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A Phase II Study of sEphB4-HSA in Metastatic Castration-Resistant Prostate Cancer

Open AccessPublished:September 07, 2022DOI:https://doi.org/10.1016/j.clgc.2022.08.012

      Abstract

      Introduction

      Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC).

      Patients and Methods

      We conducted a single arm, phase II trial in patients with progressive mCRPC who had received no more than 3 prior therapies for mCRPC. sEphB4-HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. The primary endpoint was confirmed prostate specific antigen (PSA) response rate. We employed a Simon 2-stage Minimax design with 15 patients in the first stage and 10 additional patients in the second stage.

      Results

      Fourteen eligible patients enrolled in the study with median age of 73.5 years (range: 52-83) and median baseline PSA of 65.11 ng/mL (range: 7.77-2850 ng/mL). Most patients received 3 prior therapies for mCRPC. The median treatment duration with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks). Three patients experienced a serious adverse event potentially related to therapy, including 1 patient with a grade 5 event (cerebral vascular accident) possibly related to the study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression. The median time to PSA progression was 28 days (90% CI: 28-42 days), and median time to radiologic progression was 55 days (90% CI: 54-72 days). Of 3 patients with measurable disease, 2 had stable disease and one had progressive disease.

      Conclusion

      In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity.

      Keywords

      Introduction

      Research investigating active pathways in aggressive cancers has identified Ephrins and their receptors (receptor tyrosine kinases) as potential targets for therapy in advanced cancers, including advanced or aggressive prostate cancer.
      • Boyd AW
      • Bartlett PF
      • Lackmann M.
      Therapeutic targeting of EPH receptors and their ligands.
      Ephrin receptors and their membrane-localized ligands induce bidirectional signaling with downstream effects on several pathways, including MAPK, PI3K/AKT, and VEGF. EphB4 interacts with the PI3K/AKT and MAPK pathways, which modulate androgen receptor (AR) signaling.
      • Boyd AW
      • Bartlett PF
      • Lackmann M.
      Therapeutic targeting of EPH receptors and their ligands.
      ,
      • Karantanos T
      • Corn PG
      • Thompson TC.
      Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches.
      Dysregulation of the Ephrin/Eph receptor pathway in prostate cancer cells can promote cell migration, invasion, and metastases.
      • Wang B.
      Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales of unwitting partners.
      EphB4 expression is induced in many epithelial cancers. For example, EphB4 is not expressed in normal bladder and colon, but it is highly expressed in bladder and colon tumors.
      • Li X
      • Choi WW
      • Yan R
      • et al.
      The differential expression of EphB2 and EphB4 receptor kinases in normal bladder and in transitional cell carcinoma of the bladder.
      ,
      • Stephenson S-A
      • Slomka S
      • Douglas EL
      • Hewett PJ
      • Hardingham JE.
      Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer.
      Expression of EphB4 protein is increased in most prostate cancers and is retained after exposure to ADT, but it is not commonly expressed in benign prostate tissue. In 1 study, 66% of prostate tumors analyzed had increased EphB4 protein expression, compared to 15% of benign prostate tissue.
      • Xia G
      • Kumar SR
      • Masood R
      • et al.
      EphB4 expression and biological significance in prostate cancer.
      ,
      • Lee Y-C
      • Perren JR
      • Douglas EL
      • et al.
      Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma.
      EphB4 is induced by molecular alterations implicated in CRPC development, including loss of tumor suppressors PTEN and TP53 and activation of the PI3K pathway.
      • Xia G
      • Kumar SR
      • Masood R
      • et al.
      EphB4 expression and biological significance in prostate cancer.
      The genomic signature of MYC activation, PTEN loss, and TP53 loss in prostate cancer has been associated with aggressive disease as demonstrated by a shorter time to disease relapse after primary treatment and increased risk of death.
      • Markert EK
      • Mizuno H
      • Vazquez A
      • Levine AJ.
      Molecular classification of prostate cancer using curated expression signatures.
      Accordingly, EphB4 expression is associated with worse survival in patients with prostate cancer, and its inhibition induces prostate cancer cell death through an immunogenic mechansim.
      • Sagar V
      • Vatapalli R
      • Lysy B
      • et al.
      EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells.
      The soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) is a fully human fusion protein with a soluble EphB4 extracellular domain that specifically binds EphrinB2.
      • Shi S
      • Liu J
      • Joshi SB
      • Krasnoperov V
      • Gill P
      • Middaugh CR
      • et al.
      Biophysical characterization and stabilization of the recombinant albumin fusion protein sEphB4-HSA.
      sEphB4-HSA blocks EphB4 binding to EphrinB2-expressing cells, EphrinB2-induced EphB4 phosphorylation, and EphB4-induced EphrinB2 phosphorylation. As a result, sEphB4-HSA inhibits EphB4-EphrinB2-mediated bidirectional signaling, leading to inhibited endothelial invasion, binding to extracellular matrix proteins, and tube formation at low nanomolar concentrations.
      • Kertesz N
      • Krasnoperov V
      • Reddy R
      • et al.
      The soluble extracellular domain of EphB4 (sEphB4) antagonizes EphB4-EphrinB2 interaction, modulates angiogenesis, and inhibits tumor growth.
      In in vivo models of prostate cancer, EphB4 stimulates AR by inducing cMyc expression, and inhibiting EphB4 re-sensitizes prostate cancer cells to enzalutamide both in vitro and in vivo.
      • Li C
      • Lanman NA
      • Kong Y
      • et al.
      Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance.
      sEphB4-HSA has shown safety and tolerability in a first-in-human phase I trial of 70 patients with advanced solid tumors. It was tolerated well at a dose of 10 mg/kg weekly, and there were no grade 4 or 5 treatment-related adverse events. The only grade 3 treatment related adverse event in more than 1 patient was hypertension (41%). Four of 70 patients had a partial or complete response, and 50% showed stable disease.
      • El-Khoueiry A
      • Gitlitz B
      • Cole S
      • et al.
      17 - A first-in-human phase I study of sEphB4-HSA in patients with advanced solid tumors with expansion at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).
      Several patients received 4 to 11 months of therapy, which is indicative of safety when used for prolonged duration. Given these encouraging safety data and preclinical efficacy in prostate cancer models, we conducted a phase II trial of sEphB4-HSA monotherapy in patients with advanced prostate cancer.

      Patients and Methods

      Patient Eligibility

      Eligible patients had to have pathologic diagnosis of prostate cancer, be 18 years or older and have an ECOG performance status of 2 or better. Patients were required to have prostate cancer that was progressing despite castrate levels of testosterone. All patients were continued on androgen deprivation therapy. Patients had to have progressed on at least 1 second-generation AR targeted therapy for CRPC and received no more than 3 prior treatment therapies for mCRPC. Patients were excluded if they had inadequate organ function (ANC <1000, hemoglobin <9 g/dL, creatinine clearance <30 mL/minute, bilirubin >1.5x the upper limit of normal (ULN), or AST or ALT > 3x ULN); had known active CNS metastases, small cell carcinoma, uncontrolled intercurrent illness, uncontrolled hypertension, a prolonged QTc, or any active other malignancy; or had undergone major surgery or radiotherapy within 14 days of starting the study treatment. All patients signed an informed consent to participate in the study. The study was approved by the Internal Review Board of Northwestern University.

      Trial Design and Therapy

      This was a single-arm study evaluating the efficacy, safety, and tolerability of sEphB4-HSA in patients with mCRPC. The study was approved by the Northwestern University Internal Review Board (NU 18U10) and was conducted in accordance with the Declaration of Helsinki. It was registered with clinicaltrials.gov (NCT04033432).
      Enrolled patients continued androgen deprivation therapy and received sEphB4-HSA as a 1000mg IV infusion over 60 minutes every 2 weeks on day 1 of each cycle. The duration of cycles 1-6 was 14 days. Cycles 7 and beyond were 21 days in length. Patients were premedicated with diphenhydramine and acetaminophen. Dose reductions were allowed to 750 mg or 500 mg.
      Patients were allowed to continue to receive sEphB4-HSA treatment until no longer clinically benefiting (per Prostate Cancer Working Group 3 (PCWG3) criteria), unacceptable toxicity, treatment delay ≥4 weeks, prohibitive illness/change in patient's condition, or the patient decided to withdraw from study.

      End Points

      The primary objective was to estimate the efficacy of sEphB4-HSA in patients with mCRPC, and the primary endpoint was confirmed PSA response rate defined as 50% or greater reduction in PSA. All patients who received at least 1 dose of the study drug and who also had a follow-up PSA test conducted prior to initiating subsequent therapy were considered evaluable for PSA response.
      Secondary endpoints included time to PSA progression, the objective response rate in patients with measurable disease, and radiological progression free survival using RECIST 1.1 (for soft tissue) and PCWG3 criteria for bone lesions.
      • Scher HI
      • Morris MJ
      • Stadler WM
      • Higano C
      • Basch E
      • Fizazi K
      • et al.
      Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3.
      ,
      • Eisenhauer EA
      • Therasse P
      • Bogaerts J
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      Patients with measurable disease at baseline were considered evaluable for objective response. The first imaging evaluation was after 4 cycles (8 weeks), and subsequent imaging assessments were every 12 weeks. An additional secondary endpoint was the safety and tolerability of sEphB4-HSA according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

      Immunohistochemistry

      Immunohistochemistry was performed as previously described.
      • Carneiro BA
      • Pamarthy S
      • Shah AN
      • et al.
      Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib.
      Sections were stained with EphrinB2 antibody (Abcam, ab131536). Biotinylated secondary antibody (Vector Lab) was used followed by incubation with ABC reagent (Vector Lab). Sections were counterstained with hematoxylin (Vector Laboratories), dehydrated, and mounted (Dako glycergel mounting medium).

      Statistical Analysis

      To estimate preliminary efficacy, the trial assessed PSA response rate with a Simon 2-stage Minimax design. It assumed the null response rate to be 10% or less with the alternate hypothesis suggesting success to be 30% or more. With this design, 15 patients were to be enrolled in the first stage. If 2 or more responses were seen, then an additional 10 patients would be added for a total of 25 evaluable patients. This design had a Type I error rate of less than 5% and power of 80%. It had a 55% chance of stopping early after the first stage if the true response rate was 10% or less. No responses were seen in the first 14 patients, so the study was stopped after the first stage. Time to event was estimated using the method of Kaplan-Meier, and confidence intervals (CI) were based on the log-log (log cumulative hazard) transformation.

      Results

      Between September 26, 2019, and November 30, 2020, 16 patients were screened, of which 14 eligible patients enrolled in the study and received sEphB4-HSA 1000 mg IV day 1 of each cycle. Patients’ baseline characteristics are outlined in Table 1. Enrolled patients had received a median of 3 prior therapies (range: 1-3) for mCRPC. Ten patients received prior taxane for mCRPC or hormone sensitive prostate cancer.
      Table 1Baseline Demographics
      CharacteristicN = 14
      Median (Range); n (%)
      Age (Years)73.5 (52, 83)
      Race
       Asian1 (7.1%)
       Black1 (7.1%)
       White12 (86%)
      ECOG Performance Status Score
       04 (29%)
       110 (71%)
      Number of Prior Therapies for mCRPC
       11 (7.1%)
       22 (14%)
       311 (79%)
      Prior AR Pathway Inhibitor
       14 (29%)
       210 (71%)
      Prior Taxane for mCRPC9 (64%)
      Prior Taxane for mHSPC3 (21%)
      a Median (Range); n (%)

      Efficacy

      No patient achieved a confirmed PSA response, which was the primary endpoint (Figure 1). The study was stopped for futility after 14 evaluable patients did not have a PSA response. Thirteen patients had PSA progression (>25% increase in PSA), and 1 patient withdrew from treatment after having a stable PSA for 5 weeks. Of 3 patients with measurable disease evaluable for response, 2 had stable disease and 1 had progressive disease.
      Figure 1
      Figure 1PSA response. Waterfall plot of best PSA response following treatment with sEphB4-HSA
      The median time to PSA progression was 28 days (90% CI: 28-42 days) (Figure 2). The median length of treatment with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks) (Figure 3) . The median radiographic progression free survival was 55 days (90% CI 54– 72 days).
      Figure 2
      Figure 2Time to PSA progression. Kaplan-Meier curve of time to PSA progression, with 90% confidence intervals and number at-risk for each timepoint
      Figure 3
      Figure 3Duration of therapy. The duration of therapy is shown on the bar graph. The median duration was 6.5 weeks

      Safety

      The potentially treatment-related adverse events (AEs) that occurred in 3 or more patients were hypertension (10 patients); fatigue (7 patients); and AST increased, platelet count decreased, and pruritus (3 patients each). There were 6 serious adverse events considered to be potentially related to therapy (Table 2). These included a grade 5 thromboembolic cerebral vascular accident in a patient with history of atrial fibrillation.
      Table 2Table of Serious Adverse Events Potentially Related to Therapy
      Serious Adverse Event TypeGrade 1-2Grade 3Grade 5
      Fatigue01 (7.1%)0
      Generalized muscle weakness01 (7.1%)0
      Infusion related reaction01 (7.1%)0
      Myocardial infarction01 (7.1%)0
      Stroke001 (7.1%)
      Transient ischemic attacks1 (7.1%)00

      EphrinB2 Expression

      Four patients had tissue available that was evaluable for EphrinB2 expression. Of the 4 patients, 2 were positive for expression of EphrinB2 (Figure 4). The duration of treatment was 3 weeks among patients whose tumor expressed Ephrin B2 and 8 weeks among patients that did not express Ephrin B2.
      Figure 4
      Figure 4EphrinB2 staining tumor tissue from 2 patients (01-01-10, 01-01-12) expressed significant levels of EphrinB2 (seen as red stain), and tissue from 2 patients (01-01-04, 01-01-06) did not significantly express EphrinB2. There was no indication of increased efficacy in patients whose tumors expressed EphrinB2. Images were visualized at × 20 and the scale bar represents 100 µm

      Discussion

      Metastatic castration resistant prostate cancer continues to be deadly despite the significant progress that has been made over the past decade, with the development and approval of several new therapies for this state of disease.
      • Schaeffer E
      • Srinivas S
      • et al.
      NCCN guidelines insights: prostate cancer, version 1.2021.
      These generally fall into a limited number of categories, however, including AR pathway inhibitors, taxanes, radiopharmaceuticals, and biomarker-driven therapy for patients with DNA repair deficiency.
      Preclinical data indicated the tumor-stroma interactions that are mediated by Ephrins and Eph receptors are a potential novel target. The bidirectional signaling mediated by these molecules interacts with several well-known cancer signaling pathways, including PI3K/AKT and MAPK pathways, and is thought to regulate migration, invasion, and metastases.
      • Boyd AW
      • Bartlett PF
      • Lackmann M.
      Therapeutic targeting of EPH receptors and their ligands.
      Previous work in prostate cancer clinical models demonstrated efficacy of targeting EphB4 in enzalutamide-resistant cancers.
      • Li C
      • Lanman NA
      • Kong Y
      • et al.
      Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance.
      Based on this and other preclinical data, we carried out this phase II trial, seeking to expand therapeutic options to a new category of therapies. Unfortunately, we did not find any evidence of anti-tumor activity with sEphB4-HSA monotherapy in advanced prostate cancer. Three patients had potential thrombotic events (1 each myocardial infarction, stroke, and transient ischemic attack). Though there is known cross-talk between Eph/ephrin pathways and thrombotic pathways,
      • Prévost N
      • Woulfe DS
      • Jiang H
      • et al.
      Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets.
      we are not aware of a clear link between EphB4 signaling and thrombosis. In another clinical trial 2 of 70 patients suffered a stroke,
      • Sadeghi S
      • Quinn D
      • Dorff T
      • et al.
      EphrinB2 inhibition and pembrolizumab in metastatic urothelial carcinoma.
      making this an adverse event deserving special attention in future studies.
      There are several limitations to our study. First, our primary endpoint was PSA response. For a therapy that blocks tumor-stroma interactions, it may be better to evaluate inhibition of further spread with radiographic progression free survival rather than decline in PSA. Evaluating PSA response allows an earlier evaluation of response, however, and can evaluate for actual response instead of stability of indolent disease. Moreover, the primary per-protocol indication to withdraw from therapy was clinical or objective disease progression, and the median time on treatment was just 6.5 weeks. The early halting of therapy suggests there was not a significant effect on controlling disease that was not captured by PSA.
      Another limitation is lack of biomarker selection for EphrinB2 expression and lower-than-expected expression in tissue evaluated – only 50% of 4 evaluated samples had significant expression of EphrinB2. Of patients with evaluable tissue, however, the duration of therapy for patients with high EphrinB2 expression was shorter than those with low EphrinB2 expression, suggesting that biomarker selection would not have improved response rates.
      Therapy with sEphB4-HSA has demonstrated efficacy in other solid tumors: in urothelial cancer, where it yields a 38% response rate when given in combination with pembrolizumab that, unlike in our study, is enhanced among patients with high EphrinB2 expression (58%)
      • Sadeghi S
      • Quinn DI
      • Dorff T
      • et al.
      651O Phase II trial of pembrolizumab (P) in combination with sEphB4-HSA (B4) in previously treated metastatic urothelial carcinoma (mUC).
      , and in pancreatic and biliary cancers when given in combination with cytotoxic therapy, yielding 48% and 61% disease control rates, respectively.
      • Hanna DL
      • Iqbal S
      • Habib D
      • et al.
      A phase Ib study of sEphB4-HSA combined with first-line chemotherapy in patients (pts) with advanced pancreatic (PC) and biliary cancers (BC).
      When used as monotherapy for hepatocellular carcinoma and cholangiocarcinoma, just 1 (3%) partial response was seen.
      • Thomas JS
      • Lenz H-J
      • Iqbal S
      • et al.
      A first-in-human phase I study of sEphB4-HSA (sEphB4) with expansion in hepatocellular (HCC) and cholangiocarcinoma (CCA).
      Future studies with sEphB4-HSA should focus on combination therapy, based on preclinical and clinical data suggesting that enzalutamide
      • Li C
      • Lanman NA
      • Kong Y
      • et al.
      Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance.
      and immunotherapeutics
      • Sagar V
      • Vatapalli R
      • Lysy B
      • et al.
      EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells.
      ,
      • Sadeghi S
      • Quinn DI
      • Dorff T
      • et al.
      651O Phase II trial of pembrolizumab (P) in combination with sEphB4-HSA (B4) in previously treated metastatic urothelial carcinoma (mUC).
      are potential promising combination agents.

      Conclusion

      Despite promising preclinical data, in this phase II trial of sEphB4-HSA monotherapy in patients with advanced prostate cancer there was no discernable anti-tumor activity. Future studies should focus on use of sEphB4-HSA in combination with other therapy. Though sEphB4-HSA was generally tolerable, 3 patients experienced serious vascular adverse events. Though vascular events were observed at low rates in other clinical studies of sEphB4-HSA, this may represent a new safety signal.

      Clinical Practice Points

      • What is already known about this subject? The Ephrin-Eph Receptor pathway activates many downstream pathways important for cancer and inhibiting this pathway genomically or with an inhibitor leads to prostate cancer cell death. In a phase I study blocking this pathway using soluble EphB4 conjugated to human serum albumin (sEphB4-HSA) was well tolerated and had clinical benefit across multiple tumor types.
      • What are the new findings? In this single arm, phase II trial in patients with progressive metastatic castration resistant prostate cancer (mCRPC), sEphB4-HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. None of the 14 patients enrolled in the study had a confirmed PSA response, and the median length of treatment was 6.5 weeks (range: 2-35 weeks).
      • How might it impact on clinical practice in the foreseeable future? In patients with mCRPC, sEphB4-HSA monotherapy had no discernable anti-tumor activity. In recent studies of gastrointestinal tumors monotherapy was associated with low response rates. Future studies with sEphB4-HSA should focus on combination therapy.

      Authors’ contributions

      DVW: Data curation, formal analysis, investigation, original draft, review and editing. MK: Formal analysis, methodology, supervision, review and editing. SM: Data curation, formal analysis, visualization, review and editing. BM: Data curation, investigation, review and editing. VS: Investigation, visualization, review and editing. AM: Data curation, investigation, review and editing. WS: Data curation, investigation, supervision, review and editing. SA: Conceptualization, funding acquisition, methodology, resources, supervision, review and editing. MH: Conceptualization, study design, data curation, funding acquisition, investigation, methodology, project administration, resources, supervision, review and editing

      Acknowledgments

      The authors thank all the patients, their families, and caregivers for their participation in this trial. This trial was funded by the National Cancer Institute through a Special Program Of Research Excellence (SPORE) grant for prostate cancer (NCI grant P50 CA180995 ). The funder had no role in the conduct of the research or the preparation for publication.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      REFERENCES

        • Boyd AW
        • Bartlett PF
        • Lackmann M.
        Therapeutic targeting of EPH receptors and their ligands.
        Nat Rev Drug Discov. 2014; 13: 39-62
        • Karantanos T
        • Corn PG
        • Thompson TC.
        Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches.
        Oncogene. 2013; 32: 5501-5511
        • Wang B.
        Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales of unwitting partners.
        Sci Signal. 2011; 4: pe28
        • Li X
        • Choi WW
        • Yan R
        • et al.
        The differential expression of EphB2 and EphB4 receptor kinases in normal bladder and in transitional cell carcinoma of the bladder.
        PLOS ONE. Public Library Sci. 2014; 9e105326
        • Stephenson S-A
        • Slomka S
        • Douglas EL
        • Hewett PJ
        • Hardingham JE.
        Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer.
        BMC Mol Biol. 2001; 2: 15
        • Xia G
        • Kumar SR
        • Masood R
        • et al.
        EphB4 expression and biological significance in prostate cancer.
        Cancer Res. 2005; 65: 4623-4632
        • Lee Y-C
        • Perren JR
        • Douglas EL
        • et al.
        Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma.
        BMC Cancer. 2005; 5: 119
        • Markert EK
        • Mizuno H
        • Vazquez A
        • Levine AJ.
        Molecular classification of prostate cancer using curated expression signatures.
        Proc Natl Acad Sci U S A. 2011; 108: 21276-21281
        • Sagar V
        • Vatapalli R
        • Lysy B
        • et al.
        EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells.
        Cell Death Dis. 2019; 10: 801
        • Shi S
        • Liu J
        • Joshi SB
        • Krasnoperov V
        • Gill P
        • Middaugh CR
        • et al.
        Biophysical characterization and stabilization of the recombinant albumin fusion protein sEphB4-HSA.
        J Pharm Sci. 2012; 101: 1969-1984
        • Kertesz N
        • Krasnoperov V
        • Reddy R
        • et al.
        The soluble extracellular domain of EphB4 (sEphB4) antagonizes EphB4-EphrinB2 interaction, modulates angiogenesis, and inhibits tumor growth.
        Blood. 2006; 107: 2330-2338
        • Li C
        • Lanman NA
        • Kong Y
        • et al.
        Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance.
        J Biol Chem. 2020; 295: 5470-5483
        • El-Khoueiry A
        • Gitlitz B
        • Cole S
        • et al.
        17 - A first-in-human phase I study of sEphB4-HSA in patients with advanced solid tumors with expansion at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).
        Eur J Cancer. 2016; 69: S11
        • Scher HI
        • Morris MJ
        • Stadler WM
        • Higano C
        • Basch E
        • Fizazi K
        • et al.
        Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3.
        J Clin Oncol. 2016; 34: 1402-1418
        • Eisenhauer EA
        • Therasse P
        • Bogaerts J
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Carneiro BA
        • Pamarthy S
        • Shah AN
        • et al.
        Anaplastic lymphoma kinase mutation (ALK F1174C) in small cell carcinoma of the prostate and molecular response to alectinib.
        Clin Cancer Res. 2018; 24: 2732-2739
        • Schaeffer E
        • Srinivas S
        • et al.
        NCCN guidelines insights: prostate cancer, version 1.2021.
        J Natl Compr Canc Netw. 2021; 19: 134-143
        • Prévost N
        • Woulfe DS
        • Jiang H
        • et al.
        Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets.
        Proc Natl Acad Sci. 2005; 102: 9820-9825
        • Sadeghi S
        • Quinn D
        • Dorff T
        • et al.
        EphrinB2 inhibition and pembrolizumab in metastatic urothelial carcinoma.
        JCO. Wolters Kluwer;. 2022; (JCO.21.02923)
        • Sadeghi S
        • Quinn DI
        • Dorff T
        • et al.
        651O Phase II trial of pembrolizumab (P) in combination with sEphB4-HSA (B4) in previously treated metastatic urothelial carcinoma (mUC).
        Annals of Oncology. 32. Elsevier, 2021: S678
        • Hanna DL
        • Iqbal S
        • Habib D
        • et al.
        A phase Ib study of sEphB4-HSA combined with first-line chemotherapy in patients (pts) with advanced pancreatic (PC) and biliary cancers (BC).
        JCO. Wolters Kluwer;. 2020; 38: 4640
        • Thomas JS
        • Lenz H-J
        • Iqbal S
        • et al.
        A first-in-human phase I study of sEphB4-HSA (sEphB4) with expansion in hepatocellular (HCC) and cholangiocarcinoma (CCA).
        JCO. Wolters Kluwer;. 2018; 36: e16136