informed consent.

Evaluations
Before random assignment, all patients underwent complete history and physical examinations, routine hematology and biochemistry, toxicity evaluation, left ventricular ejection fraction, ECG, and quality-of-life (QoL) assessment; where applicable, a pregnancy test was performed within 72 hours of random assignment. Samples for pharmacokinetics (PK) and tissue banking (consenting patients) were also collected. Imaging studies including computed tomography (CT) chest and abdomen and bone scans (and any additional radiology performed before initiation of induction therapy that had been abnormal) had to be performed within 42 days before random assignment.

QoL assessment, physical examination, and biochemistry were repeated every 4 weeks during protocol therapy; hematology, ECG, and PK were performed every 1 to 2 weeks for the first 8 weeks and then every 4 weeks. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria version 2.0. Response was assessed, using Response Evaluation Criteria in Solid Tumors¹⁶ criteria at 4 weeks and then every 8 weeks thereafter until progression.

Treatment
Random assignment had to take place within 42 days of the last dose of chemotherapy, unless radiation was administered subsequently (random assignment required within 21 or fewer days of completion) and could not occur before recovery from toxicity. Patients were randomly assigned to receive vandetanib 300 mg/d orally or matched placebo. Doses were modified for toxicity (held for grade 3 or worse toxicity; resumed at reduced dose when grade 2 or better) or evidence of QT_C prolongation (held if single 550- or 100-ms increase compared with baseline; or confirmed 500-ms increase or 60- to 99-ms increase from baseline; dose reduced after recovery to 460 ms). Patients continued treatment until disease progression or unacceptable toxicity, or for a maximum of 2 years. Treatment was double blinded, and patients were unblinded only if essential for the management of toxicity.

QoL
The European Organisation for Research and Treatment of Cancer (EORTC) core QoL questionnaire (QLQ-C30)¹⁷ and lung cancer module (QLQ-LC13)¹⁸ were completed before random assignment, at 4 weeks, and then every 8 weeks until disease progression. The EORTC QLQ-C30 is a self-administered cancer-specific questionnaire with multidimensional scale. It consists of five functional domains: physical, role, emotional, cognitive, and social; three symptom domains: fatigue, nausea and vomiting, and pain; six single-symptom items: dyspnea, sleep, appetite, constipation, and diarrhea; and a global assessment domain. The QLQ-LC13 lung cancer module assesses cough hemoptysis, dyspnea, sore mouth, dysphagia, peripheral neuropathy, alopecia, site-specific pain, and pain medication. For each functional domain and symptom item, a linear transformation is applied to standardize the raw score to the range from 0 to 100. All analyses were exploratory and included all randomly assigned patients who had at least one follow-up evaluation for QoL in addition to the baseline evaluation. No formal adjustment on P values was made for multiple tests.

Statistical Considerations
The primary end point of the study was progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, and QoL. The sample size was calculated on the basis of an estimated PFS of 4 months for placebo patients, assuming equal accrual of extensive- and limited-disease patients. To have an 80% chance of detecting a 2.5-month delay in median PFS in the treatment arm using a one-sided, 10%-level test, 77 events were required (an estimated 120 patients were needed). Because of the slower than expected accrual rate, the sample size was modified in March 2005 to 100 patients. No interim analysis was planned or conducted.

Random assignment was by a Web-based program that dynamically minimizes the chance of an imbalance in the two treatment arms within the following stratification factors: center, thoracic radiotherapy (early [before day 1 of cycle 4] v late v none), extent of disease at diagnosis (extensive v limited disease), and response to prior therapy (CR v PR).

Analysis of pretreatment characteristics, response rate, and all efficacy analyses included all randomly assigned patients, as assigned, irrespective of eligibility. Safety and drug exposure analyses were performed on all patients who received at least one dose of study medication (vandetanib/placebo), on the basis of the actual drug they received. Patients who completed a baseline evaluation and at least one evaluation during the trial were included in the QoL analyses. For efficacy analyses, all comparisons between treatment arms were carried out using a one-sided test at an level of 10% or two-sided of 20% level unless otherwise specified. No formal adjustments were made for the multiplicity of inferences for multiple clinical end points. ECOG PS (0 v 1+2), sex (male v female), age (< 60 v 60 years) and race (white v other), in addition to the described stratification factors, were used in adjusted analyses. PFS was calculated from the date of random assignment until the date of progressive disease (PD) or death resulting from any cause occurred. For patients without documented PD, PFS was censored on the date salvage therapy began; or on the date of the last disease assessment. The log-rank test stratified by the stratification factors at random assignment was used to compare the difference in the PFS between the two treatment arms. Overall survival was calculated in months from the date of random assignment to the date of death, or excluded at the last day the patient was known alive on or before the data cutoff date.

Data management and statistical analyses were performed at National Cancer Institute of Canada–Clinical Trials Group central office in Kingston, Ontario, Canada.

	RESULTS

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The study was activated in May 2003 and closed to accrual in April 2006; the date of data cutoff was June 30, 2006. Median follow-up was 13.5 months.

Patient Characteristics
Among 107 randomly assigned patients, four were found ineligible (prior cardiac condition, progression before random assignment [n = 2], and untreated brain metastases). All 107 patients were included in the efficacy analyses, whereas 105 were included in the toxicity and exposure analyses (two patients did not receive study drug). Patient characteristics are summarized in Table 1. Vandetanib patients were less likely to have ECOG PS of 0, be age 60 years or older, have had late radiotherapy, and have had CR to prior therapy, but were more likely to have liver metastases. All patients had received chemotherapy, usually platinum and etoposide based. Two thirds of patients underwent prior radiation treatment. Seventy-three percent of patients had comorbid conditions such as cardiovascular and endocrine disease (data not shown).

Toxicity
Hospitalization rates were similar between the two arms. Hematologic effects were generally comparable between the two treatment arms, with 6% grade 3 or 4 neutropenia. Two patients receiving placebo underwent blood transfusion as supportive care. Biochemistry effects were mild; vandetanib patients were slightly more likely to have mild alkaline phosphatase and ALT rises.

Vandetanib patients tended to have more severe toxicity (grade 3, 4, and 5, 26 of 53 v nine of 52; P = .1), more QT_C prolongation (eight of 52 v zero of 53; P = .003), hypertension (21% v 9%), diarrhea (41 of 52 v 21 of 53; P < .001) and rash (37 of 52 v 26 of 53; P < .001), but were slightly less likely to have thromboembolism (2% v 6%) or hemoptysis and pneumonitis (4% v 8% each) compared with placebo patients (Table 2). There were no drug-related deaths reported.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Progression-free survival. HR, hazard ratio.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival. HR, hazard ratio.

Vandetanib patients had worse QoL at baseline in terms of role functioning (P = .09), cough (P = .04), hemoptysis (P = .08), pain elsewhere (P = .03), and financial difficulties (P = .02), but other domains were comparable. During the trial, the QoL was comparable in all five functional domains between vandetanib and placebo patients. Vandetanib patients had better QoL symptom items in hemoptysis (P = .13) and pain elsewhere (P = .12), but inferior to placebo patients in diarrhea (P = .01) and sore mouth (P = .05).

	DISCUSSION

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SCLC offers a unique opportunity to evaluate an angiogenesis inhibitor as maintenance therapy because a high proportion of patients respond to chemotherapy, yet most relapse shortly after discontinuing treatment, and the median survival, even for limited-stage patients, is less than 2 years. For three decades, trials of new chemotherapy regimens and drugs have failed to substantially⁵ improve survival, and a platinum-based doublet, usually in combination with etoposide, remains the globally accepted standard of care.⁴ To improve outcomes, numerous strategies have been tried, including dose intensification, bone marrow transplantation, maintenance therapy with both chemotherapy and other agents, and, more recently, trials of molecularly targeted agents^19,20 To date, none of these approaches has had a significant effect on survival, and several trials have shown considerable toxicity from the added therapy, sometimes accompanied by a statistically significant and clinically meaningful¹³ negative impact on quality of life.

BR.20 is the first randomized controlled trial of a VEGF receptor tyrosine kinase inhibitor to be reported in SCLC. Disappointingly, the study failed to show a benefit for adjuvant or maintenance treatment with vandetanib after achievement of maximal benefit with chemotherapy and radiation. However, significant interaction was seen with stage, with limited-stage patients showing a trend toward a benefit in overall survival, although at .07, the P value did not quite reach significance. Another interesting observation was the trend toward greater treatment effect in women for PFS, although, again, the difference was not significant. A similar trend was seen in a trial of vandetanib in NSCLC.²¹ In contrast, however, in ECOC 4599, women with advanced NSCLC did not appear to derive an overall survival benefit from the addition of bevacizumab to paclitaxel/carboplatin, although they did have higher response rates and longer PFS.⁹

Vandetanib targets both the EGF and the VEGF receptors, although it is thought that, at lower doses such as 100 mg, its activity is mainly directed against VEGFR. In NSCLC, it has been evaluated at doses of 300 and 100 mg/d with no evidence of greater activity at the higher dose. It is possible that if the 100-mg dose had been used in BR.20, the antiangiogenic effect of the drug might have been the same, yet vandetanib might have been better tolerated, thereby leading to fewer dose reductions and discontinuations.

Other studies of novel maintenance therapy have, for the most part, also had negative results in SCLC. In the National Cancer Institute of Canada–Clinical Trials Group and EORTC BR.12 trial of maintenance marimastat, there was no survival benefit for patients treated with MMPIs compared with placebo.¹³ Furthermore, significant musculoskeletal toxicity required discontinuation of therapy in almost 20% of patients, and caused significant worsening of their QoL.

The interferons are a family of naturally occurring cytokines that have immunomodulatory, antiviral, and antiangiogenic properties. Four randomized trials have evaluated interferons as adjuvant therapy after response to chemotherapy in SCLC.^22-25 Overall, there was no increase in overall survival in the interferon-treated patients in any of the trials. In fact, in two of the trials, interferon treatment was associated with poorer survival, although a trend toward superior long-term survival was reported in two studies for patients with limited-stage disease who had achieved complete remission. This is of interest in view of the trend toward improved survival in limited-stage patients in our trial.

In contrast to the aforementioned studies, the results from a French Intergroup randomized phase III placebo-controlled trial of thalidomide provide some reason for optimism.¹⁴ In patients with previously untreated extensive stage SCLC a statistically significant survival benefit was demonstrated in favor of thalidomide treatment. In this study, thalidomide was administered concurrently with chemotherapy from cycle 2 to 4 in responding patients, and thereafter as maintenance therapy. We elected to administer vandetanib as single-agent maintenance therapy after completion of all first-line treatment. In view of the results of the French thalidomide trial, we question whether our results might have been better if vandetanib treatment had been administered concurrently with chemotherapy from the start of treatment. However, in limited-stage disease, where we saw our greatest treatment effect, phase I dose escalation trials would have to be performed to confirm the safety of triple therapy with chemotherapy, concurrent radiotherapy, and this angiogenesis inhibitor. The results of similar trials of thalidomide in both SCLC and NSCLC performed by the London Lung Cancer Group and those of bevacizumab and the tyrosine kinase inhibitors sorafenib and sunitinib in SCLC are awaited with great interest to determine the future role of angiogenesis inhibitors in the treatment of SCLC.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Peter Langmuir, AstraZeneca (C) Consultant or Advisory Role: Christopher W. Lee, AstraZeneca (C); Glenwood Goss, AstraZeneca (C); Charles Butts, AstraZeneca (C); Frances Shepherd, AstraZeneca (C) Stock Ownership: Lesley Seymour, AstraZeneca; Frances Shepherd, AstraZeneca Honoraria: Andrew M. Arnold, AstraZeneca; Peter Ellis, AstraZeneca; Glenwood Goss, AstraZeneca; Charles Butts, AstraZeneca; Frances Shepherd, AstraZeneca Research Funding: Andrew M. Arnold, AstraZeneca; Lesley Seymour, AstraZeneca; Christopher W Lee, AstraZeneca Expert Testimony: None Other Remuneration: Peter Ellis, AstraZeneca; Charles Butts, AstraZeneca

	AUTHOR CONTRIBUTIONS

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Conception and design: Andrew M. Arnold, Lesley Seymour, Keyue Ding, Christopher W. Lee, Marina Djurfeldt, Frances Shepherd

Financial support: Peter Langmuir

Administrative support: Lesley Seymour, Marina Djurfeldt, Marlo Whitehead

Provision of study materials or patients: Andrew M. Arnold, Lesley Seymour, Michael Smylie, Yee Ung, Brian Findlay, Christopher W. Lee, Marina Djurfeldt, Peter Ellis, Glenwood Goss, Adrien Chan, Jacinta Meharchand, Yasmin Alam, Richard Gregg, Charles Butts, Frances Shepherd

Collection and assembly of data: Lesley Seymour, Keyue Ding, Marina Djurfeldt, Marlo Whitehead

Data analysis and interpretation: Andrew M. Arnold, Lesley Seymour, Michael Smylie, Keyue Ding, Yee Ung, Brian Findlay, Christopher W. Lee, Marina Djurfeldt, Marlo Whitehead, Peter Ellis, Glenwood Goss, Peter Langmuir, Frances Shepherd

Manuscript writing: Andrew M. Arnold, Lesley Seymour, Keyue Ding, Christopher W. Lee, Marina Djurfeldt, Marlo Whitehead, Peter Ellis, Glenwood Goss, Richard Gregg, Charles Butts, Frances Shepherd

Final approval of manuscript: Andrew M. Arnold, Lesley Seymour, Yee Ung, Peter Langmuir, Frances Shepherd

	ACKNOWLEDGMENTS

 
The following investigators and centers participated in this National Cancer Institute of Canada Clinical Trials Group study: Francis Laberge, Quebec City, Canada; Vera Hirsh, Danielle Charpentier, David Small, Montreal, Canada; Richard Gregg, Anna Tomiak, Kingston, Canada; Glenwood Goss, Scott Laurie, Ottawa, Canada; Brian Findlay, Janice Giesbrecht, Richard Shao, St Catharines, Canada; Andrew Arnold, Peter Ellis, Susan Knight, Hamilton, Canada; Lisa Barbera, Natasha Leighl, Jacinta Meharchand, Stephane Metivier, Ian Poon, Yasmin H. Rahim, Frances Shepherd, Yee Ung, Toronto, Canada; Z.Yasmin Alam, Sindu M. Kanjeekal, Windsor, Canada; Adrien Chan, Thunder Bay, Canada; Desiree Hao, Calgary, Canada; Charles Butts, Quincy Chu, David Fenton, Anil A. Joy, Anthony J. Reiman, Michael Smylie, Edmonton, Canada; Janessa J. Laskin, Barbara L. Melosky, Nevin Murray, Vancouver, Canada; Kevin V.J. Jasas, Christopher W. Lee, Surrey, Canada; and Elaine Bouttell, Sanjay C. Rao, Kelowna, Canada.

	NOTES

 
Supported in part by a grant to the National Cancer Institute of Canada–Clinical Trials Group from AstraZeneca Ltd, and in part by grants from the National Cancer Institute of Canada and the Canadian Cancer Society.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 25, 2007; accepted June 26, 2007.

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				L. Seymour and on behalf of the BR.20 study team In Reply: J. Clin. Oncol., December 20, 2007; 25(36): 5840 - 5841. [Full Text] [PDF]

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