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Phase III Study of Gemcitabine and Cisplatin With or Without Aprinocarsen, a Protein Kinase C-Alpha Antisense Oligonucleotide, in Patients With Advanced-Stage Non–Small-Cell Lung Cancer

Luis Paz-Ares, Jean-Yves Douillard, Piotr Koralewski, Christian Manegold, Egbert F. Smit, José Miguel Reyes, Gee-Chen Chang, William J. John, Patrick M. Peterson, Coleman K. Obasaju, Michael Lahn, David R. Gandara

From the Servicio de Oncología Médica, Doce de Octubre University Hospital, Madrid, Spain; Centre René Gauducheau, Saint Herblain, France; Wojewodzki Szpital Specjalistyczny, Krakow, Poland; Heidelberg University Medical Center, Mannheim, Germany; VU University Medical Center, Amsterdam, the Netherlands; Instituto de Oncología, Clínica Las Condes, Santiago, Chile; Taichung Veterans General Hospital, Taichung, Taiwan, People’s Republic of China; Commonwealth Cancer Center, Richmond, KY; Eli Lilly and Co, Indianapolis, IN; University of California Davis Cancer Center, Sacramento, CA

Address reprint requests to L. Paz-Ares, MD, PhD, Servicio de Oncología Médica, Doce de Octubre University Hospital, Madrid, Spain; e-mail: lpaz.hdoc{at}salud.madrid.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To determine whether aprinocarsen, an antisense oligonucleotide directed against protein kinase C-alpha, when added to the chemotherapy regimen of gemcitabine and cisplatin improved survival in patients with advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with previously untreated stage IIIB/IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned to either a control arm of gemcitabine 1,250 mg/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1, or experimental arms consisting of the identical chemotherapy plus aprinocarsen 2 mg/kg/d as continuous infusion for 14 days, starting on either day 1 or 3 days before chemotherapy. Cycles were repeated every 21 days.

RESULTS: A total of 670 patients were randomly assigned between the control (n = 328) and experimental arms (n = 342). Due to the results from another phase III study of aprinocarsen in NSCLC, further enrollment was stopped, and the study was terminated early. The median number of cycles was four on the control arm and three on the combined experimental arms. Median overall survival was not different between the two groups (control, 10.4 months [95% CI, 8.6 to 12.2]; experimental, 10.0 months [95% CI, 8.4 to 10.8]; P = .613; hazard ratio = 1.05 [95% CI, 0.88 to 1.25]). Response rates (control arm, 35.0%; experimental arms, 28.9%; P = .124) and other time-to-event measures were not significantly different. Grade 3 and 4 toxicities were significantly increased for thrombocytopenia (P < .0001), epistaxis, and thrombosis/embolism in the experimental arms.

CONCLUSION: Adding aprinocarsen to gemcitabine and cisplatin regimen did not enhance survival and other efficacy measures in patients with advanced NSCLC.

	INTRODUCTION

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Non–small-cell lung cancer (NSCLC) accounts for over 85% of all new cases of lung cancer. Patients diagnosed with advanced stage (stage IV and some subsets of stage IIIB) NSCLC have a poor prognosis, and chemotherapy remains the only treatment option proven to prolong survival. Platinum-based chemotherapy doublets are the current standard treatment for these patients, but a plateau in efficacy has been reached.^1,2 Targeting specific molecules or pathways using antisense technology is a novel approach to improving the efficacy of existing chemotherapy regimens.

The protein kinase C family of serine threonine kinases is involved in signal transduction pathways and is a possible target for anticancer therapy.^3,4 Aprinocarsen (Affinitak, LY900003, formerly ISIS 3521; Isis Pharmaceuticals Inc, Carlsbad, CA) is a 20-mer oligonucleotide that binds to the 3'-untranslated region of the human mRNA for protein kinase C-alpha (PKC-) and inhibits PKC- expression.⁵ In human NSCLC cell line A549, aprinocarsen resulted in sequence-specific inhibition of the mRNA for PKC- and reduced the production of PKC- protein.⁵ Aprinocarsen phase I studies favored a continuous intravenous infusion as the optimal administration choice.⁶ Single-agent aprinocarsen has demonstrated objective responses in non-Hodgkin’s lymphoma and ovarian cancer, while stable disease was the best response in NSCLC.^6-8 Nevertheless, a phase I/II trial of aprinocarsen, carboplatin, and paclitaxel in patients with advanced NSCLC produced a 42% response rate and a 19-month median survival, suggesting potentiation of chemotherapy activity.⁹ Another phase I/II NSCLC trial with aprinocarsen, gemcitabine, and cisplatin showed a 38% response rate and stable disease in 55%.¹⁰ Therefore, the randomized phase III study described here was designed to directly evaluate the addition of aprinocarsen to the standard chemotherapy regimen of gemcitabine and cisplatin in this patient population.

The primary objective was to determine the overall survival duration in patients with stage IIIB/IV NSCLC treated with aprinocarsen, gemcitabine, and cisplatin (experimental arms), as compared to chemotherapy alone (control arm). Secondary objectives included comparison of response rate, time-to-event parameters, and toxicity in the two groups.

	PATIENTS AND METHODS

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Eligibility Criteria
Eligible patients were 18 years with histologically/cytologically diagnosed stage IV or stage IIIB (N₃ and/or pleural effusion) NSCLC not amenable to curative surgery or radiation therapy. Presence of one or more unidimensionally measurable lesions per the Response Evaluation Criteria In Solid Tumors (RECIST) was required.¹¹ Patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow, liver, and renal functions. All patients of childbearing potential were required to be abstinent or use approved contraception during and for 3 months after the treatment period. Female patients were also required to be nonlactating and to have a negative serum pregnancy test.

Patients were excluded if they received any prior chemotherapy, biologic therapy, or any treatment 30 days before our treatment with a drug that had not received regulatory approval. Patients were excluded for uncontrolled active infection that required therapy, grade 2 peripheral neuropathy, or CNS metastases other than locally treated lesions.

The institutional review boards at each participating center approved the study, and all patients provided signed informed consent. The study was conducted in accordance with the ethical principles in the Declaration of Helsinki.

Trial Design
This was a multicenter, randomized, phase III, open-label study of gemcitabine and cisplatin with or without aprinocarsen in patients with advanced NSCLC.

Patients were randomly assigned to either a control arm (arm A) or an experimental arm (arm B) using a centralized interactive voice-activated response system. Randomization factors included history of brain metastasis (yes or no), disease stage (IIIB or IV), and ECOG performance status (0 or 1). Following a protocol amendment, another experimental arm (arm C) was added, where gemcitabine and cisplatin was administered 3 days after pretreatment with aprinocarsen.

Treatment
In arm A, gemcitabine 1,250 mg/m² was administered as a 30-minute infusion on days 1 and 8, followed by cisplatin 80 mg/m² on day 1, every 21 days. Arm B received the same regimen as arm A plus aprinocarsen 2 mg/kg/d over the first 14 days of the 21-day cycle, starting 30 minutes after cisplatin administration was completed. In arm C, patients received aprinocarsen 2 mg/kg/d over the first 14 days of the 21-day cycle, and gemcitabine 1,250 mg/m² was administered on days 4 and 11 followed by cisplatin 80 mg/m² on day 4. Patients were to receive six or fewer cycles; however, in the case of patient benefit, additional cycles were allowed at the investigator’s discretion.

For continuous administration of aprinocarsen, portable volumetric infusion pumps (Deltec, St Paul, MN) were used. After 7 days, the cartridge and catheter were changed, and the infusion continued for 7 more days. Dosing was based on the patient’s weight at initial screening: patients weighing less than 65 kg received 125 mg, those weighing 65 to 90 kg received 175 mg, and those weighing more than 90 kg received 225 mg per day. Aprinocarsen was provided by Isis Pharmaceuticals Inc (Carlsbad, CA).

Dose Adjustments
If, on day 1 or day 4 of a new cycle, absolute neutrophil count (ANC) was less than 1.5 (x 10⁹/L) and/or platelets were less than 100 (x 10⁹/L), the cycle was delayed 1 week. For febrile neutropenia, grade 4 neutropenia lasting 7 days, grade 4 thrombocytopenia, or grade 2 bleeding associated with grade 3 thrombocytopenia, the subsequent doses of gemcitabine and cisplatin were reduced 25%. For grade 4 thrombocytopenia or grade 2 bleeding associated with grade 3 thrombocytopenia, aprinocarsen was reduced 50 or 25 mg. To begin a new cycle, nonhematologic toxicity had to be either baseline grade or less than 2. For any grade 3 nonhematologic toxicity (except nausea and vomiting), gemcitabine and cisplatin were reduced 25%. For grade 4 nonhematologic toxicities, gemcitabine and cisplatin were reduced 50% or delayed, and aprinocarsen was reduced or delayed. For grade 2 peripheral neurotoxicity, cisplatin was reduced 50%. For grade 3/4 peripheral neurotoxicity, grade 3/4 tinnitus, or calculated creatinine clearance less than 50 mL/min, cisplatin was delayed until the toxicity was grade 2 or calculated creatinine clearance was 50 mL/min, then, cisplatin was reduced 50%.

Dose adjustments within a cycle occurred on day 8 (arms A and B) or day 11 (arm C). If gemcitabine was omitted, the cycle continued per protocol. For an ANC of 0.5 to 0.99 or platelets 50 to 99, gemcitabine was reduced 25%; for an ANC less than 0.5 and platelets more than 50, gemcitabine was omitted. For platelets less than 50, gemcitabine was omitted, and aprinocarsen was reduced. If platelets were less than 25, aprinocarsen was omitted. For any grade 3 nonhematologic toxicity (except nausea and vomiting), gemcitabine was reduced 50% or omitted. For any grade 4 toxicity, gemcitabine was omitted, and aprinocarsen was reduced 50 mg or omitted.

Baseline and Treatment Assessments
All baseline evaluations were performed 28 days before random assignment. Each patient was radiologically assessed for tumor measurement. These assessments were repeated every other cycle and at follow-up visits. Approximately 2 weeks before random assignment, patients were seen for medical history, physical examination, ECOG performance status, and complete hematologic and biochemical laboratory analysis. These tests were repeated on day 1 of every cycle. Hematology and clinical chemistry tests were performed on days 8 and 15 (arms A and B) or days 11 and 15 (arm C).

Responses were evaluated using RECIST¹¹ criteria and confirmed 4 to 6 weeks after first observation. The best response was determined from the sequence of responses assessed.

Overall survival was measured from the date of random assignment to the date of death. Progression-free survival (PFS) was measured from the date of random assignment to the first date of progressive disease or death. Time to progressive disease (TtPD) was measured from the date of random assignment to the first date of progressive disease. Time to treatment failure (TTF) was measured from the date of random assignment until the date of study discontinuation due to adverse event, progressive disease, or death. Response duration was measured from the date of the first objective status assessment of complete/partial response to the first date of progressive disease or death.

Toxicities were assessed according to National Cancer Institute Common Toxicity Criteria (version 2) before each cycle.

Statistical Analyses
The amended study design was to enroll 1,000 patients (450 patients in arm A, 250 in arm B, and 300 in arm C). Time-to-event efficacy analyses were performed for the intent-to-treat patient population. Tumor response was measured in protocol-qualified patients. The protocol-qualified subset for response evaluation included all patients who did not violate inclusion/exclusion criteria, completed at least one full cycle of study therapy without a dose adjustment, and had tumor measurements at baseline and after completing one cycle. Safety analyses were performed for patients who received one or more doses of the study drug (treated population). Fisher’s exact P values were calculated for comparing safety results for the groups.

Efficacy measures were analyzed using Kaplan-Meier estimation and Cox proportional hazard regression models. The estimation and analysis of hazard ratios (HRs) was performed in the intent-to-treat patient population. Two-tailed 95% CIs were constructed. Assuming 450 observed deaths, the primary comparison would have 80% power, for HR = 0.768.

	RESULTS

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Between March 2002 and July 2004, 670 patients were enrolled at 106 study centers in 20 countries. The study was terminated early due to the results from another phase III NSCLC trial of aprinocarsen, carboplatin, and paclitaxel, which indicated that adding aprinocarsen did not improve overall survival.¹² When the present study stopped, the control arm (arm A) had 328 patients, experimental arm B had 301 patients, and experimental arm C had 41 patients. Due to the comparatively small number of patients in arm C, data from arms B and C were combined for the subsequent analyses, and the combined results are reported. The outcome data from arm C was numerically very similar to the combined aprinocarsen arms (arm B and arm C). Table 1 summarizes the baseline patient characteristics. The reasons for patient discontinuations are summarized in Table 2.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves of patients on the control arm (n = 328), and the experimental arms (n = 342); P = .613, hazard ratio 1.05 (95% CI, 0.88 to 1.25).

Toxicity and Safety
Toxicity was evaluated for 321 patients on the control arm and 322 patients on the experimental arms. Grade 3/4 toxicities are listed in Table 6. Hematologic toxicities were predominant, and nonhematologic toxicities were comparatively mild. Grade 3/4 thrombocytopenia occurred in 59.3% of patients on the experimental arms, compared with 29.3% on the control arm (P < .0001). Other hematologic toxicities were not significantly different between the two groups. Although they were observed in a small proportion of patients, the experimental arms had statistically significant differences in grade 3/4 epistaxis (P = .0022) and thrombosis/embolism (P = .0068).

	DISCUSSION

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A phase III study of aprinocarsen, paclitaxel, and carboplatin in patients with advanced NSCLC was ongoing at the time this trial was initiated and did not show any significant differences in survival and other efficacy measures with the addition of aprinocarsen.¹² Also, a randomized phase II trial of gemcitabine and cisplatin with or without aprinocarsen that only enrolled 18 patients with advanced NSCLC did not show any improvement in efficacy for those patients allocated to the experimental arm.¹⁵ Taken together, these results indicate that, irrespective of the treatment regimen, aprinocarsen fails to increase survival or other efficacy measures in patients with advanced NSCLC who are treated with chemotherapy.

Many targeted agents have been tested in combination with chemotherapy in patients with advanced NSCLC. To date, these trials have been uniformly negative, with the exception of the recent ECOG study of bevacizumab.¹⁴ For example, small molecule inhibitors of the EGFR tyrosine kinase (eg, gefitinib and erlotinib) have been combined with standard chemotherapy regimens in phase III trials in NSCLC.^16-18 However, neither gefitinib nor erlotinib enhanced the overall survival achieved with chemotherapy alone. Two potential reasons could explain these negative effects: (1) lack of patient selection by a predictive biomarker, and (2) potential sequence-specific negative interaction between the targeted agent and concurrent chemotherapy.¹⁹

In support of position one, recent data suggest that a direct correlation exists between responses to gefitinib or erlotinib and the presence of activating EGFR mutations,^20,21 or increased gene copy number measured by fluorescence in situ hybridization (FISH).²² In another therapeutic approach to this signal transduction pathway, a monoclonal antibody to HER2 (trastuzumab) was used in combination with gemcitabine and cisplatin in patients with NSCLC. Results from a randomized trial demonstrated that trastuzumab did not significantly improve patient outcomes. However, the high response rate (85%) and median PFS (8.5 months) observed in six patients with HER2 3+/FISH–positive tumors treated with trastuzumab should be noted.²³ These results reinforce the idea that patient selection may be crucial in evaluating the efficacy of targeted therapies. Alternatively, and in support of position two above, data in breast cancer suggest that concurrent administration of the antiestrogen tamoxifen and chemotherapy is less effective than sequential use, perhaps related to G1 cell cycle arrest from tamoxifen and subsequent inhibition of apoptosis from chemotherapy.²⁴

Taking these findings and other observations into account, there are several potential explanations for aprinocarsen’s lack of efficacy in the current study. First, there is at present no validated biomarker predictive of benefit from aprinocarsen, and patients were not screened for expression levels of the target (PKC-) as a prerequisite for study entry. Prior clinical studies of purported PKC inhibitors as antineoplastic therapy, attempting to identify a pattern of PKC isoenzyme expression associated with response, have had limited success.^25-27

Secondly, toxicities during treatment resulted in aprinocarsen dose reduction and potentially suboptimal concentrations in target tumor tissue. While on-study deaths were comparable in both groups, adverse event–related discontinuations were higher in the experimental arms (20.2%) versus the control arm (11.8%). Toxicity-related discontinuations in experimental arms likely explains the lower number of cycles administered (1,150 v 1,366), the lower median number of cycles administered (3 v 4), and the lower percentage of patients completing six or more cycles (23.3% v 44.2%). Similar toxicity patterns have been reported in other studies of aprinocarsen plus chemotherapy.^9,15,28 Interestingly, in our study, the cisplatin dose and dose-intensity were not different across arms, and this may have contributed to the lack of outcome differences observed despite the aprinocarsen negative impact on treatment delivery.

Alternatively, aprinocarsen has shown limited cytotoxic activity. Although objective responses were observed in lymphomas and ovarian cancer in early single-agent aprinocarsen trials, growth inhibition more consistent with cytostatic activity (stable disease) was the best response in NSCLC trials.^7,8 Unfortunately, and in agreement with recent preclinical data, these clinical results suggest that other PKC isoforms, but not PKC-, may be a driving force for cell proliferation and/or survival in NSCLC; therefore, it is not a bonafied therapeutic target in this tumor type.²⁹ Further preclinical aprinocarsen studies, alone and in combination with other targeted agents, particularly those modulating upstream or downstream signals in the same pathways, may help to establish a better understanding of its cellular actions and antitumor potential.

Finally, an optimal administration sequence of aprinocarsen and cytotoxic agents may not have been realized in the current study.¹² Because of the short half-life of the antisense construct, and based on the findings from aprinocarsen phase I/II studies, protracted infusions were selected as the best schedule for the development of this agent.^6,9,10,28 Although our study was amended to add a third arm specifically to address this issue, few patients received this alternative dose schedule before study closure.

In conclusion, adding aprinocarsen to gemcitabine and cisplatin did not enhance survival and other efficacy measures. Enhanced toxicity in the experimental arms contributed to lower dose delivery and a reduction in therapy completion. Combined with the results of other phase III studies of targeted agents in patients with advanced NSCLC, these results suggest the importance of development of predictive biomarkers and subsequent patient selection in order to optimize the benefits of targeted therapy.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
We sincerely thank the patients and the physicians from the following countries, for participating in this study

Argentina: Moises Rosenberg, Claudia I. Bagnes, Daniel Maldonado, Angelis Lucero, Silvia Jovtis

Belgium: L. Bosquee, P. Germonpre, D. Schrijvers, W. Verhaeghe, D. Verhoeven

Chile: Jose M. Reyes

France: Etienne Lemarie, Luc Thiberville, Gilles Robinet, Bernard Milleron, Jean-Yves Douillard, Jean-Louis Pujol, Dominique Spaeth, Jean-Marc Vernejoux

Germany: Christian Manegold, Ulrich Gatzemeier, Uwe Keppler, Bernhard Heinrich, Alexander Knuth, A. Chemaissani, H. Wirtz, T. Muller, R.M. Huber, Axel Hanauske, W. Dornoff, P.D. Digel, Helmut Oettle, Martin Hetzel

Hungary: Pal Magyar

India: Shona Nag, Sunil Gupta, Radhesshyam Nayak, Govind Babu, J.S. Sekhon

Italy: Armando Santoro, Anna Ceribelli

Netherlands: G. Giaccone, P.E. Postmus, E.F. Smit, F.M.N.H. Schramel, B. Biesma, J.M. Smit, J.A. Stigt

Norway: Steinar Aamdal, Jan Vilsvik

Poland: Andrzej Deptala, Piotr Koralewski, Tomasz Klaniewski, Piotr Tomczak

Puerto Rico: Roberto Velazquez, Luis Baez, Madeline Garcia

Romania: Tudor Ciuleanu

Russia: Avgust Garin

Spain: Rafael Rosell, Mariano Provencio, Luis Paz-Ares, Ales, Nogue, José L. Gonzalez-Larriba, Emilio Esteban, Dolores Isla, Angel Artal, Bartomeu Massuti, Felipe Cardenal, Gumersindo Perez-Manga, Monica Guillot

South Africa: Daniel Vorobiof, L. Goedhals

Sweden: Florin Sirzen, Christer Sederholm, Ola Brodin, Thomas Brezicka, Sven-Borje Ewers

Switzerland: Rolf Stahel

Taiwan: Chung-Ming Tsai, Gee-Chen Chang, Thomas Chang Yao Tsao, Chih-Hsin Yang, Te-Chun Hsia

United Kingdom: Michael Lind, Penella Woll, Peter Johnson, David Dunlop, Fergus Macbeth

United States: Thaddeus Beck, Helen Ross, Timothy Larson, Forrest Swan, Mohammad Khan, Charles Weissman, Timothy Webb, Sumeet Bhatia, Barry Firstenberg, Michael Guarino, John Cole, Peter Kennedy, Nelson Kalil, David Hoffman, Antoinette Wozniak, Peter Raich

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Luis Paz-Ares Eli Lilly and Co (A) Eli Lilly and Co (B) Christian Manegold Eli Lilly and Co (A) Eli Lilly and Co (A) Jose Reyes Eli Lilly and Company (B) G.C. Chang Eli Lilly and Company (B) William John Eli Lilly and Co (A) Eli Lilly and Co (A) Eli Lilly and Co (A) Patrick Peterson Eli Lilly and Co (N/R) Eli Lilly and Co (A) Coleman Obasaju Eli Lilly and Co (N/R) Eli Lilly and Co (A) Michael Lahn Eli Lilly and Co (N/R) Eli Lilly and Co (A) David Gandara Eli Lilly and Co (A) Eli Lilly and Co (A) Eli Lilly and Co (A) Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Luis Paz-Ares, William John, Patrick Peterson, Coleman Obasaju, Michael Lahn, David Gandara Financial support: Luis Paz-Ares Administrative support: Luis Paz-Ares, G.C. Chang, Michael Lahn Provision of study materials or patients: Luis Paz-Ares, Jean-Yves Douillard, Piotr Koralewski, Christian Manegold, E.F. Smit, Jose Reyes, G.C. Chang Collection and assembly of data: Luis Paz-Ares, Piotr Koralewski, E.F. Smit, Jose Reyes, G.C. Chang, William John Data analysis and interpretation: Luis Paz-Ares, Piotr Koralewski, William John, Patrick Peterson, Coleman Obasaju, Michael Lahn Manuscript writing: Luis Paz-Ares, Jean-Yves Douillard, Christian Manegold, EF Smit, Jose Reyes, William John, Patrick Peterson, Coleman Obasaju, Michael Lahn, David Gandara Final approval of manuscript: Luis Paz-Ares, Jean-Yves Douillard, Piotr Koralewski, Christian Manegold, E.F. Smit, Jose Reyes, G.C. Chang, William John, Patrick Peterson, Coleman Obasaju, Michael Lahn, David Gandara

 

	Acknowledgment

 
We acknowledge the clinical trial support provided by Irene Tomlin, data management and statistical support provided by Erika Horan, Jennifer Ferguson, Nancy Iturria, and manuscript preparation/editorial support provided by Ghulam Kalimi, Peter Fairfield, and Diana Kelley.

	NOTES

 
Supported by Eli Lilly and Co, Indianapolis, IN.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

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

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Submitted September 21, 2005; accepted January 6, 2006.

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