Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer

Ogita, Shin; Tejwani, Sheela; Heilbrun, Lance K.; Fontana, Joseph A.; Heath, Elisabeth I.; Freeman, Stacy; Smith, Daryn; Baranowski, Karen; Vaishampayan, Ulka N.

doi:10.5402/2012/242850

Cited by 13 publications

(14 citation statements)

References 26 publications

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“…In sharp contrast, prostate carcinomas, with a rather low TP53 mutation frequency (approximately 11%; ref. 19), failed to demonstrate benefit from bevacizumab (20).…”

Section: Resultsmentioning

confidence: 99%

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Schwaederlé¹,

Lazar

Validire³

et al. 2015

Cancer Research

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Bevacizumab is one of the most widely used antiangiogenic drugs in oncology, but the overall beneficial effects of this VEGF-A targeting agent are relatively modest, in part due to the lack of a biomarker to select patients most likely to respond favorably. Several molecular aberrations in cancer influence angiogenesis, including mutations in the tumor suppressor gene TP53, which occur frequently in many human malignancies. In this study, we present a multiple regression analysis of transcriptomic data in 123 patients with non-small cell lung cancer (NSCLC) showing that TP53 mutations are associated with higher VEGF-A expression (P ¼ 0.006). This association was interesting given a recent retrospective study showing longer progression-free survival in patients with diverse tumors who receive bevacizumab, if tumors harbor mutant TP53 instead of wild-type TP53. Thus, our current findings linking TP53 mutation with VEGF-A upregulation offered a mechanistic explanation for why patients exhibit improved outcomes after bevacizumab treatment when their tumors harbor mutant TP53 versus wild-type TP53. Overall, this work warrants further evaluation of TP53 as a ready biomarker to predict bevacizumab response in NSCLC and possibly other tumor types. Cancer Res; 75(7);

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“…In sharp contrast, prostate carcinomas, with a rather low TP53 mutation frequency (approximately 11%; ref. 19), failed to demonstrate benefit from bevacizumab (20).…”

Section: Resultsmentioning

confidence: 99%

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Schwaederlé¹,

Lazar

Validire³

et al. 2015

Cancer Research

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“…High blood pressure appeared to be dose dependent and predominantly driven by the systemic vanucizumab-mediated VEGF-A inhibition. Across clinical studies, the frequency of G3/4 hypertension is 9%-32% with bevacizumab monotherapy (21)(22)(23)(24)(25) but 6% for single-agent Ang-1/2 antagonists (26)(27)(28)(29)(30)(31)(32)(33). Moreover, hypertension rates with bevacizumab treatment did not increase by concurrent inhibition of the Ang/ Tie-2 signaling pathway in patients with metastatic breast cancer [39%-40% (G!3: 18%-23%) compared with 38% (G!3: 19%) without concurrent Ang/Tie-2 inhibition; ref.…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors

Hidalgo

Martinez-García

Tourneau

et al. 2018

Clinical Cancer Research

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Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. .

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“…The use of anti-VEGF therapies in preclinical and clinical studies has been associated with increased side effects, including hypertension, gastrointestinal bleeding, intestinal perforation, and pulmonary embolism (Mangoni et al 2012, Ogita et al 2012. Although bevacizumab has shown some promise with improved progression-free survival, no significant improvement in overall survival has been achieved even in combination therapies (reviewed by Small & Oh (2012) and Armstrong et al (2013)).…”

Section: Anti-vegf Signaling Therapies In the Clinical Management Of Pcamentioning

confidence: 99%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to w30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically %24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling.

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Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer

Cited by 13 publications

References 26 publications

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors

Regulation of vascular endothelial growth factor in prostate cancer

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