Phase I Dose-Escalation Study of VB-111, an Antiangiogenic ...istration, VB-111 can serve as a means...

Cancer Therapy: Clinical

Phase I Dose-Escalation Study of VB-111, an AntiangiogenicVirotherapy, in Patients with Advanced Solid Tumors

Andrew J. Brenner1, Yael C. Cohen2, Eyal Breitbart2, Livnat Bangio2, John Sarantopoulos1, Francis J. Giles3,Ernest C. Borden4, Dror Harats2, and Pierre L. Triozzi4

AbstractPurpose:VB-111 is an antiangiogenic agent consisting of a nonreplicating adenovirus vector (Ad-5) with

a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a

Fas-chimera transgene in angiogenic endothelial cells. In a phase I dose-escalation study, pharmacokinetics,

pharmacodynamics, safety, and efficacy of a single dose of VB-111 in patients with advanced solid tumors

were evaluated.

ExperimentalDesign:VB-111was administered as a single i.v. infusion at escalating doses from1�1010

(cohort 1) to 1 � 1013 (cohort 7) viral particles (VP) in successive cohorts. Assessments included

pharmacokinetic and pharmacodynamic profiles, tumor response, and overall survival.

Results: Thirty-three patients were enrolled. VB-111 was safe and well-tolerated; self-limited fever and

chills were seen at doses above 3 � 1011 VPs. Transgene expression was not detected in blood but was

detected in an aspirate from a subcutaneous metastasis after treatment. One patient with papillary thyroid

carcinoma had a partial response.

Conclusions: VB-111 was safe and well tolerated in patients with advanced metastatic cancer at a single

administration of up to 1� 1013 VPs. Evidence of transgene expression in tumor tissue and tumor response

was observed. Clin Cancer Res; 19(14); 3996–4007. �2013 AACR.

IntroductionThe development of adequate tumor vascularity is essen-

tial for tumor growth, invasion, and metastasis. Antiangio-genic agents, including VEGF and other tyrosine kinasereceptor inhibitors, are now in common clinical use in themanagement of a variety of cancers, including colon, lung,kidney, thyroid, and glioblastoma (1). Several limitationshave been recognized in the clinical application of thesevascular-targeted agents. Only limited and transient antitu-mor activity has been shown, mostly as part of a chemo-therapeutic regimen and not as a monotherapy. As currentagents target factors that regulate a variety of key cellularprocesses, specificity to tumor vasculature is limited, result-ing in various clinical toxicities (1,2).

VB-111, a novel antiangiogenic agent, targets the endo-thelial cells in the tumor vasculature, driving it to apo-ptosis. VB-111 comprises a nonreplicating adenovector

(Ad-5, E1-deleted), which contains a proprietary modi-fied murine pre-proendothelin promoter (PPE-1-3X) anda Fas-chimera transgene (Fas and human TNF receptor 1).This modified murine promoter is able to specificallytarget the expression of the Fas-chimera transgene toangiogenic blood vessels, leading to targeted apoptosisof these vessels (refs. 3,4; Fig. 1). Via systemic i.v. admin-istration, VB-111 can serve as a means to debulk tumorburden even in well-advanced rodent xenografts withextensive tumor burden (3).

The Fas pathway effectively mediates cell death in nor-mal and in malignant cells. Its activation by Fas ligand,which is highly expressed in nontumoral normal tissues, ishighly toxic. Hepatotoxicity is circumvented by the spec-ificity of the PPE-1-3X promoter, which restricts activationof the Fas pathway to angiogenic endothelial cells. Thisspecificity is further enhanced, as the Fas component of thechimeric transgene is activated via binding of the chimericTNFR-1 receptor with TNF-a, which is less prevalent innontumoral normal tissues (5). The transcriptional rate ofendothelin-1 is also augmented in the presence of cyto-kines like TNF-a, which also contributes to tumor speci-ficity (3,6).

Preclinical studies showed antitumor activity of VB-111monotherapy in several models, including Lewis lung car-cinoma in mice (3), mouse B16 melanoma model (3), andnude rat glioblastoma xenograft model (7). Synergisticeffects were identified in combination with chemothera-peutic agents (8) and antiangiogenic agents (9).

Authors' Affiliations: 1Institute for Drug Development, Cancer Therapyand Research Center, University of Texas Health Science Center at SanAntonio, Texas; 2VBL Therapeutics, Or Yehuda, Israel; 3HRB ClinicalResearch Facilities, National University of Ireland Galway & Trinity CollegeDublin, Ireland; and 4Department of Solid Tumor Oncology, ClevelandClinic Taussig Cancer Institute, Cleveland, Ohio

Corresponding Author: Pierre L. Triozzi, Cleveland Clinic Taussig CancerInstitute R4,9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-445-5141; Fax: 216-636-2498; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-12-2079

�2013 American Association for Cancer Research.

ClinicalCancer

Research

Clin Cancer Res; 19(14) July 15, 20133996

on July 6, 2020. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst April 15, 2013; DOI: 10.1158/1078-0432.CCR-12-2079

http://clincancerres.aacrjournals.org/

We present here the results of a phase I, first-in-human,single-dose administration of a VB-111 in patients withadvanced solid tumors. The primary objectives of the studywere to evaluate the safety and find the maximal tolerateddose (MTD) or maximal feasible dose of VB-111. Thesecondary objectives were to assess the pharmacokineticand pharmacodynamic profile of VB-111, to document anyclinical responses, and to evaluate changes in angiogenesisbiomarkers in response to VB-111 treatment.

Patients and MethodsStudy design

This is a phase I, open-label, multisite, sequential dose-escalation "3þ 3" design study of a single dose of VB-111 inpatients with advanced solid tumors. The study was con-ducted at Cleveland Clinic Foundation (CCF) in Ohio andat the Cancer Therapy and Research Center (CTRC) in SanAntonio, TX, betweenNovember 2007 andDecember 2010(clinicaltrials.gov identifier NCT00559117). All patientsprovided written informed consent. The study was con-ducted in accordance with the Declaration of Helsinki andthe ICHHarmonized Tripartite Guideline for GoodClinicalPractice and was approved by the relevant Regulatory andInstitutional Review Boards.

Patient selectionPatients eligible for this study were 18 years or older with

a confirmed diagnosis of progressive and advanced solidtumors for which no effective treatment was available.Other key eligibility criteria included provision of writteninformed consent, a Karnofsky performance status of atleast 70%, and an adequate hematologic profile and renaland hepatic function. Exclusion criteria included recentlyactive cardiovascular disease, recent surgery, proliferativeretinopathy, liver disease or central nervous system (CNS)metastasis, recent antiangiogenic therapy or immunosup-pressive treatment, recent chemo/radiotherapy or use of aninvestigative agent (within 4 weeks), or an uncontrolledcomorbidity.

Formulation, dosing, and concomitant medicationsVB-111 was manufactured in a GMP facility. It was

propagated in Per6 cells, purified, and formulated as a

Translational RelevanceVB-111 is a novel antiangiogenic agent that targets

endothelial cells in the tumor vasculature, containinga nonreplicating adenovector (Ad-5, E1 deleted), a pro-prietary modified murine pre-proendothelin promoter(PPE-1-3X), and a Fas-chimera transgene (Fas andhuman TNF receptor 1). The modified promoter specif-ically targets the expression of the Fas-chimera transgeneto angiogenic tumor blood vessels, leading to theirapoptosis. VB-111 is the first agent based on transcrip-tional targeting of tumor endothelium to be assessed in aclinical trial. Robust efficacy and specificity towardtumor endothelium of VB-111 have been shown inseveral cancer preclinical models. This phase I trial con-firms the specificity to tumor endothelium in humans,which is the basis for the safety of VB-111. This transgenewas expressed in a metastasis postdosing but not inwhole blood in any patient. Evidence for antitumoractivity included tumor response and superior overallsurvival in the 1 � 1013 VPs cohort compared withsubtherapeutic doses.

Figure 1. Mechanism of action ofVB-111. VB-111 targeted toangiogenic endothelial cells.

2. Angiogenic

endothelial cell

gene expression

4. Endothelial cell

apoptosis

3. Tumor-associated

TNF-α activates Fas

pathway

TNFαTNFα

PPP-1-3X Fas-c

TNFR1

TNFα

Fas

TNFα

Fas-c

Ad5

VB-111

TNF-αTNF-α

TNFR1

TNFα

Fas

TNFR-1

TNF-α

Fas

TNF-α

1. Recombinant

adenovirus

internalizes into cell

Study of VB-111: An Antiangiogenic Virotherapy in Cancer

www.aacrjournals.org Clin Cancer Res; 19(14) July 15, 2013 3997




sterile vector solution. The vials were diluted with normalsaline for infusion and administered as a single i.v. infusion.

The starting dose, 1 � 1010 viral particles (VP), repre-sented a safetymargin of 2,800-fold below theno-observed-adverse-effect-level in the mouse toxicology studies.Planned dose levels of 3 � 1010, 1 � 1011, 3 � 1011, 1 �1012, 3� 1012, and 1� 1013 VPs [VP/plaque-forming units(PFU) � 30] were examined in cohorts of 3 patients in thedose-escalation phase. If one patient experienced a dose-limiting toxicity (DLT; defined as any treatment-related,grade 3 toxicity), the cohort was to be expanded to 6patients. If noneof the remaining3patients in the expandedcohort experienced a DLT, escalation continued. The MTDwas defined as the highest dose at which fewer than 33%patients experienced a DLT. Toxicity was graded accordingto the National Cancer Institute Common Toxicity Criteria(Version 3). Dose-escalation continued until the MTD orthe maximum-planned dose was reached. In the dose-expansion phase, 12 patients were enrolled at dose level6 and 6 patients at dose level 7 (3 � 1012 VPs and 1 � 1013

VPs) to obtain additional safety and efficacy data. To avoidfever following study drug administration, patients received1 g of acetaminophen before dosing, then as needed for72 hours after dosing.

Pretreatment and follow-up visits: safety and tumorresponse

The trial was initially designed as a 56-day follow-up afterthe single dose. It was later amended to include follow-upvisits until disease progression, and, thereafter, bimonthlyphone contacts for survival.

Pretreatment evaluation included a complete history,physical examination, and routine laboratory studiesincluding a complete blood count (CBC), chemistry[electrolytes, blood urea nitrogen, creatinine, uric acid,glucose, alkaline phosphatase, lactate dehydrogenase, alka-line aminotransferase (ALT), aspartate aminotransferase(AST), total bilirubin, calcium, total protein, albumin,cholesterol, and triglycerides], urinalysis, electrocardiogra-phy (ECG), and tumor markers. Radiologic assessment wasbased on chest, abdomen, and pelvic computed tomo-graphic (CT) or MRI scans. During the trial, radiologicstudies for disease status were repeated at week 4 and 8 andevery 8 weeks thereafter (cohorts 6–7 only, after protocolamendment) until disease progression. Tumor responsewas assessed by Response Evaluation Criteria in SolidTumors (RECIST 1.0) at these prespecified time points.Hematology (CBC, coagulation) and chemistry blood testswere collected at each study visit. Adverse events wererecorded on an ongoing basis and up to 2months followingthe administration of the test drug. Patients were observedfor 6 hours after dosing. Upon disease progression, patientswere followed every 2 months for survival.

Pharmacokinetic and pharmacodynamic testingTesting was conducted under Good Laboratory Practice

compliance at Southern Research Institute, Birmingham,AL. Blood and urine samples were collected before dos-

ing, at the end of the infusion, at 3 hours and 6 hours,and on days 4, 7, 14, 28, and 56 for evaluation of viralDNA levels in blood and urine and the expression ofthe transgene (mRNA in blood). The presence of vectorDNA was tested using a quantitative real-time PCR(qPCR) method. The presence of mRNA derived fromtransgene expression was determined using quantitativereal-time reverse transcriptase PCR (qRT-PCR). Bothassays were developed and validated at Southern ResearchInstitute. Optionally, accessible tumor lesions were biop-sied and analyzed for transgene expression before andafter dosing.

Immune response to VB-111Serumsampleswere diluted andanalyzed for adenovirus-

specific immunoglobulin G (IgG) for adenovirus 5 (Ad-5)by ELISA. For the ELISA, 96-well flat-bottomed, high-bind-ing Immulon-IV plates were coated with 100 mL Ad-5antigen (Penn Vector Core) at 5 � 108 particles/well incarbonate buffer (coating buffer, pH 9.5) overnight at 4�C,washed twice in PBS/0.05% Tween, blocked in PBS/1%horse serum albumin (HSA) for 1 hour at 24�C, and thenwashed twice in PBS/0.05% Tween. Appropriately diluted(3-fold) samples were added to antigen-coated plates andincubated for 2 hours on an orbital shaker at room tem-perature. Plates were washed three times with PBS/0.05%Tween and incubatedwith peroxidase-conjugated goat anti-human Ig (1:5,000 dilution; Jackson ImmunoResearchLaboratories, Inc.) for 1 hour at room temperature. Plateswere washed three times as above, and 3,30,5,50-tetra-methylbenzidine substrate (Sigma-Aldrich) was added at100 mL/well for 30 minutes. Reaction was stopped when100 mL 2 N H2SO4 was added, and optical densities wereread at 450 nm on a VersaMAX tunable microplate reader(Molecular Devices). Titer was the dilution achieving 0.5maximum optical density.

Serum cytokines and receptorsSerum levels of interleukin (IL)-6, IL-8, VEGF, TNF-a,

soluble TNF receptor (sTNFR)-1, sTNFR-2, soluble intercel-lular adhesion molecule 1 (sCD54), soluble E-selectin(CD62E), and fibroblast growth factor (FGF) were mea-sured by cytometric bead array (CBA) and measured inperipheral blood of patients at baseline and at 6 hours and4, 7, 14, 28, and 56 days after dosing. Samples were diluted,and CBA Flex Sets (BD Biosciences Pharmingen) were usedaccording to the manufacturer’s instructions. Flow cytome-try was conducted using a BD LSR II System (BD Bios-ciences). Data were analyzed using the BD CBA software(FCAP Array Software, BD Biosciences). Standard curves foreach cytokine/receptor were generated using the premixedlyophilized standards provided in the kits, and the concen-trations in samples were determined from the appropriatestandard curve.

Statistical analysisThe trial was planned to present a descriptive statistical

data summary. Cohorts 6 and 7 were expanded as

Brenner et al.

Clin Cancer Res; 19(14) July 15, 2013 Clinical Cancer Research3998




prespecified in the study protocol. From dose equivalencebased on efficacy results in animal models, cohorts 1 to 5were expected to be below efficacy levels, cohort 6 wasexpected to provide borderline efficacy, and cohort 7 wasequivalent to efficacious doses in the animalmodel. As a posthoc exploratory analysis, we compared the time to progres-sion of disease and overall survival, assessed with the use ofKaplan–Meier curves for cohorts 1 to 6 versus 7 and forcohorts 1 to 5 versus 7 and tested for significance by the log-rank test.

ResultsPatient characteristicsA total of 33 patients [3 in each of cohorts 1–5 (total of

15 patients), 12 in cohort 6, and 6 in cohort 7] withprogressive advanced and/or metastatic solid organ can-cers were enrolled in the study. Cohorts 6 and 7 wereextended to 12 and 6 patients, respectively, to enabledetection of an efficacy signal. Patients’ baseline charac-teristics are detailed in Table 1. Most patients hadreceived multiple lines of antitumor therapy, 60.6% hadprevious antiangiogenic therapy, 45.5% had previous

radiation therapy, and 84.9% had previous cancer-relatedsurgery.

Safety and tolerabilityVB-111 was found to be safe and well tolerated, except

for transient febrile reaction after dosing in cohort levels 5to 7 (dose levels 1012–1013 VPs). One cohort 7 patientexperienced a DLT of grade 3 pyrexia (temperature of40.3�C) that was considered related to the study medica-tion. It was not a serious adverse event and resolved withthe use of acetaminophen with no sequelae. Three seriousadverse events occurred; all were judged to be caused byprogression of malignancy and unrelated to study med-ication. The most frequent adverse events were pyrexia,fatigue, and chills. Pyrexia and chills occurred mostly inthe higher-dose groups and were usually considered relat-ed to study medication. Related adverse events are sum-marized in Table 2.

Several patients had declines in hemoglobin and hemat-ocrit values after study treatment. Also, mild to moderatelyelevated activated partial thromboplastin time (aPTT) levelsoccurred (without clinical consequence) in some patientsbefore day 28.No clinically significant posttreatment chem-istry or urinalysis abnormalities occurred during the studywith the exception of a patient with bile duct obstructiondue to progression of cancer who developed markedlyelevated alkaline phosphatase and elevations of ALT, AST,and total bilirubin. In cohort 7, transient mild elevations ofALT, AST, and alkaline phosphatase were observed afterdosing in some patients, and 2 patients had transientthrombocytopenia; none of these events were consideredclinically significant, and all were classified as CommonTerminology Criteria for Adverse Events grade 1, except forone grade 2 ALT elevation (118 IU).

No clinically significant posttreatment changes in vitalsigns were observed, except for the occurrence of fever 6hours after infusion in 83% (15 of 18) of the patients incohort 6 to 7; these patients with fever also had increasedheart rates, and some had transient blood pressure changes.All patients remained hemodynamically stable. No treat-ment-related changes were observed on physical examina-tions or ECGs.

Pharmacokinetic analysisMean levels of adenovirus vector DNA found in whole

blood after dosing showed a dose-dependent effect (Fig.2A). By day 56, levels of Ad-5 decreased by at least 2-logfold or were undetectable. No vector DNAwas found in thepredose samples from any patient. In most patients withdetectable levels of Ad-5 in the urine, the presence wastransient, with levels detectable only within the initial 24hours after the i.v. infusion of VB-111. All of the bloodsamples were found to be negative for transgene expres-sion. One patient (01-036 with esophageal cancer) under-went a fine-needle aspiration from a subcutaneous metas-tasis on three separate occasions: predose and days 4 and28 after dosing. Although the predose sample was negative,detectable levels of transgene expression were found in the

Table 1. Demographics and baselinecharacteristics

N ¼ 33

Age, median (range), y 59 (35—77)GenderMale 17 (52%)Female 16 (48%)

Karnofsky, median (range) 90 (70–100)Tumor typeColorectal/adenocarcinoma 11Carcinoid/neuroendocrine 4NSCLC 3RCC 3Melanoma 2Sarcoma 2Thyroid 2Merkel cell 1Small cell lung 1Bladder/transitional cell 1Gastrointestinal stromal tumor 1Testicular/sex cord 1Esophageal adenocarcinoma 1

Treatment historySurgery 24 (73%)Radiotherapy 15 (45%)Chemotherapy 29 (88%)1 prior regimen 2 (6%)2 prior regimens 9 (6%)

�3 prior regimens 18 (55%)

Abbreviations: NSCLC, non–small cell lung cancer; RCC,renal cell carcinoma.






aspirate on days 4 (1.4� 105 copies/mg RNA) and 28 (3.9�104 copies/mg RNA) after treatment, representing a 72%reduction in the transgene expression over the two timepoints.

ImmunogenicityAll patients had predose antibodies to Ad-5. Postdose

total antibody titers to Ad-5 increased at least 5-fold; therewas no correlation between a higher IgG predose titer andhigher fold increase in level of IgG antibodies, and therewasno apparent relationship of dose administered to posttreat-ment antibody response, as shown in Fig. 2B.

Variability was observed in the level of neutralizingAd-5 antibodies at baseline: 7 of 33 (21.2%) patients hadhighly elevated baseline levels (>titer of 620), 13 of 33

(39.4%) patients had moderately elevated levels (>15 and�620), and 13 of 33 (39.4%) patients had low levels(�15). No correlation was observed between neutralizingantibody levels at baseline and disease state followingdrug administration (data not shown). Peak anti-Ad-5IgG titers were also not associated with preinfusion neu-tralization titer.

Cytokine and angiogenic biomarker responseConsiderable variability in cytokine/cytokine receptor

levels was observed in cytokine and angiogenic biomarkerresponses. An approximately 100-fold increase in IL-6occurred in cohort 6 patients at 6 hours postdosing, corre-lating with the fever that occurred in cohort 6 patients atthe same time. This elevation was transient, returning to

Table 2. Summary of adverse events

Cohorts 1–4(n ¼ 12) Cohort 5 (n ¼ 3) Cohort 6 (n ¼ 12) Cohort 7 (n ¼ 6) Total (N ¼ 33)

Adverse event Grade 1–2 Grade 3 Grade 1–2 Grade 3 Grade 1–2 Grade 3 Grade 1–2 Grade 3 Grade 1–2 Grade 3

Frequent drug-relatedadverse eventsNausea 0 0 0 0 2 0 2 0 4 0Chills 0 0 1 0 6 0 2 0 9 0Fever 1 0 2 0 9 0 5 1 18 1aPTT prolonged 0 0 0 0 3 0 0 0 3 0ALT increased 0 0 0 0 0 0 3 0 3 0AST increased 0 0 0 0 1 0 3 0 4 0Anorexia 0 0 1 0 2 0 0 0 3 0Dizziness 0 0 1 0 0 0 2 0 3 0Hyperhidrosis 0 0 0 0 3 0 0 0 3 0

Cohorts 1–4(n ¼ 12) Cohort 5 (n ¼ 3) Cohort 6 (n ¼ 12) Cohort 7 (n ¼ 6) Total (n ¼ 33)

All Related All Related All Related All Related All Related

All grade 3–4adverse eventsAbdominalpain/cramping

0 0 0 0 1 0 1 0 2 0

Asthenia 0 0 0 0 1 0 0 0 1 0Disease progression 1 0 0 0 0 0 0 0 1 0Fatigue 2 0 0 0 0 0 0 0 2 0Pyrexia 0 0 0 0 0 0 1 1 1 1LFT increase 0 0 0 0 1 0 0 0 1 0Hyperbilirubinemia 0 0 0 0 1 0 0 0 1 0Anemia 1 0 0 0 0 0 0 0 1 0Hemoglobin decreased 1 0 0 0 0 0 0 0 1 0Hyperglycemia 0 0 0 0 1 0 0 0 0 0Electrolyte disorders 5 0 0 0 1 0 0 0 6 0Spinal cord compression 0 0 0 0 0 0 1 0 1 0Suicidal ideation 0 0 0 0 1 0 0 0 1 0

NOTE: All events occurring in 3 or more patients and all grade 3–4 events.Abbreviation: LFT, liver function test.

Brenner et al.





preinfusion levels by day 4. Cohort 6 results also showedtransient but smaller increases in IL-8, sTNFR-1, and sTNFR-2levels at the 6-hour postdosing time point (P ¼ 0.006).There were small transient increases in sCD54 (P ¼ 0.03)and TNFR-2 (P ¼ 0.002) at several time points 28 days afterdosing in cohorts 6 and 7. Other cytokines assayed did notshow consistent or statistically significant changes from pre-to postinfusion at any of the time points assayed. Inadver-tently, cytokine data were not available 6 hours after dosingfor cohort 7 patients.

Overall survival, progression-free survival, and tumorresponse

Assessment of RECIST responses at day 28 indicated that17 of 32 (53%) patients in the entire study had stabledisease at day 28. Of these, 5 of 14 (35.7%) cohort 1 to5 patients had stable disease, compared with 12 of 18(66.7%) patients in cohorts 6 to 7, whereas at day 56, 12of 32 (37%) patients in the entire study had stable disease;of these, 3 of 14 (21.4%) patients in cohorts 1 to 5 and 9 of18 (50%) patients in cohorts 6 to 7 (Table 3, Fig. 3A and B).

Figure 2. A, pharmacokinetics:copies of Ad-5 DNA detected inwhole blood (mean) by treatmentcohort. Dose response shows atleast 2-log reduction in Ad-5 levelsby RT-PCR at day 56. B, levels ofanti-Ad-5 IgG postdosing, cohorts6–7. Levels reach a plateau at 14 to28 days, without apparent doseresponse.

A 1.00E+08

1.00E+07

1.00E+06

1.00E+05

1.00E+04

1.00E+03

1.00E+02

1.00E+01

1.00E+00PRE End 3HR 6HR Day 4

Anti-Ad5 IgG

1/titer

(mean)

Day0

100,000

10,000

1,000

100

107 14 28

Cohort 1

1e10 vp C1

3e10 vp C2

1e11 vp C3

3e11 vp C4

1e12 vp C5

3e12 vp C6

1e13 vp C7

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Cohort 6

Cohort 7

Day 7 Day 14 Day 28 Day 56

B






In a post hoc comparison between cohorts 1 to 5, 6, and 7,overall survival was greater in cohort 7: 187 days, 173 days,andnot reached, in cohorts 1 to 5, 6, and7, respectively (P¼0.012, Fig. 3C).Median time to progressionwas 31, 55, and121 days in cohorts 1 to 5, 6, and 7, respectively (P ¼0.24; Fig. 3D). In another post hoc exploratory analysis,overall survival was greater in cohort 7 (1� 1013 VPs) thanin cohorts 1 to6: 173days andnot reached, in cohorts 1 to6,and 7, respectively (P¼ 0.0098; Fig. 3E). Median follow-upin cohort 7 was 487 days (range, 122–599 days); 4 of 6

patients in cohort 7 remain alive to date. Median time toprogression was 34.5 and 121 days in cohorts 1 to 6 and 7,respectively (P ¼ 0.10; Fig. 3F).

One patient with metastatic papillary thyroid cancerwho was resistant to radioiodine was dosed in cohort 6.Baseline CT scan showed a mass lesion in the neck withpressure on the airway. Day 28 and 56 scans showedstable disease, and follow-up scans 6 and 12 months aftertreatment showed greater than 30% reduction in the longdiameter of the mass and no pressure on the airway, with

Table 3. Patient disease response

Individual patient data Cohort summary

Day 28 Day 56PFS OS

Cohort Patient Cancer type Day 28 Day 56 SD PD PR SD PD PR (median), mo (median), mo

1 01–001 Gastrointestinalstromal tumor

PD PD 1/3 (33%) 2/3 (67%) 0/3 (0%) 0/3 (0%) 2/3 (67%) 0/3 (0%) 1.0 3.9

01–002 Sarcoma SD LTFU01–003 Testicular/sex

cord carcinomaPD PD

2 01–004 TCC bladder PD PD 1/3 (33%) 2/3 (67%) 0/3 (0%) 0/3 (0%) 3/3 (100%) 0/3 (0%) 0.9 10.501–005 Sarcoma SD PD01–006 CRC PD PD

3 01–007 CRC SD SD 1/3 (33%) 2/3 (67%) 0/3 (0%) 1/3 (33%) 2/3 (66%) 0/3 (0%) 1.9 8.501–008 Melanoma PD PD01–009 NSCLC PD PD

4 01–010 CRC SD SD 1/3 (33%) 1/3 (33%) 0/3 (0%) 1/3 (33%) 1/3 (33%) 0/3 (0%) 0.9 3.702–013 CRC PD PD01–014 NSCLC LTFU LTFU

5 02–020 CRC PD PD 1/3 (33%) 2/3 (67%) 0/3 (0%) 1/3 (33%) 2/3 (67%) 0/3 (0%) 0.9 2.702–021 SCLC SD SD01–024 CRC PD PD

6 02–022 Carcinoid SD SD 8/12 (67%) 4/12 (33%) 0/12 (0%) 5/12 (42%) 6/12 (50%) 0/12 (0%) 1.8 5.802–025 Melanoma SD N/A02–026 Papillary thyroid

carcinomaSD SD

02–027 CRC PD PD02–028 CRC SD SD01–029 NET SD SD02–030 CRC SD SD02–032 RCC SD PD01–033 CRC PD PD02–035 Merkel cell

carcinomaSD PD

01–036 Esophagealcarcinoma

PD PD

01–038 CRC PD PD7 01–039 NET PD PD 4/6 (67%) 2/6 (33%) 0/6 (0%) 4/6 (67%) 2/6 (33%) 0/6 (0%) 4.0 16.2

02–040 Medullary thyroidcarcinoma

SD SD

01–041 NET SD SD01–042 NSCLC SD SD02–043 RCC SD SD02–044 RCC PD PD

Abbreviations: CRC, colorectal carcinoma; LTFU, lost to follow-up; NET, neuroendocrine tumor; NSCLC, non–small cell carcinoma;OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RCC, renal cell carcinoma; SCLC,small cell lung carcinoma; SD, stable disease; TCC, transitional cell carcinoma.

Brenner et al.





some central necrosis (Fig. 4). This patient received asecond dose of VB-111 (3 � 1012 VPs) following diseaseprogression after 18-month stability with VB-111; thepatient’s tumor remained stable 8 months after thesecond dose. Tumor marker responses were observed in2 patients: papillary thyroid cancer (thyroglobulin) andmedullary thyroid cancer (calcitonin).

DiscussionWe report results from a dose-escalation, first-in-human

trial of VB-111, an antiangiogenic gene therapeutic forsystemic administration, in 33 patients with refractorymetastatic cancers. VB-111 is based on transcriptional tar-geting of tumor endothelial cells. By means of a proprietaryPPE-1-3X promoter within a modified Ad-5 nonreplicatingvector, a suicide Fas-chimera transgene is selectivelyexpressed in tumor angiogenic endothelial cells, leading toapoptosis of angiogenic tumor vasculature.Currently approved antiangiogenic agents are based on

targeting mediators of angiogenesis involved in triggeringsignaling pathways that result in activation, proliferation,and migration of quiescent endothelial cells. The rationalefor transcriptional targeting of tumor endothelium is basedon advances in the understanding of the molecular biologyof angiogenesis (10). Thus, recent exploration of geneexpression patterns has shown that tumor-associatedendothelial cells are molecularly distinct from physiologicendothelial cells. These differences are thought to reflectunique availability of specific promoters with specific andtemporal combinations of transcription factors in thetumor angiogenic endothelial cells (11, 12). On the basisof such differences, it is conceivable to achieve specific andhigh transcription of therapeutic transgenes in the tumorendothelium.Indeed, more than 10 different endothelial cell–specific

promoters have been discovered and explored for transcrip-tional targeting of tumor angiogenesis in vitro and in vivo,with various degrees of success, including VEGF receptor 1(VEGFR-1), VEGFR-2, von Willebrand factor, and others(13,14). One of these promoters is PPE-1-3X, a modifiedpre-proendothelin promoter used inVB-111. The specificityof VB-111 toward the tumormicroenvironment, as well as arobust antitumor effect, has been shown in several animalmodels (3,4,6,8). It is the first agent of transcriptionaltargeting of the tumor endothelium to be tested in a clinicaltrial.In this phase I, single-dose clinical trial, VB-111 was

found to be safe and well-tolerated up to the maximumadministered single dose of 1 � 1013 VPs. MTD was notreached. There were no drug-related serious adverse events.A self-limited febrile reaction was frequent among patientsreceiving a dose of 1�1012VPs and above, as has previouslybeen described with adenovirus vectors (15). There was noevidence of significant hepatotoxicity, hypertension, bleed-ing or thrombosis. There were no infusion reactions, and allpatients remained hemodynamically stable. A transientincrease in IL-6 after infusion was observed; however, therewas no suggestion of a cytokine storm. As expected, most

patients had serologic evidence for prior exposure to ade-novirus, and titers of anti-adenovirus antibodies increasedafter infusion, reaching a plateau at 14 to 28 days. In thistrial, only predose samples were tested for neutralizingantibodies. Preliminary data from an ongoing phase II trialof VB-111 in patients with recurrent glioblastoma show apostdosing increase in Ad-5 neutralizing antibodies in all 5patients with available data (increased range, 36- to 2,000-fold). An increase in PTT levels after dosingwas seen in 12of33 patients, without any clinical sequelae. This finding islikely to be associated with a transient lupus anticoagulant(LAC), as was found subsequently in 4 patients enrolled infurther VB-111 cancer trials. A similar phenomenon haspreviously been reported after adenovirus infections (16),as well as with other virotherapeutic agents based on Ad-5vectors (17); for example, 6 of 11 patients developedtransient prolongation of PTT and LAC positivity withanother antitumor Ad-5–based agent in a prostate cancertrial. There too, no clinical adverse events of bleeding orthrombosis had occurred.

This favorable safety and tolerability profile is attribut-able to the selective expression of the chimeric TNFR/Fastransgene in the tumor environment, coupled with thesafety and tolerability of the Ad-5 vector. The adenoviralvector is stable in vivo and is an efficient gene delivery vehiclethat rarely causes any significant disease by itself (14, 18); ithas been widely used without safety concern, includinglarge clinical trials of Ad-5–basedHIV vaccines (19). One ofthe limitations of gene therapy using the adenoviral vector isthe nonspecific expression of therapeutic genes in normalcells causing toxicity to noncancerous tissues. Targetedexpression of therapeutic genes is essential to prevent thistoxicity. The proprietary PPE-1-3X promoter restricts theexpression of the Fas-chimeric transgene to the angiogenicvasculature in the tumor environment, providing a safe-guard against unwanted expression in normal cells andtissues and allowing for systemic administration. TNF-a,which activates Fas-c in minimal quantities, is abundant inthe tumormicroenvironment and is sufficient to activate thegene. Findings reported in this phase I trial confirmed theselective expression of the chimeric transgene, as was pre-viously shown in animal models (3,6). Thus, transgene wasfound to be expressed in a subcutaneous metastasis follow-ing dosing andwas detectable by RT-PCRup to 28 days aftertherapy, whereas all whole blood samples were negative fortransgene expression for this index case as well as all othertreated patients.

Although efficacy was not a primary endpoint of thistrial, we found evidence of antitumor activity after asingle-dose administration as well as evidence of a doseresponse. One patient (with papillary thyroid carcinoma)developed a partial response at 6 months, which persistedfor 18 months after dosing. In an exploratory post hocanalysis, a statistically significant increase was seen inoverall survival in cohort 7 (1 � 1013 VPs) compared withlower doses (cohorts 1–6; P ¼ 0.0098), as well as a trendtoward improved progression-free survival in this cohort(P ¼ 0.10). Four of 6 patients in cohort 7 remain alive,






with a median follow-up of 487 days. This dose responseis consistent with the results seen in the Lewis lungcarcinoma model, in which robust reduction in tumorburden was reached at a dose of 109 to 1011 VPs permouse (25 g), a dose/kg equivalent of 2.8 � 1012 to 2.8 �1014 VPs for an average 70-kg patient. Accordingly, wehypothesized that more potent antitumor activity wouldoccur in patients in cohort 7 (n¼ 6, 1� 1013 VPs), and wetherefore compared the outcomes of this cohort to thoseof cohorts 1 to 6 (n ¼ 27, doses of 1010 to 3 � 1012 VPs),who received subtherapeutic or borderline therapeuticdrug levels and served as an internal control. Thesefindings should be interpreted with caution consideringthat this is a single-arm trial in which the comparisons oftime-to-event endpoints in different non-prespecified end-points is exploratory and the outcome could be dependent

on differences in patient and tumor characteristics. Itshould be noted that all patients had advanced cancerwith evidence of recent progression. Also, all patients incohort 7 had tumor types that are known to be responsiveto antiangiogenics [2 cases of renal cell carcinoma (RCC),2 neuroendocrine tumors (NET), 1 medullary thyroid, and1 NSCLC]; however, 2 of them enrolled after failure ofprior antiangiogenic therapy.

The findings from this trial suggest a durable effect of VB-111 after a single administration. Pharmacokinetic find-ings show that presence of the Ad-5 in whole blooddeclines gradually after drug administration, reaching atleast 2-log decline 2 months after dosing. The durability ofthis effect may be explained by VB-111 transfection andactivation patterns. After the drug is infused, VB-111transfects many tissues, including quiescent endothelial

A

C

B Cohort 6–7 (n = 18):9 /18 (50%)

Cohorts 1–5 (n = 15, 14 evaluable):3/14 (21%)

Day 28Day 0

SD

PD*

RE

CIS

T s

co

reP

rob

ab

ility

120

100

80

60

40

20

0

–20

–40

1.0

0.8

0.6

0.4

0.2

0.0

120

100

80

60

40

20

0

–20

–40

Day 56 Day 28Day 0 Day 56

*RECIST score > 20% or new lesions

0 200 400

Time to death (d)

Cohorts 1–5 Cohort 6 Cohort 7

600 800

+ Censored

1,000

Median overall survivalCohorts 1–5: 187 days

Cohort 6: 173 days

Cohort 7: Not reached

Median follow-up222 Days

Range: 25–1,044 days

Figure 3. Tumor response, overallsurvival, and progression-freesurvival. A, cohorts 1–5 tumorresponse at day 56. B, cohorts 6and 7 tumor response at day 56. C,overall survival: 187 versus 173days versus not reached in cohort1–5 versus 6 versus 7, respectively(P ¼ 0.012). (Continued on thefollowing page).

Brenner et al.





Figure 3. (Continued ) D, time toprogressive disease: 31 versus 55versus 121 days in cohort 1–5 versus6 versus 7, respectively (P¼ 0.24). E,overall survival in cohort 1–6 versus7: 173 days versus not reached(P ¼ 0.0098). F, time to progressivedisease in cohort 1–6 versus 7: 34.5vs. 121 days (P ¼ 0.10).

D

E

F

Pro

babili

tyP

rob

ab

ility

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

Pro

babili

ty

1.0

0.8

0.6

0.4

0.2

0.0

0 100 200 300 400 500

0 200 400 600 800 1,000

0 200 400 600 800 1,000

Time to death (d)

Cohorts 1–6 Cohort 7

Time to PD (d)

Cohorts 1–6 Cohort 7

Time to PD (d)

Cohorts 1–5 Cohort 7Cohort 6

+ Censored

+ Censored

Median time to PDCohorts 1–5: 31 days

Cohort 6: 55 days

Cohort 7: 121 days

Median overall survivalCohorts 1–6: 173 days

Cohort s7: Not reached

Median follow-up222 Days

Range: 25–1,044 days

Median time to PDCohorts 1–6: 34.5 days

Cohort 7: 121 days






cells; yet, at this stage, there is no transgene expression.Upon further tumor growth, there is induction of angio-genesis in these quiescent transfected endothelial cells,which may become activated, leading to transgene expres-sion and apoptosis.

The efficacy signal seen in this trial suggests primarily adisease stabilization effect of VB-111, rather than robusttumor regression. Similar effects have been seen with otherantiangiogenic agents such as bevacizumab and tyrosinekinase inhibitor (TKI) drugs (1,2). Moreover, in someindications (e.g., colorectal cancer, lung cancer, andothers),antiangiogenics were found to be efficacious only whencombined with cytotoxic agents. Currently available anti-angiogenic agents have several limitations due to primaryrefractoriness or development of resistance through a vari-ety of mechanisms and compromised tolerability and safe-ty, which are probably related to their effect on a variety oftargets associated with normal physiologic processes unre-lated to angiogenesis (1,20). The transcriptional targeting ofVB-111 limits effects to proliferating endothelial cells,enhancing the selectivity to the tumor microenvironment.By directing gene expression to angiogenic endothelial cells,this tissue-specific gene therapeutic may be less toxic tonormal tissues than TKIs and anti-VEGF antibodies. Target-ing of host cells rather than tumor cells provides an addi-tional measure against the development of resistance. Thehost endothelial cells have inherent genetic stability, with acentral role in the endothelin pathway.

A potential limitation of Ad-5 vector is the developmentof neutralizing antibodies (21). In the presence of suchantibodies, Ad-5 is cleared primarily by hepatic seques-tration (21). This may compromise efficacy amongpatients with prior exposure to adenovirus or upon repeatadministrations. Nevertheless, the target of VB-111 is theendothelial lining of the blood vessels, which is the firstcellular layer this agent will encounter after systemic i.v.administration. It is plausible that a first-pass effect withhigher local concentration of transduction at the endo-thelium may suffice for transfection of endothelial cells,even in the presence of neutralizing antibodies (22).In the current clinical trial, no relationship was seen

between prior levels of neutralizing antibodies and anti-tumor effects.

To conclude, we report results of a first-in-human clinicaltrial of VB-111, a novel viral therapy agent for systemicadministration, which targets tumor vasculature. Althoughseveral antitumor gene therapeutics have been explored, tothe best of our knowledge, this is the first clinical trial of agene therapeutic agent targeting tumor vasculature (13,18).This trial confirms preclinical findings in animal modelsand suggests targeted expression of the Fas-chimera trans-gene selectively in tumor vasculature. The drug showed afavorable safety and tolerability profile. Tumor activity wasshown. In a post hoc exploratory analysis, a dose responsewas seen, with greater overall survival at the highest doselevel cohort.

Now that safety has been established, VB-111 is beingevaluated to confirm its activity in further clinical trials, withrepeat dose administration in several indications, includingglioblastoma multiforme, differentiated thyroid cancer,NETs, and RCC.

Disclosure of Potential Conflict of InterestA. Brenner has a commercial research grant from and is a consultant/

advisory board member of Vascular Biogenics. Y.C. Cohen, E. Breitbart, L.Bangio, and D. Harats are employed by and have ownership interest inVBL Therapeutics. P. Triozzi has a commercial research grant from and isa consultant/advisory board member of VBL Therapeutics. No potentialconflicts of interest were disclosed by the other authors.

Authors' ContributionsConception and design: Y.C. Cohen, E. Breitbart, L. Bangio, F. Giles, E.Borden, P.L. TriozziDevelopmentofmethodology:Y.C.Cohen, E. Breitbart, L. Bangio, F.Giles,E. Borden, P.L. TriozziAcquisitionofdata (provided animals, acquired andmanagedpatients,provided facilities, etc.): A. Brenner, J. Sarantopoulos, F. Giles, E. Borden,P.L. TriozziAnalysis and interpretation of data (e.g., statistical analysis, biosta-tistics, computational analysis):A. Brenner, Y.C. Cohen, J. Sarantopoulos,F. Giles, P.L. TriozziWriting, review, and/or revision of the manuscript: A. Brenner, Y.C.Cohen, E. Breitbart, J. Sarantopoulos, F. Giles, E. Borden, D. Harats, P.L.TriozziAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): A. Brenner, Y.C. CohenStudy supervision: A. Brenner, Y.C. Cohen, J. Sarantopoulos, F. Giles, P.L.Triozzi

October 2008 - Baseline April 2009 - Six Months After VB-111

Figure 4. Partial response(RECIST criteria) in a patient withmetastatic papillary thyroidcancer, radioiodine resistant.At 6 months, there is a 30%reduction in the lesion diameter,central necrosis, and no pressureon trachea.

Brenner et al.





AcknowledgmentsThe authors thank the participating patients and their families for their

committment, and the study investigators for their invaluable contributionto this research. They also thank Andi Leubitz for editorial support.

Grant SupportThis study was sponsored by VBL Therapeutics.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received June 24, 2012; revised March 6, 2013; accepted March 10, 2013;published OnlineFirst April 15, 2013.

References1. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications

of angiogenesis. Nature 2011;473:298–307.2. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and develop-

ment of bevacizumab, an anti-VEGF antibody for treating cancer. NatRev Drug Discov 2004;3:391–400.

3. Greenberger S, Shaish A, Varda-Bloom N, Levanon K, Breitbart E,Goldberg I, et al. Transcription-controlled gene therapy against tumorangiogenesis. J Clin Invest 2004;113:1017–24.

4. Varda-BloomN,ShaishA,GonenA, LevanonK,Greenberger S, FerberS, et al. Tissue-specific gene therapy directed to tumor angiogenesis.Gene Ther 2001;8:819–27.

5. Boldin MP, Mett IL, Varfolomeev EE, Chumakov I, Shemer-Avni Y,Camonis JH, et al. Self-association of the "death domains" of the p55tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signalingfor TNF and Fas/APO1 effects. J Biol Chem 1995;270:387–91.

6. Harats D, Kurihara H, Belloni P, Oakley H, Ziober A, Ackley D, et al.Targeting gene expression to the vascular wall in transgenic miceusing the murine preproendothelin-1 promoter. J Clin Invest 1995;95:1335–44.

7. Brenner AJ, Rogge J, Cohen Y, Breitbart E, Bangio L. Antiangiogenicgene therapy with VB111 is active in glioblastoma xenografts[abstract]. In: Proceedings of the 102nd Annual Meeting of the Amer-ican Association for Cancer Research; 2011 Apr 2–6; Orlando, FL.Philadelphia (PA): AACR; 2011. Abstract nr 5400.

8. PeledM, Shaish A, Greenberger S, Katav A, Hodish I, Ben-Shushan D,et al. Antiangiogenic systemic gene therapy combined with doxoru-bicin administration induced caspase 8 and 9-mediated apoptosis inendothelial cells and an anti-metastasis effect. Cancer Gene Ther2008;15:535–42.

9. Breitbart E,CohenYC,BangioL.VB-111anovel anti-angiogenic vectorand a promising treatment for metastatic cancer in combination withother anticancer drugs [abstract]. In: Proceedings of the 102nd AnnualMeeting of the American Association for Cancer Research; 2011 April2–6; Orlando, FL. Philadelphia (PA): AACR; 2011. Abstract nr 3283.

10. Dong Z, Nor JE. Transcriptional targeting of tumor endothelial cells forgene therapy. Adv Drug Deliv Rev 2009;61:542–53.

11. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Mon-tgomery E, et al. Genes expressed in human tumor endothelium.Science 2000;289:1197–202.

12. Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St CroixB. Genes that distinguish physiological and pathological angiogene-sis. Cancer Cell 2007;11:539–54.

13. Liu Y, Deisseroth A. Tumor vascular targeting therapy with viralvectors. Blood 2006;107:3027–33.

14. Fukazawa T, Matsuoka J, Yamatsuji T, Maeda Y, Durbin ML, NaomotoY. Adenovirus-mediated cancer gene therapy and virotherapy(Review). Int J Mol Med 2010;25:3–10.

15. Pesonen S, Kangasniemi L, Hemminki A. Oncolytic adenoviruses forthe treatment of humancancer: focus on translational and clinical data.Mol Pharm 2011;8:12–28.

16. Uthman IW, Gharavi AE. Viral infections and antiphospholipid anti-bodies. Semin Arthritis Rheum 2002;31:256–63.

17. Malaeb BS, Gardner TA, Margulis V, Yang L, Gillenwater JY, ChungLW, et al. Elevated activated partial thromboplastin time during admin-istration of first-generation adenoviral vectors for gene therapy forprostate cancer: identification of lupus anticoagulants. Urology 2005;66:830–4.

18. Heilbronn R, Weger S. Viral vectors for gene transfer: current status ofgene therapeutics. Handb Exp Pharmacol 2010;143–70.

19. Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D,Gilbert PB, et al. Step Study Protocol Team. Efficacy assessment of acell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet2008;372:1881–93.

20. Cao Y, Langer R. Optimizing the delivery of cancer drugs that blockangiogenesis. Sci Transl Med 2010;2:15ps3.

21. Hall K, Blair Zajdel ME, Blair GE. Unity and diversity in the humanadenoviruses: exploiting alternative entry pathways for gene therapy.Biochem J 2010;431:321–36.

22. Driessen WH, Ozawa MG, Arap W, Pasqualini R. Ligand-directedcancer gene therapy to angiogenic vasculature. Adv Genet 2009;67:103–21.






2013;19:3996-4007. Published OnlineFirst April 15, 2013.Clin Cancer Res Andrew J. Brenner, Yael C. Cohen, Eyal Breitbart, et al. Virotherapy, in Patients with Advanced Solid TumorsPhase I Dose-Escalation Study of VB-111, an Antiangiogenic

Updated version

10.1158/1078-0432.CCR-12-2079doi:

Access the most recent version of this article at:

Cited articles

http://clincancerres.aacrjournals.org/content/19/14/3996.full#ref-list-1

This article cites 19 articles, 5 of which you can access for free at:

Citing articles

http://clincancerres.aacrjournals.org/content/19/14/3996.full#related-urls

This article has been cited by 1 HighWire-hosted articles. Access the articles at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected]

To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://clincancerres.aacrjournals.org/content/19/14/3996To request permission to re-use all or part of this article, use this link



http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-12-2079

http://clincancerres.aacrjournals.org/content/19/14/3996.full#ref-list-1

http://clincancerres.aacrjournals.org/content/19/14/3996.full#related-urls

http://clincancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://clincancerres.aacrjournals.org/content/19/14/3996


Phase I Dose-Escalation Study of VB-111, an Antiangiogenic ...istration, VB-111 can serve as a means...

Documents

Transcript of Phase I Dose-Escalation Study of VB-111, an Antiangiogenic ...istration, VB-111 can serve as a means...