~rostate journal.
`· 3• no. 2 (Apr-Jun 2001)
`General Collection
`W1 PR771S
`2002-03-04 08:01 :44
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`Hospira 1011
`1 of 9
`
`

`
`Daniel P. Petrylak, M.D.
`New York, New York, USA
`
`Alan Pollack, M.D., Ph.D.
`Houston, Texas, USA
`
`Jerome P. Richie, M.D.
`Boston, Massachusetts, USA
`
`Oliver Sartor, M.D.
`New Orleans, Louisiana, USA
`
`William R. Sellers, M.D.
`Boston, Massachusetts, USA
`
`Nicholas Vogelzang, M.D.
`Chicago, Illinois, USA
`
`Hiraki Watanabe, M.D.
`Kyoto, Japan
`
`Tomoyuki Shirai, M.D., Ph.D.
`Nagoya, Japan
`
`Kenneth I. Wishnow, M.D.
`Boston, Massachusetts, USA
`
`Mack Roach, M.D.
`San Francisco, California, USA
`
`Eric J. Small, M.D.
`San Francisco, CA, USA
`
`David P. Wood, Jr., M.D.
`Detroit, Michigan, USA
`
`Bruce J. Roth, M.D.
`Indianapolis, Indiana, USA
`
`Howard Sandler, M.D.
`Ann Arbor, Michigan, USA
`
`James Talcott, M.D., S.M.
`Boston, Massachusetts, USA
`
`Bruce R. Zetter, Ph.D.
`Boston, Massachusetts, USA
`
`Clare Tempany, M.D.
`Boston, Massachusetts, USA
`
`Anthony Zietman, M.D., B.S.
`Boston, Massachusetts, USA
`
`Editorial Office. Philip W. Kantoff, M.D., Editor, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115 (617)
`632-3466 Fax (617) 632-2165. Production Editor. Mary Thomas Stone, Blackwell Science, Inc., Malden, MA. Publish(cid:173)
`ing, Subscription, and Advertising Office. Blackwell Science, Inc., Commerce Place, 350 Main Street, Malden, MA
`02148 (781) 388-8250 Fax (781) 388-8260. POSTMASTER SEND ADDRESS CHANGES TO The Prostate Journal, Blackwell
`Science, Inc., Commerce Place, 350 Main Street, Malden, MA 02148. Published Quarterly. Advertising and Reprint
`Requests. Please direct to Tom Palmisano, Blackwell Science, Inc. Annual Rates (2001): Individual, USA $75; Individual,
`Canada/Mexico $90; Individual, Overseas $100; Institution, USA $150; Institution, Canada/Mexico $165; Institution, Overseas $175;
`Single issue $25, prices include postage. Subscription Information. The Prostate Journal (ISSN 1095-5100) is published
`quarterly by Blackwell Science, Inc., Commerce Place, 350 Main Street, Malden, MA 02148 (781) 388-8250 Fax (781)
`388-8260. Subscription term is Jan.-Dec. Claims for missing issues will be serviced at no charge if received within 90 days
`of the cover date for domestic subscribers and 6 months for subscribers outside the US. Duplicate copies cannot be sent to
`replace issues not delivered because of failure to notify publisher of change of address. Please notify publisher of new address
`six weeks in advance of moving date. All subscriptions are payable in advance in US funds drawn on a US bank. If not fully
`satisfied, notify publisher for a refund on all unmailed issues. For Canadian orders, our GST number is 129864823RT-OOOI.
`Copyright © Blackwell Science, Inc.
`Copyright Notice. It is a condition of publication that manuscripts submitted to this journal have not been published and
`will not be simultaneously submitted or published elsewhere. By submitting a manuscript, the authors agree that the copyright for
`their article is transferred to Blackwell Science, Inc. if and when the article is accepted for publication. The copyright covers
`the exclusive rights to reproduce and distribute the article, including reprints, photographic reproductions, microform or any
`other reproductions of similar nature and translations. No part of this publication may be reproduced, stored in a retrieval
`system or transmitted in any form or by any means, electronic, electrostatic, magnetic tape, mechanical, photocopying,
`recording or otherwise, without permission in writing from the copyright holder. Photocopying information for users
`in the USA. The Item-Fee Code for this publication indicates that authorization to photocopy items for internal or personal
`use is granted by the copyright holder for libraries and their users registered with the Copyright Clearance Center (CCC)
`Transactional Reporting Service provided the stated fee for copying beyond that permitted by Section 107 or 108 of the
`United States Copyright Law is paid. The appropriate remittance of $15.00 per copy per article is paid directly to the
`Copyright Clearance Center Inc., 222 Rosewood Drive, Danvers, MA 01923. Permission for other use. The copyright
`owner's consent does not extend to copying for general distribution, for promotion, for creating new works, or for resale.
`Specific written permission must be obtained from Blackwell Science, Inc. for such copying. The Item-Fee Code for this
`publication is: 1095-5100/01/$15.00/0.
`
`Hospira 1011
`2 of 9
`
`

`
`The Prostate Journal
`
`TABLE OF CONTENTS
`
`Vol. 3, Number 2, April/May/June 2001
`
`Minireviews - Section Editor: Daniel George, MD
`HER-Kinase-Directed Therapy of Prostate Cancer
`D. B. Solit, D. B. Agus
`
`Is Neoadjuvant Hormonal Therapy Before Radical Prostatectomy Indicated?
`J. Chun, R. S. Pruthi
`
`Original Articles
`A Phase II Trial of Humanized Anti-Vascular Endothelial Growth Factor
`Antibody for the Treatment of Androgen-Independent Prostate Cancer
`D. M. Reese, P. Fratesi, M. Corry, W. Novotny, E. Holmgren, E. J. Small
`
`Treatment of Metastatic Hormone Refractory Prostate Cancer with
`Ketoconazole Hydrocortisone, and Cyclophosphamide
`A. Pecora, F. Richter, A. Pavlick, V. Lanteri, J. Scheuch, S. Levy, G. Rosenberg,
`J. Vitenson
`
`Structure-Based Androgen Receptor Gene Mutation Database: A Tool to Link
`Molecular Location and Receptor Function
`L. Brive, D. B. Agus, K. R. Ely
`
`Expression of Prostate Specific Molecules in Bacille Calmette-Guerin:
`An Immunotherapeutic Approach to Prostate Cancer
`C. D. Zeoli, M. Maitland, H. Rose, B. Bloom, A. Mittleman, J. Geliebter
`
`Lack of Effect of Aminoglutethimide and Hydrocortisone Added to High-Dose
`Bicalutamide for Androgen-Independent Prostate Cancer
`G. J. Bubley, S. P. Balk, R. M. Joyce, M.-E. Taplin
`
`Sustained Activation of Extracellular Signal-Regulated Kinase (ERK) Signaling
`in Human Prostate Cancer LNCaP Cells Depleted of Androgen
`L. Drew, R. L. Fine, A. J. Raffo, D. P. Petrylak
`
`Intermediate-Term Outcome with Radical Prostatectomy for Localized Prostate
`Cancer: The Cleveland Clinic Experience
`P. E. Clark, H. S. Levin, P. A. Kupelian, C. Reddy, C. D. Zippe, E. A. Klein
`
`Article Reviews - Section Editor: William Oh, M.D.
`
`The Prostate Journal Database - William Oh, M.D.
`
`53
`
`59
`
`65
`
`71
`
`76
`
`92
`
`98
`
`105
`
`118
`
`126
`
`131
`
`Hospira 1011
`3 of 9
`
`

`
`A Phase II Trial of Humanized Anti-Vascular
`Endothelial Growth Factor Antibody for the
`Treatment of Androgen-Independent
`Prostate Cancer
`
`David M. Reese, PhD,* Paige Fratesi, BS,* Michelle Corry, RN,*
`William Novotny, MD,t Eric Holmgren, PhD/ and
`Eric J. Small, MD*
`*Department of Medicine, Division of Hematology-Oncology, Urologic
`Oncology Program, University of California, San Francisco, California,
`U.S.A.
`tGenentech, Inc., South San Francisco, California, U.S.A.
`
`ABSTRACT
`
`Objective: Vascular endothelial growth factor (VEGF)
`is a glycoprotein that is important in promoting tumor
`angiogenesis. Recombinant humanized anti
`(rhuMAb)-VEGF is a humanized murine monoclonal
`antibody that neutralizes VEGF activity and has shown
`promise in animal tumor models. Methods: To evalu(cid:173)
`ate the efficacy and safety of single-agent rhuMAb
`VEGF in metastatic androgen-independent prostate
`cancer (AIPC), we treated 15 patients with 10 mg/kg
`rhuMAb VEGF every 14 days for six infusions (one
`cycle), followed by additional treatment for selected
`patients who had a response or were stable. Results:
`After one cycle, none of the 15 patients who were
`evaluable for tumor response had an objective com(cid:173)
`plete or partial response. Three possible mixed re(cid:173)
`sponses were observed. No patient achieved a >50%
`decrease in serum prostate specific antigen (PSA) level
`
`INTRODUCTION
`Vascular endothelial growth factor (VEGF) is a
`secreted glycoprotein with potent effects on both
`normal and pathologic angiogenesis (1). Many
`solid tumors, including lung, thyroid, breast, co(cid:173)
`lon, kidney, bladder, ovary, and brain cancers,
`have increased VEGF expression (2). It has been
`postulated that paracrine growth loops exist
`whereby tumor cells secrete VEGF, which then
`interacts with specific receptors (e.g., Flk-1/
`KDR) on endothelial cells to promote tumor an(cid:173)
`giogenesis.
`
`Address correspondence and reprint requests to: Eric J.
`Small, MD, UCSF Comprehensive Cancer Center, 2356
`Sutter Street, 5th Floor, San Francisco, CA 94115, U.S.A.
`
`fl) 2001, Blackwell Scie11ce, Inc. 1095-5100/01/$15.00/65
`The Prostate .Jo11mal. Volume 3, Number 2, 2001 65-70
`
`after one cycle. Four patients (27'Yo) had a PSA decline
`of <50%, three patients (20%) had a PSA level in(cid:173)
`crease of <50%, and eight patients (53%) had a PSA
`increase of >50%. The median time to objective pro(cid:173)
`gression was 118 days, and the median time to PSA
`progression was 57 days. Toxicity was generally mild,
`with asthenia present in 6 (40%) of 15 patients. Se(cid:173)
`vere hyponatremia developed in two patients, al(cid:173)
`though the association with rhuMAb VEGF was un(cid:173)
`clear. Conclusions: We concluded that single-agent
`rhuMAb VEGF in this dose and with this schedule did
`not produce significant objective responses in patients
`with AIPC. Further development of this agent in pa(cid:173)
`tients with prostate cancer should focus on earlier
`stage disease or should evaluate it in combination with
`other therapies.
`
`VEGF may play a role in the pathogenesis
`and progression of human prostate cancer. Flk-
`1 /KDR receptors are expressed in human pros(cid:173)
`tate cancer, and their presence may correlate
`with higher grade lesions (3). In addition, VEGF
`is present in both localized and metastatic pros(cid:173)
`tate tumors as well as the plasma of patients with
`metastatic disease, and increasing expression
`may correlate with disease progression (4,5). Fi(cid:173)
`nally, antibodies to VEGF have caused tumor re(cid:173)
`gression in preclinical animal prostate tumor
`models (6-8).
`Recombinant humanized anti-VEGF
`(rhuMAb VEGF) is a monoclonal immuniglolrn(cid:173)
`lin gl antibody generated by engineering the
`VEGF-binding residues in a murine antibody into
`the framework of a normal human antibody (9).
`
`65
`
`Hospira 1011
`4 of 9
`
`

`
`66
`
`The Prostate Journal, Volume 3, Number 2, April 2001
`
`rhuMAb VEGF effectively neutralizes VEGF ac(cid:173)
`tivity in vivo and inhibits the growth of a variety
`of human cancer cell lines in nude mouse tumor
`models (10-12). in Phase I clinical trials in hu(cid:173)
`mans, there was minimal toxicity of rhuMAb
`VEGF ( 13), and the antibody is now being evalu(cid:173)
`ated for the treatment of a variety of solid tu(cid:173)
`mors.
`Based on the above observations, a Phase II
`trial of rhuMAb VEGF in patients with androgen(cid:173)
`independent prostate cancer (AIPC) was con(cid:173)
`ducted. The primary objectives of this trial were
`to determine whether single-agent rhuMAb
`VEGF would result in objective responses in pa(cid:173)
`tients with AIPC, to test the effect of rhuMAb
`VEGF on prostate specific antigen (PSA) levels in
`these patients, and to further evaluate the safety
`of this antibody.
`
`MATERIALS AND METHODS
`Patients
`Eligibility criteria for inclusion in the study in(cid:173)
`cluded histologic diagnosis of prostatic adenocar(cid:173)
`cinoma and disease progression despite androgen
`deprivation and antiandrogen therapy with(cid:173)
`drawal. Patients had to have documented mea(cid:173)
`surable or evaluable metastatic disease and a se(cid:173)
`rum PSA level >5 ng/ml. Three consecutive
`increases in the serum PSA level, each measured
`at least 2 weeks apart, were required. Prior sec(cid:173)
`ond-line hormonal therapy, chemotherapy, im(cid:173)
`munotherapy, radiation therapy, surgery, or
`other investigational therapy was permitted pro(cid:173)
`vided that treatment was completed at least 4
`weeks before enrollment and that disease pro(cid:173)
`gression had occurred despite that therapy. Prior
`radioisotope therapy (strontium-89 or sa(cid:173)
`marium-153) was permitted provided that treat(cid:173)
`ment had occurred at least 60 days preceding the
`rhuMAb VEGF therapy. If patients were receiv(cid:173)
`ing a luteinizing hormone-releasing hormone
`analog, this was continued. A life expectancy of
`26 months and an Eastern Cooperative Oncol(cid:173)
`ogy Group (ECOG) performance status score of
`0-1 were required. Because of the possibility that
`rhuMAb VEGF could inhibit angiogenesis in
`nontumor tissues, patients were excluded if they
`had clinically significant cardiovascular disease
`(i.e., uncontrolled hypertension, recent unstable
`angina or myocardial infarction, congestive heart
`failure, cardiac arrhythmia requiring medication,
`or significant peripheral vascular disease). In ad(cid:173)
`dition, patients with any history or radiologic
`
`evidence of central nervous system metastases
`were excluded. Because Phase I studies with
`rhuMAb VEGF therapy reported severe episodes
`of bleeding, the current or recent use of oral or
`parenteral anticoagulants, including aspirin, was
`an exclusion criterion. Required values for initial
`laboratory data included the following: white
`blood cell count >2500/pl and absolute neutro(cid:173)
`phil count (ANC) >1000/pl; platelet count
`>75,000/µl; total bilirubin, AST, and ALT less
`than twice the upper limits of normal; serum cre(cid:173)
`atinine :.:;l,5 mg/dl; and hemoglobin >9 g/dl. The
`protocol was approved by the University of Cali(cid:173)
`fornia, San Francisco, Institutional Review
`Board, and written informed consent was ob(cid:173)
`tained from all patients.
`
`Treatment Plan
`rhuMAb VEGF was supplied by Genentech, Inc
`(South San Francisco, CA) and was administered
`intravenously in the outpatient clinic. The anti(cid:173)
`body was administered at a dose of 1 O mg/kg
`every 14 days for six infusions (one cycle). The
`initial dose was given over a 90-min period, the
`second dose over 60 min, and all subsequent
`doses over 30 min if the prior infusions were
`tolerated without infusion-associated adverse
`events. Patients experiencing infusion-related ef(cid:173)
`fects such as fever, chills, myalgia, headache,
`rash, fatigue, dyspnea, or hypotension were
`treated symptomatically with acetaminophen,
`diphenhydramine, meperidine, or other medica(cid:173)
`tions as clinically indicated. Patients with an ob(cid:173)
`jective response or stable disease were eligible to
`receive additional rhuMAb VEGF treatment be(cid:173)
`yond one cycle.
`
`Response, Assessments, and Toxicity
`A physical examination, vital signs, ECOG per(cid:173)
`formance status evaluation, and laboratory
`evaluation were performed every 2 weeks. Se(cid:173)
`rum and plasma also were collected every 2
`weeks to determine VEGF and rhuMAb VEGF
`levels.
`Toxicity was graded according to the Na(cid:173)
`tional Cancer Institute Common Toxicity Criteria
`(Version 1). Response to therapy was assessed
`with serial scrum PSA measurements and imag(cid:173)
`ing studies. Bone scans and, when appropriate,
`computed axial tomography scans were obtained
`at baseline and after every cycle of therapy. For
`patients with bidimensional measurable disease,
`
`Hospira 1011
`5 of 9
`
`

`
`Reese et al.: Anti-VEGF Antibody in Androgen-Independent Prostate Cancer
`
`67
`
`the standard response criteria were used. Stable
`disease was not used as a response category but
`was used to determine eligibility for additional
`VEGF treatment after the first cycle. A PSA re(cid:173)
`sponse was defined as a 250% decrease in serum
`PSA level relative to baseline during three con(cid:173)
`secutive measurements each made at least 2
`weeks apart. Progression was defined as the fol(cid:173)
`lowing: development of new bone pain lasting
`>2 weeks that required a persistent increase in
`opioid analgesic use; the appearance of new le(cid:173)
`sions on bone scan, a >25% increase in the size
`of a metastatic lesion present at screening, or
`both; or a 250% increase in serum PSA level
`from baseline or nadir, whichever was lower, on
`two or more determinations each at least 2
`weeks apart. Stable patients with disease had
`neither a response nor progressive disease and
`also were required to have an unchanged or im(cid:173)
`proved ECOG performance status score.
`
`Pharmacokinetic Analysis
`Individual and mean serum rhuMAb VEGF con(cid:173)
`centration-time data and serum VEGF concen(cid:173)
`tration-time data were obtained and plotted, and
`estimates of pharmacokinetic parameters were
`summarized. In addition, serum rhuMAb VEGF
`concentration-time data were analyzing using a
`one-compartment model by nonlinear least(cid:173)
`squares regression. Serum rhuMAb data were
`not available at all time points for each patient
`since patients withdrew from the study at differ(cid:173)
`ent times and the number of sample collections
`varied. Mean rhuMAb VEGF concentration-time
`profiles were therefore plotted for the period
`from Day 0 to Day 70, for which data were avail(cid:173)
`able for all patients (using nominal times).
`
`Statistical Analysis
`The primary end points of the study were objec(cid:173)
`tive tumor response and changes in serum PSA
`level from baseline. Secondary end points in(cid:173)
`cluded response duration, time to progression,
`overall survival, and changes in quality of life,
`pain, and analgesic use. The study had a three(cid:173)
`stage design, in which 15 patients were to be
`treated with an initial cycle of rhuMAb VEGF. If
`one or more responses were observed in the first
`15 patients, a total of up to 60 patients could be
`enrolled. An analysis of efficacy and safety was
`performed on all patients who received at least
`one dose of rhuMAb VEGF.
`Demographic and baseline characteristics
`
`were summarized by descriptive statistics. The
`percentage of patients with an objective response
`or a decline in PSA level of 250% was calculated
`with 95% confidence intervals. Response dura(cid:173)
`tion, time to progression, and overall survival
`time were estimated using Kaplan-Meier meth(cid:173)
`odology. Group changes in quality-of-life mea(cid:173)
`sures, pain, and analgesic usage were assessed
`with the Wilcoxon signed rank test.
`
`RESULTS
`Patient Characteristics
`A total of 15 patients were enrolled, all of whom
`were evaluable for efficacy and toxicity. Patient
`characteristics are summarized in Table 1. The
`median age of patients was 71 years. Fourteen
`patients (93%) had bone metastases, and 8 pa(cid:173)
`tients (53%) had soft-tissue disease (lymph
`nodes in 7 patients, and liver metastases in 1
`patient). The median pretreatment PSA level was
`85 ng/ml (range 9.0-466 ng/ml), and all patients
`had an ECOG performance status score of 0 (n =
`
`TABLE I. Patient characteristics
`
`Characteristic
`
`Patients enrolled
`Median age (yr)
`ECOG performance status
`0
`
`Median laboratory values (range)
`PSA, ng/ml
`Alkaline Phosphatase, U/l
`LDH, U/I
`Hemoglobin, g/dl
`Patients with positive bone scan
`findings
`Patients with measurable disease
`Lymph node
`Liver
`Prior systemic therapy
`Antiandrogen
`Ketoconazole
`Aminoglutethimide
`Immunotherapy
`Chemotherapy
`
`No. of
`Patients(%)
`
`15
`71 (range 62-83)
`
`14 (93%)
`1 (7%)
`
`85 (9-466)
`87 (55-437)
`195 (136-434)
`12.2 (10.1-14.1)
`14 (93%)
`
`8 (53%)
`7
`
`14 (93%)
`3 (20%)
`2 (13%)
`3 (20%)
`0
`
`Hospira 1011
`6 of 9
`
`

`
`68
`
`The Prostate Journal, Volume 3, Number 2, April 2001
`
`14) or 1 (n == 1). Fourteen patients had received
`prior therapy with an antiandrogen (all of whom
`underwent antiandrogen withdrawal), 3 patients
`had received prior ketoconazole therapy, 2 pa(cid:173)
`tients had received prior aminoglutethimide
`therapy, and 3 patients had received prior im(cid:173)
`munotherapy with dendritic cells (n == 1) or
`granulocyte macrophage-colony-stimulating fac(cid:173)
`tor (n == 2). No patient had received prior che(cid:173)
`motherapy. The median number of rhuMAb
`VEGF doses received was 10 (range 5-13). How(cid:173)
`ever, seven patients (47%) received seven or
`fewer doses.
`
`Efficacy
`Efficacy was evaluated radiographically and by
`measuring serial changes in PSA levels. At Day
`70, none of the eight patients with measurable
`disease had experienced an objective complete or
`partial response. Although there were no un(cid:173)
`equivocal cases of tumor shrinkage, there were
`some mixed responses. One patient had a Week
`12 bone scan that showed a decrease or disap(cid:173)
`pearance of lesions in the cervical and thoracic
`spine but also showed a single new lesion in the
`left femur. Another patient had a Week 12 com(cid:173)
`puted axial tomography scan that demonstrated
`a 50% decrease in volume of the iliac and para(cid:173)
`aortic lymph nodes, but a bone scan showed
`multiple new areas of uptake. Both of these pa(cid:173)
`tients had accompanying increases in serum PSA
`level.
`No patient had a sustained decline in PSA
`level of >50%. Four patients (27%) had tran(cid:173)
`sient PSA level declines of <50% (range
`4-26%), while eight patients (53%) had an in(cid:173)
`crease in PSA level of <50% at Week 12. Three
`patients (20%) had a <50% increase in PSA
`level at Week 12.
`The median time to objective progression
`was 118 days (95% confidence interval 71-178
`days), and the median time to PSA progression
`was 57 days.
`
`discontinued therapy because of progressive he(cid:173)
`patic metastases. Approximately 4 weeks after
`the last infusion, he presented with fatigue and
`mental status changes, and was found to have a
`serum sodium level of 108 mEq/l. His condition
`improved with conservative therapy, and the hy(cid:173)
`ponatremia was felt to be due to disease progres(cid:173)
`sion. A second patient received five doses of
`rhuMAb VEGF, but then fatigue, anorexia, vom(cid:173)
`iting, and confusion developed, and the patient
`was found to have a scrum sodium level of 119
`mEq/l. He was treated with conservative mea(cid:173)
`sures, and his condition improved. The etiology
`of his hyponatremia was uncertain. Additional
`significant Grade 3 or 4 toxicities included hy(cid:173)
`perglycemia (n == 2), anemia (n == 1 ), and hyper(cid:173)
`kalemia (n == 3 ), all of which were thought to be
`unrelated to rhuMAb VEGF administration.
`
`Pharmacoldnetics
`rhuMAb VEGF serum concentrations were not
`measurable in any patient before treatment. Af(cid:173)
`ter the first dose, the mean peak and trough con -
`centrations of rhuMAb VEGF were 247 and 67
`pg/ml, respectively. Over time, the mean peak
`and trough concentrations increased. At Day 98,
`the mean peak and trough concentrations were
`450 and 180 pg/ml, respectively.
`Before rhuMAb VEGF administration, serum
`VEGF concentrations were not quantifiable (i.e.,
`<20 pg/ml) in 8 of the 15 patients. In patients in
`whom the serum VEGF level was measurable,
`baseline concentrations ranged from 24.3 to 178
`pg/ml. After rhuMAb VEGF administration, se(cid:173)
`rum VEGF concentrations were detectable and
`increased over time in all patients (mean maxi(cid:173)
`mum concentration 590 pg/ml). An examination
`of baseline rhuMAb VEGF and VEGF concentra(cid:173)
`tions, and of rhuMAb VEGF clearance and cen(cid:173)
`tral volume distributions, did not suggest a rela(cid:173)
`tionship between rhuMAb exposure and the rise
`in serum VEGF concentrations.
`
`Toxicity
`In general, treatment with rhuMAb VEGF was
`well-tolerated. No patient discontinued therapy
`due to adverse events, and there were no treat(cid:173)
`ment-related deaths. The most common adverse
`event was fatigue (60%), although this was rated
`at Grade 2 or less in all patients. Severe hypona(cid:173)
`tremia developed in two patients ( 13 % ) . The first
`patient received six doses of rhuMAb VEGF, but
`
`DISCUSSION
`The development of new therapies for patients
`with AIPC is critical, because existing treatments
`have not demonstrated a survival benefit. In this
`trial, we evaluated the efficacy of rhuMAb VEGF
`and did not find evidence of objective responses
`or meaningful PSA level declines. Four patients
`(27%) did have a decline in PSA level of< 50%,
`but this was not sustained, and the median time
`
`Hospira 1011
`7 of 9
`
`

`
`Reese et al.: Anti-VEGF Antibody in Androgen-Independent Prostate Cancer
`
`69
`
`to PSA progression was relatively short at 57
`days. While two patients had a possible mixed
`response as seen on radiographic studies, the se(cid:173)
`rum PSA level was increasing in both. Thus,
`there was no convincing evidence of a significant
`antitumor effect in this patient population.
`Patient selection would not appear to explain
`the results obtained in this trial. Fourteen of
`15 patients had an ECOG performance status
`score of 0, and the patients were not heavily pre(cid:173)
`treated (3 patients had received prior high-dose
`ketoconazole, 2 patients had received aminoglu(cid:173)
`tethimide, and 3 patients had received immuno(cid:173)
`therapy, while none had received chemo(cid:173)
`therapy). Furthermore, the median PSA level
`was comparable to that reported in large trials of
`patients with AIPC (14-16). However, eight pa(cid:173)
`tients ( 53 % ) did have soft-tissue (albeit largely
`nodal) metastases, and in some series this group
`of patients has been reported to have an inferior
`prognosis when compared to patients with bone(cid:173)
`only disease (17). Nevertheless, the patients in
`this study do not appear to have had exception(cid:173)
`ally advanced or resistant disease.
`The serum concentrations of rhuMAb VEGF
`observed in this trial were consistent with the
`levels predicted from animal-scaling models and
`pharmacokinetic analyses using comparable dos(cid:173)
`ing and schedules ( 18). In addition, the concen(cid:173)
`trations of antibody that were achieved were in
`the range of those reported to have antitumor
`efficacy in xenograft models (12). Thus, the fail(cid:173)
`ure to achieve target antibody concentrations is
`not likely to be an explanation for the lack of
`antitumor efficacy observed in this study.
`The toxicity of rhuMAb VEGF observed in
`this trial was, in general, modest. However, sig(cid:173)
`nificant hyponatremia developed in two pa(cid:173)
`tients. In the first, the hyponatremia was likely
`due to underlying disease progression, because
`the patient had extensive progressive visceral
`disease and had not received antibody therapy
`for 4 weeks before a low scrum sodium level
`developed. The second patient was actively re(cid:173)
`ceiving rhuMAb VEGF, however, and the anti(cid:173)
`body may have contributed to the development
`of hyponatremia. The mechanism by which this
`might occur is unknown, and hyponatremia was
`not observed in previous Phase I trials of the an(cid:173)
`tibody ( 13). In addition, animal studies of phar(cid:173)
`macokinetics did not demonstrate a significant
`accumulation of the antibody in the kidney ( 18).
`Despite the limited therapeutic activity of
`rhuMAb VEGF that was observed in this trial,
`further investigation of the antibody in patients
`
`with prostate cancer may be warranted. In par(cid:173)
`ticular, the use of the compound in earlier stages
`of the disease, when the tumor burden is mini(cid:173)
`mal, may yield a more potent antitumor re(cid:173)
`sponse. For example, the use of rhuMAb VEGF
`in patients with PSA progression (but no docu(cid:173)
`mented metastases) after primary local therapy
`would be reasonable, especially because macro(cid:173)
`molecules such as monoclonal antibodies may
`have restricted tumor penetration in clinically
`detectable metastatic lesions ( 19). In addition,
`combining rhuMAb VEGF with cytotoxic che(cid:173)
`motherapy agents may be a fruitful approach.
`The antibody has had potent interactions with
`cisplatin in one lung cancer xenograft model
`(20), and evaluating its efficacy in combination
`with effective anti-prostate cancer agents is logi(cid:173)
`cal. To determine whether rhuMAb has a role in
`the treatment of patients with advanced prostate
`cancer will require further clinical trials explor(cid:173)
`ing these hypotheses, because it is unlikely that
`the antibody has clinically relevant activity as a
`single agent in the treatment of metastatic AIPC.
`
`ACKNOWLEDGMENTS
`This research was sponsored in part by Gencn(cid:173)
`tcch, Inc. (South San Francisco, CA).
`
`REFERENCES
`1. Ferrara N. ( 1999) Role of vascular endothe(cid:173)
`lial growth factor in the regulation of angio(cid:173)
`genesis. Kidney Int. 56: 794-814.
`2. Ferrara N, Davis-Smyth T. ( 1997) The biol(cid:173)
`ogy of vascular endothelial growth factor.
`Endocr. Rev. 18: 4-25.
`3. Ferrer FA, Miller LJ, Lindquist R, et al.
`( 1999) Expression of vascular endothelial
`receptors in human prostate cancer. Urology
`54: 567-572.
`4. Ferrer FA, Miller LJ, Andrawis RI, ct al.
`( 1997) Vascular endothelial growth factor
`(VEGF) expression in human prostate can(cid:173)
`cer: In situ and in vitro expression of VEGF
`by human prostate cancer cells. J. Ural. 157:
`2329-2333.
`5. Duque JL, Loughlin KR, Adam RM, et al.
`( 1999) Plasma levels of vascular endothelial
`growth factor are increased in patients with
`metastatic prostate cancer. Urology 54:
`523-527.
`6. Melynk O, Simmerman M, Kim IO, et al.
`( 1999) Neutralizing anti-vascular endotheli-
`
`Hospira 1011
`8 of 9
`
`

`
`70
`
`The Prostate Journal, Volume 3, Number 2, April 2001
`
`al growth factor antibody inhibits further
`growth of established prostate cancer and
`metastases in a pre-clinical model. J. Urol.
`161: 960-963.
`7. Borgstrom P, Bourdon MA, Hillan KJ, et al.
`( 1998) Neutralizing anti-vascular endotheli(cid:173)
`al growth factor antibody completely inhib(cid:173)
`its angiogenesis and growth of human pros(cid:173)
`tate carcinoma micro tumors in vivo. Prostate
`35: 1-10.
`8. Kirschenbaum A, Wang J-P, Ren M, et al.
`( 1997) Inhibition of vascular endothelial cell
`growth factor suppresses the in vitro growth
`of human prostate tumors. Urol. Oncol. 3:
`3-10.
`9. Presta LG, Lahr SJ, Shields RL, et al. ( 1993)
`Humanization of an antibody directed
`against IgE. J. Immunol. 151: 2623-2632.
`10. Kim KJ, Li B, Winer J, et al. (1993) Inhibi(cid:173)
`tion of vascular endothelial growth factor(cid:173)
`induced angiogenesis suppresses tumor
`growth in vivo. Nature 362: 841-844.
`11. Warren RS, Yuan I-I, Matli MR, et al. (1995)
`Regulation by vascular endothelial growth
`factor of human colon cancer tumorigenesis
`in a mouse model of experimental liver me(cid:173)
`tastasis. J. Clin. Invest. 95: 1789-1797.
`12. Mordenti J, Thomsen K, Licko V, Chen H,
`Meng YG, Ferrara N. ( 1999) Efficacy and
`concentration-response of murine anti(cid:173)
`VEGF monoclonal antibody in tumor(cid:173)
`bearing mice and extrapolation to humans.
`Toxicol. Pathol. 27: 14-21.
`13. Gordon MS, Margolin K Talpaz M, et al.
`(2001 ). Phase I safety and pharmacokinetic
`study of recombinant human anti-vascular
`endothelial growth factor in patients with
`advanced cancer. J. Clin. Oncol. 19: 851-856.
`14. Tannock I, Osoba D, Stockler M, et al. ( 1996)
`Chemotherapy with mitoxantrone plus
`prednisone or prednisone alone for symp-
`
`tomatic hormone-resistant prostate cancer:
`A Canadian randomized study with pallia(cid:173)
`tive end points. J. Clin. Oncol. 14: 1756-1764.
`15. Kantoff P, Halabi S, Conaway M, et al.
`( 1999) Hydrocortisone with or without mi(cid:173)
`toxantrone in men with hormone-refractory
`prostate cancer: Results of the Cancer and
`Leukemia Group B 9182 study. J. Clin. Oncol.
`17: 2506-2513.
`16. Small EJ, Meyer M, Marshall ME, et al.
`(2000) Suramin therapy for patients with
`symptomatic hormone-refractory prostate
`cancer: Results of a randomized Phase Ill
`trial comparing suramin plus hydrocortisone
`to placebo plus hydrocortisone. J. Clin. Oncol.
`18: 1440-1450.
`17. Hussain M, Wolf M, Marshall E, Crawford
`ED, Eisenberger M. ( 1994) Effects of contin(cid:173)
`ued androgen-deprived therapy and other
`prognostic factors on response and survival
`in phase II chemotherapy trials for hor(cid:173)
`mone-refractory prostate cancer: A South(cid:173)
`west Oncology Group report. J. Clin. Oncol.
`12: 1868-1875.
`18. Lin YS, Nguyen C, Mendoza JL, et al. (1999)
`Preclinical pharmacokinetics, interspecies
`scaling, and tissue distribution of a human(cid:173)
`ized monoclonal antibody against vascular
`endothelial growth factor. J. Pharmacol. Exp.
`Ther. 288: 371-378.
`19. Netti PA, Hamberg LM, Babich JW, et al.
`( 1999) Enhancement of fluid filtration
`across tumor vessels: implication for delivery
`of macromolecules. Proc. Natl. Acad. Sci. USA
`96: 3137-3142.
`20. Kabbinavar F, Wong JT, Ayala RE, et al.
`(1995) The effect of antibody to vascular en(cid:173)
`dothelial growth factor and cisplatin on the
`growth of lung tumors in nude mi