Current Clinical Trials of the Anti-VEGF Monoclonal Antibody Bevacizumab

Given the well-established role ofangiogenesis (or new blood vessel formation) in tumor growth and metastasis,antiangiogenic therapy, a concept first proposed by Dr. Judah Folkman,[1] hasbecome increasingly recognized as a promising new anticancer strategy. As theangiogenic switch in tumors reflects the net balance of a diverse group ofendogenous angiogenic promoters and inhibitors, a multitude of agents have beendeveloped to target different factors and pathways. Over 20 antiangiogenic drugsare currently undergoing evaluation in phase I, II, and III trials.

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to clinical trials of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, Internet access is available at http://cancernet.nci.nih.gov/pdqfull.html, or contact the Cancer Information Service offices (1-800-4-CANCER).

Of known proangiogenic factors, vascular endothelial growthfactor (VEGF; also known as the vascular permeability factor) is one of the mostpotent and specific, and has been identified as a crucial regulator of bothnormal and pathologic angiogenesis. VEGF is a secreted, heparin-binding proteinthat exists in multiple isoforms due to alternative splicing. The action of VEGFis mainly mediated through binding of the circulating VEGF peptides to receptortyrosine kinases on endothelial cells, VEGFR-1 (Flt-1), and VEGFR-2(KDR/Flk-1).The biological effects of VEGF include endothelial cell mitogenesisand migration, induction of proteinases leading to remodeling of theextracellular matrix, increased vascular permeability, maintenance of survivalfor newly formed blood vessels, and possibly suppression of dendritic cellmaturation.[2]

Overexpression of VEGF has been demonstrated in most humancancers examined to date. In breast cancer, increased levels of VEGF, asmeasured in the circulation or in tumor tissues, correlated with an increase inmicrovessel density and advanced disease stages, and in some cases,independently predicted reduced relapse-free and overall survival.[3,4] Asimilar correlation was also implicated in a variety of other solid tumors.[5]More recently, the importance of endothelial cells and angiogenesis has alsobeen suggested in hematologic malignancies, such as aggressive lymphoma,myelogenous leukemia, multiple myeloma, myelodysplasia, and others.

The apparent significance of VEGF in cancer pathogenesissupports the rationale for VEGF-targeting therapeutics. Anti-VEGF agentscurrently in clinical trials include monoclonal antibodies targeting the VEGFligand (eg, bevacizumab) and inhibitors directed at the receptors (eg, SU5416).

Bevacizumab (rhuMAb VEGF, Genentech, Inc) is a recombinanthumanized anti-VEGF monoclonal antibody (MAb) that recognizes all biologicallyactive isoforms of VEGF and blocks their binding to the VEGF receptors.[6,7]Bevacizumab is composed of the antigen-binding complementarity-determiningregions from a murine anti-VEGF MAb (A.4.6.1) and the human immunoglobulin G₁framework. Anti-VEGF MAbs have shown potent growth inhibition in vivo in avariety of human cancer xenograft[7,8] and metastasis models,[9] includingrhabdomyosarcoma, glioblastoma, breast, lung, colon cancer, and others. Such agrowth inhibitory effect was accompanied by a reduction in vascularpermeability, decrease in tumor vessel density, and in some cases, completesuppression of angiogenesis.[11,12] Furthermore, the combination of anti-VEGFMAb and chemotherapeutic agents, such as doxorubicin[10] and cisplatin(Platinol), resulted in enhanced antitumor activity compared to either agentalone.

Several clinical trials have evaluated bevacizumab at differentdoses and schedules.[13,14] Pharmacokinetics appeared to be linear at dosesabove 1 mg/kg, with a half-life of ~15 days. Recommended doses for furtherstudies are 5 or 10 mg every 2 weeks or 15 mg every 3 weeks. Evidence ofsingle-agent activity has been demonstrated in a phase II study in patients withpreviously treated metastatic breast cancer,[14] where objective tumorresponses, including one complete response, were documented.

The combination of bevacizumab and chemotherapy was alsoevaluated. In a phase II trial of bevacizumab and fluorouracil (5-FU) plusleucovorin, 104 patients with untreated metastatic colorectal cancer wererandomized to either chemotherapy alone, or in combination with two dose levelsof bevacizumab.[15,16] Although the study was not designed and powered tocompare efficacy, the combination arms suggested a trend toward a higherresponse rate and longer time to tumor progression. Genentech is currentlysponsoring a phase III trial comparing irinotecan (CPT-11, Camptosar), 5-FU, andleucovorin with or without bevacizumab as first-line therapy for metastaticcolorectal cancer.

The combination of bevacizumab with carboplatin (Paraplatin)plus paclitaxel (Taxol) was also tested for safety and feasibility in a smallrandomized phase II trial in patients with advanced non-small-cell lung cancer(NSCLC).[17,18] There appeared to be an advantage for the higher dose ofbevacizumab (15 mg/kg every 2 weeks), but the results were not statisticallysignificant. In this trial, several major hemorrhagic events were reported inthe bevacizumab arm, as indicated below.[19]

A variety of side effects have been reported in the clinicalstudies of bevacizumab. Most significant were hemorrhagic events in the NSCLCstudy of the bevacizumab and carboplatin/paclitaxel combination, in which 6 ofthe 66 patients developed life-threatening pulmonary hemorrhage (4 of which werefatal)[19]; most patients had tumors of squamous cell histology or centrallocation. Life-threatening hemorrhage was not observed in other bevacizumabtrials, although bleeding graded as serious has been reported. Hypertensionattributable to bevacizumab was common (about 20%) but in most cases, was mildor controllable with medication. Proteinuria of varying severity has beenreported. In the study of bevacizumab with 5-FU and leucovorin, there alsoappeared to be an increase in thromboembolic events in the combination armcompared to chemotherapy alone. Other events less clinically significantincluded epistaxis, headache, diarrhea, fever, and rash.

The mechanisms and risk factors for bevacizumab-relatedtoxicities remain unknown. At present, all ongoing clinical trials haveimplemented specific exclusion criteria and early stopping rules to minimizerisk to patients, with special attention to bleeding, thrombosis, andcardiovascular events.

In view of the critical role of VEGF in tumor pathogenesis andthe preliminary efficacy data of bevacizumab, the Cancer Therapy EvaluationProgram (CTEP) of the National Cancer Institute (NCI) has established anagreement to develop bevacizumab in collaboration with Genentech, Inc. The CTEPis currently sponsoring a number of clinical trials of bevacizumab, ranging fromphase I to phase III.

The general goals of these trials include: (1) assessing theactivity of bevacizumab in various solid tumors and hematologic malignancies,(2) evaluating the safety and efficacy of combining bevacizumab withconventional chemotherapy and radiation, or with other targeted and biologicalagents, (3) exploring the surrogate and predictive markers of anti-VEGF therapy,and (4) understanding the mechanism of action and treatment failure. A list ofcurrently open or approved NCI-sponsored trials is provided below. Informationabout these trials can be obtained from the contact listed for each trial orfrom Helen Chen, MD, at the NCI’s CTEP (chenh@ctep.nci.nih.gov),(301) 496-8798.

Head and Neck Cancer

Title: A Phase I Study of Bevacizumab (RecombinantHumanized Monoclonal Antibody to Vascular Endothelial Growth Factor) in additionto Fluorouracil and Hydroxyurea as Initial Chemotherapy with ConcomitantRadiotherapy (B-FHX) for Poor Prognosis Head and Neck Cancer
Protocol Number: 2630
Participating Institution: University of Chicago
Protocol Status: In review
Contact: Everett E. Vokes, MD, (773) 702-9306

Non-Small-Cell Lung Cancer

Title: Phase II/III Randomized Study of Paclitaxel andCarboplatin With or Without Bevacizumab in Patients With Advanced, Metastatic,or Recurrent Non-Squamous Cell Non-Small Cell Lung Cancer
Protocol Number: E-4599 (Intergroup)
Participating Group: Eastern Cooperative Oncology Group
Protocol Status: Active
Contact: Robert L. Comis, Eastern Cooperative Oncology Group, (215)789-3645 (CTSU Investigators: see footnote)*
Latest Information:http://cancernet.nci.nih.gov/

*Cancer Trials Support Unit (CTSU) investigatorswith scientific questions about this trial should contact the principalinvestigator at the sponsoring Cooperative Group. CTSU investigators interestedin enrolling patients on this trial through the CTSU should contact the CTSUGeneral Information line for further information at (888) 823-5923 or ctsucontact@westat.com.

Title: A Phase II Study of Neoadjuvant rhuMAb VEGF(Bevacizumab) in Combination with Paclitaxel and Carboplatin in SurgicallyResectable Non-Small-Cell Lung Cancer
Protocol Number: 2655
Participating Institution: Ohio State University Hospital
Protocol Status: In review
Contact: Gregory Otterson, MD, (614) 293-6786

Mesothelioma

Title: A Double Blind, Placebo Controlled RandomizedPhase II Trial of Gemcitabine and Cisplatin with or without the VEGF InhibitorBevacizumab (NSC #704865) in Patients with Malignant Mesothelioma
Protocol Number: 2710 (in review)
Participating Institutions: University of Chicago, Lutheran GeneralHospital, Evanston Hospital, University of Illinois, Weiss Memorial Hospital,Decatur Memorial Hospital, Oncology-Hematology Associates, Fort Wayne MedicalOncology/Hematology Incorporated, Michiana Hematology Oncology PC, CentralIllinois Hematology Oncology Center
Protocol Status: In review
Contact: Hedy Lee Kindler, MD, (773) 702-0360

Breast Cancer

Title: Phase II Pilot Study of Bevacizumab, Docetaxel,Doxorubicin, and Filgrastim (G-CSF) in Patients With Previously Untreated StageIIIB or IV Inflammatory Breast Cancer
Protocol Number: 2772
Participating Institution: National Cancer Institute Medicine Branch
Protocol Status: Active
Contact: Sandra M. Swain, Medicine Branch, (301) 496-4916
Latest Information:http://cancernet.nci.nih.gov/

Title: A Randomized Phase II Study of Bevacizumab inCombination with Docetaxel in Locally Advanced Breast Cancer
Protocol Number: 2722
Participating Institution: Case Western Reserve University
Protocol Status: In review
Contact: Beth A. Overmayer, MD, (216) 844-8573

Title: Phase II Study of Concurrent Bevacizumab andVinorelbine in Patients With Stage IV Breast Cancer
Protocol Number: NCI-2716
Participating Institutions: Dana-Farber Cancer Center, MassachusettsGeneral Hospital, Beth Israel Deaconess Medical Center
Protocol Status: Active
Contact: Harold J. Burstein, MD, (617) 632-5340
Latest Information:http://cancernet.nci.nih.gov/

Title: Phase II Study of Bevacizumab in Combination withDocetaxel in Patients with Advanced and metastatic Breast Cancer
Protocol Number: 2715
Participating Institution: University of Colorado
Protocol Status: In review
Contact: Pablo J. Cagnoni, MD, (303) 372-9000

Title: A Randomized Phase III Trial of Paclitaxel vsPaclitaxel plus Bevacizumab (rhuMAB VEGF) as First-Line Therapy for LocallyRecurrent or Metastatic Breast Cancer
Protocol Number: E2100
Participating Group: Eastern Cooperative Oncology Group
Protocol Status: In review
Contact: Jean MacDonald, (617) 632-3610

Pancreatic Cancer

Title: A Phase II Trial of Bevacizumab (NSC #704865) plusGemcitabine in Patients with Advanced Pancreatic Cancer
Protocol Number: 2675
Participating Institutions: University of Chicago, Loyola UniversityMedical Center, Weiss Memorial Hospital, Decatur Memorial Hospital,Oncology-Hematology Associates, Ingalls Memorial Hospital, La Grange MemorialHospital, La Grange Treatment Pavillion, Fort Wayne Medical Oncology/HematologyIncorporated, Michiana Hematology Oncology PC, Lakeland Medical Center SaintJoseph
Protocol Status: In review
Contact: Hedy Lee Kindler, MD, (773) 702-0360

Colorectal Cancer

Title: Phase II Study of Fluorouracil, LeucovorinCalcium, Irinotecan, and Bevacizumab (Monoclonal Antibody Anti-VEGF) in PatientsWith Previously Untreated Advanced Colorectal Cancer
Protocol Number: E-2200
Participating Group: Eastern Cooperative Oncology Group
Protocol Status: Active
Contact: Bruce J. Giantonio, Eastern Cooperative Oncology Group, (215)662-8756; for a complete listing of study contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Trial of Bevacizumab, Oxaliplatin,Fluorouracil, and Leucovorin vs Oxaliplatin, Fluorouracil, and Leucovorin vsBevacizumab Alone in Previously Treated Patients with Advanced Colorectal Cancer
Protocol Number: E3200 (Intergroup, in review)
Participating Group: Eastern Cooperative Oncology Group
Protocol Status: In review
Contact: Jean MacDonald, (617) 632-3610, (CTSU Investigators: seefootnote)*

*Cancer Trials Support Unit (CTSU) investigatorswith scientific questions about this trial should contact the principalinvestigator at the sponsoring Cooperative Group. CTSU investigators interestedin enrolling patients on this trial through the CTSU should contact the CTSUGeneral Information line for further information at (888) 823-5923 or ctsucontact@westat.com.

Renal Cancer

Title: Phase II Randomized Study of Monoclonal AntibodyVEGF in Patients With Unresectable Advanced Renal Cell Cancer
Protocol Number: T98-0035
Participating Institution: National Cancer Institute Surgery Branch
Protocol Status: Active
Contact: James Chung-Yin Yang, Surgery Branch, (301) 496-1574
Latest Information:http://cancernet.nci.nih.gov/

Prostate Cancer

Title: A Randomized Phase II Trial of NeoadjuvantBevacizumab, Docetaxel, and Emcyt vs Docetaxel Plus Emcyt in Patients withHigh-Grade Prostate Cancer Eligible for Radical Prostatectomy
Protocol Number: 2619
Participating Institution: University of California at Los Angeles
Protocol Status: In review
Contact: Fairooz F. Kabbinavar, MD, (310) 206-0868

Ovarian and Peritoneal Cancer

Title: Phase II Study of Bevacizumab in Patients WithPersistent or Recurrent Ovarian Epithelial or Primary Peritoneal Cancer
Protocol Number: GOG-0170-D
Participating Group/Institutions: Gynecologic Oncology Group, Universityof California Medical Center at Irvine, Orange County Regional Cancer Center
Protocol Status: Active
Contact: Robert C. Park, Gynecologic Oncology Group, (215) 854-0770
Latest Information:http://cancernet.nci.nih.gov/

Cervical Cancer

Title: A Phase II Trial of Bevacizumb (rhuMAB VEGF) (NSC#704865, IND #7921) in the Treatment of Advanced and Recurrent Squamous CellCarcinoma of the Cervix
Protocol Number: GOG-0227-C
Participating Group: Gynecologic Oncology Group
Protocol Status: In review
Contact: Bradley J. Monk, MD, (714) 456-6570

Melanoma

Title: A Phase II Study of Bevacizumab andInterferon-Alfa-2b in Metastatic Malignant Melanoma
Protocol Number: 2669
Participating Institution: Ohio State University Hospital
Protocol Status: In review
Contact: William E. Carson, MD, (614) 293-6306

Hematological Malignances Multiple Myeloma

Title: Phase II Randomized Study of Bevacizumab With orWithout Thalidomide in Patients With Relapsed or Refractory Multiple Myeloma
Protocol Number: 2712
Participating Institutions: City of Hope Medical Center, University ofSouthern California, Stanford University, University of California at Davis
Protocol Status: Active
Contact: George Somlo, Beckman Research Institute, City of Hope, (626)359-8111
Beckman Research Institute, City of Hope
Latest Information:http://cancernet.nci.nih.gov/

Non-Hodgkin’s Lymphoma (NHL)

Title: Phase II Study of Bevacizumab in Patients WithRelapsed Aggressive Non-Hodgkin's Lymphoma
Protocol Number: S0108
Participating Group: Southwest Oncology Group
Protocol Status: Active
Contact: Alison T. Stopeck, Southwest Oncology Group, (520) 626-2816; for a complete listing of study contacts, clickhereLatest Information:http://cancernet.nci.nih.gov/

Chronic Myelogenous Leukemia (CML)

Title: A Phase II Study of Bevacizumab (rhuMAB VEGF, NSC#704865), Idarubicin, and Cytarabine in Patients with Chronic Myeloid Leukemiain Blast Phase
Protocol Number: 2431
Participating Institution: M. D. Anderson Cancer Center
Protocol Status: In review
Contact: Jorge E. Cortes, MD, (713) 794-5783

Acute Myelogenous Leukemia (AML)

Title: Phase II Study of Bevacizumab, Cytarabine, andMitoxantrone in Patients With Poor-Risk Hematologic Malignancies
Protocol Number: NCI-2490
Participating Institutions: University of Maryland CancerCenter, Johns Hopkins University
Protocol Status: Active
Contact: Judith E. Karp, Marlene & Stewart Greenebaum Cancer Center,University of Maryland, (410) 328-7394
Latest Information:http://cancernet.nci.nih.gov/

Myelodysplastic Syndrome

Title: Phase I/II Study of Bevacizumab in Patients WithMyelodysplastic Syndrome
Protocol Number: NCI-2771
Participating Institution: Stanford University, M. D.Anderson Cancer Center, Arizona Cancer Center
Protocol Status: Active
Contact: Peter L. Greenberg, Stanford University Medical Center, (650)725-8355
Latest Information:http://cancernet.nci.nih.gov/

Genentech-Sponsored Trials

Title: Phase III Randomized Study of Bevacizumab WithCapecitabine Versus Capecitabine Alone in Women With Previously TreatedMetastatic Breast Cancer
Protocol Number: AVF2119g
Participating Institutions: Multiple institutions in theUnited States
Protocol Status: Active
Contact: Ginny Langmuir, Genentech Inc., (650) 225-4985; for a complete listing of study contacts, clickhereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Bevacizumab WithFluorouracil and Leucovorin Calcium With or Without Irinotecan in Patients WithMetastatic Colorectal Cancer
Protocol Number: AVF2107g
Participating Institutions: Multiple institutions in theUnited States
Protocol Status: Active
Contact: Beth Drena, Genentech Inc., (650) 225-6762; for a complete listing of study contacts, clickhereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase II Randomized Study of Fluorouracil andLeucovorin Calcium With or Without Bevacizumab in Patients With PreviouslyUntreated Metastatic Colorectal Cancer Who Are Not Optimal Candidates forFirst-Line Irinotecan
Protocol Number: AVF2192g
Participating Institutions: Multiple institutions in theUnited States
Protocol Status: Active
Contact: Spencer Guthrie, Genentech Inc., (650) 225-7647; for a complete listing of study contacts, clickhereLatest Information:http://cancernet.nci.nih.gov/

References:

1. Folkman J: Angiogenesis in cancer, vascular, rheumatoid andother disease. Nat Med 1:27-31, 1995.

2. Ferrara N, Davis-Smyth T: The biology of vascular endothelialgrowth factor. Endocr Rev 18:4-25, 1997.

3. Linderholm B, Grankvist K, Wilking N, et al: Correlation ofvascular endothelial growth factor content with recurrences, survival, and firstrelapse site in primary node-positive breast carcinoma after adjuvant treatment.J Clin Oncol 18:1423-31, 2000.

4. Gasparini G: Clinical significance of determination ofsurrogate markers of angiogenesis in breast cancer. Crit Rev Oncol Hematol37:97-114, 2001.

5. Poon RT, Fan ST, Wong J: Clinical implications of circulatingangiogenic factors in cancerpatients. J Clin Oncol 19:1207-25, 2001.

6. Kim KJ, Li B, Houck K, et al: The vascular endothelial growthfactor proteins: identification of biologically relevant regions by neutralizingmonoclonal antibodies. Growth Factors 7:53-64, 1992.

7. Presta LG, Chen H, O’Connor SJ, et al: Humanization of anantivascular endothelial growth factor monoclonal antibody for the therapy ofsolid tumors and other disorders. Cancer Res 57:4593-4599, 1997.

8. Kim KJ, Li B, Winer J, et al: Inhibition of vascularendothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.Nature 362:841-844, 1993.

9. Warren RS, Yuan H, Matli MR, et al: Regulation by vascularendothelial growth factor of human colon cancer tumorigenesis in a mouse modelof experimental liver metastasis. J Clin Invest 95:1789-1797, 1995.

10. Borgstrom P, Gold DP, Hillan KJ, et al: Importance of VEGFfor breast cancer angiogenesis in vivo: implications from intravital microscopyof combination treatments with an anti-VEGF neutralizing monoclonal antibody anddoxorubicin. Anticancer Res 19:4203-4214, 1999.

11. Yuan F, Chen Y, Dellian M, et al: Time-dependent vascularregression and permeability changes in established human tumor xenograftsinduced by an antivascular endothelial growth factor/vascular permeabilityfactor antibody. Proc Natl Acad Sci U S A 93:14765-14770, 1996.

12. Borgstrom P, Hillan KJ, Sriramarao P, et al: Completeinhibition of angiogenesis and growth of microtumors by antivascular endothelialgrowth factor neutralizing antibody: novel concepts of angiostatic therapy fromintravital videomicroscopy. Cancer Res 56:4032-4039, 1996.

13. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety andpharmacokinetic study of recombinant human antivascular endothelial growthfactor in patients with advanced cancer. J Clin Oncol 19:843-850, 2001.

14. Sledge G, Miller K, Novotny W, et al: A Phase II trial ofsingle-agent rhumab VEGF (recombinant humanized monoclonal antibody to vascularendothelial cell growth factor) in patients with relapsed metastatic breastcancer (abstract 5c). Proc Am Soc Clin Oncol 19:3a, 2000.

15. Bergsland E, Hurwitz H, Fehrenbacher L, et al: A randomizedphase II trial comparing rhuMAb VEGF (recombinant humanized monoclonal cntibodyto vascular endothelial cell growth factor) plus 5-fluorouracil/leucovorin(FU/LV) to FU/LV alone in patients with metastatic colorectal cancer (abstract939). Proc Am Soc Clin Oncol 19:242a, 2000.

16. Bergsland EK, Fehrenbacher L, Novotny W, et al: Bevacizumab(BV) + chemotherapy (CT) may improve survival in metastatic colorectal cancer(MCRC) subjects with unfavorable prognostic indicators (abstract 2247). Proc AmSoc Clin Oncol 19:124b, 2001.

17. DeVore RF, Fehrenbacher L, Herbst R, et al: A randomizedphase II trial comparing rhumab VEGF (recombinant humanized monoclonal antibodyto vascular endothelial cell growth factor) plus carboplatin/paclitaxel (CP) toCP alone in patients with stage IIIB/IV NSCLC (abstract 1896). Proc Am Soc ClinOncol 19:485a, 2000.

18. Kabbinavar FF, Johnson D, Langmuir VK, et al: Patterns oftumor progression during therapy with bevacizumab (BV) and chemotherapy (CT) formetastatic colorectal cancer (MCRC) and advanced non-small-cell lung cancer(NSCLC) (abstract 1105). Proc Am Soc Clin Oncol 19:277a, 2001.

19. Novotny W, Holmgren E, Griffing S, et al: Identification ofsquamous cell histology and central, cavitary tumors as possible risk factorsfor pulmonary hemorrhage in patients with advanced NSCLC receiving bevacizumab(abstract 1318). Proc Am Soc Clin Oncol 19:330a, 2001.