A phase 1, multicenter, open-label study of the safety of two dose levels of a human monoclonal antibody to human αv integrins, intetumumab, in combination with docetaxel and prednisone in patients with castrate-resistant metastatic prostate cancer

Chu, Franklin; Picus, Joel; Fracasso, Paula M.; Dreicer, Robert; Lang, Zhihui; Foster, Brenda J.

doi:10.1007/s10637-010-9388-4

Cited by 28 publications

(25 citation statements)

References 15 publications

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“…We have previously shown that intetumumab is a potential radiation sensitizer when used in combination with fractionated radiation therapy in human cancer xenograft models in nude mice (5). Data from two multicenter clinical phase I studies in patients with advanced solid tumors have shown that intetumumab was safe and well tolerated either alone or in combination with docetaxel (6,7). Intetumumab is now in phase II clinical trials for the treatment of a variety of malignancies.…”

Section: Introductionmentioning

confidence: 99%

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

et al. 2010

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We previously reported that intetumumab (CNTO 95), a fully human anti-αv integrin monoclonal antibody, is a radiosensitizer in mice with xenograft tumors. Because intetumumab does not cross-react with mouse integrins, but has cross-reactivity with rat integrins, we next studied the potential combined use of radiation therapy and intetumumab in human cancer xenograft models in nude rats to assess effects on both tumor cells and the tumor microenvironment. Nude rats bearing human head and neck cancer and non-small cell lung cancer (NSCLC) xenografts were treated with intetumumab and fractionated local tumor radiotherapy. Effects on tumor growth and metastasis, blood perfusion, oxygenation, and gastrointestinal toxicity were studied. Intetumumab alone had a moderate effect on tumor growth. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone. Treatment with intetumumab also significantly reduced lung metastasis in the A549 NSCLC xenograft model. The oxygenation and blood perfusion in xenograft tumors measured by microbubble-enhanced ultrasound imaging were substantially increased after treatment with intetumumab. The combined use of intetumumab and radiation therapy reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. Toxicity studies showed that treatment with intetumumab did not cause the histopathologic changes in the lungs and did not sensitize the sensitive gastrointestinal epithelium to the effect of radiation therapy. Intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats without increased toxicity.

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Section: Introductionmentioning

confidence: 99%

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

et al. 2010

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“…14 Phase I clinical trials have been conducted, showing that it is well tolerated in patients with advanced solid tumors 17 and in hormone-refractory prostate cancer patients when administered with docetaxel and prednisone. 18 …”

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confidence: 99%

Expression of αV-Integrins in Uterine Serous Papillary Carcinomas; Implications for Targeted Therapy With Intetumumab (CNTO 95), a Fully Human Antagonist Anti-αV-Integrin Antibody

Bellone

Cocco

Varughese

et al. 2011

International Journal of Gynecological Cancer

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Objective Uterine serous papillary carcinoma (USPC) is an aggressive variant of endometrial cancer characterized by an innate resistance to chemotherapy and poor prognosis. In this study, we evaluated the expression of αV-integrins in primary USPC cell lines and the in vitro ability of intetumumab (CNTO 95), a fully human monoclonal antibody against αV-integrins, to inhibit USPC cell adhesion and migration. Materials and Methods The surface expression of integrins belonging to the αV-family, including αVβ3, αVβ5, and αVβ6, was evaluated in 6 primary USPC cell lines using flow cytometry analysis. To test the ability of intetumumab to inhibit USPC cell adhesion and migration, adhesion assays in the presence of vitronectin and migration assays through an 8.0-μm pore polycarbonate membrane also were performed. Results We found high expression of the αV-subunit on the cell surface of all 6 primary USPC cell lines tested (100% positive cells; mean fluorescence intensity range, 13.1–39.5). When the expression of single heterodimeric integrins was evaluated, αVβ3, αVβ5, and αVβ6 were expressed on 37.5%, 32.0%, and 16.3% of cells (mean fluorescence intensity range, 6.5–16.2, 9.2–32.5, and 6.2–11.5, respectively). Importantly, in functional assays, low doses of intetumumab were effective in inhibiting adhesion (0.15 μg/mL, P = 0.003) and migration (1.25 μg/mL P = 0.02) of primary USPC cell lines. Conclusions The αV-integrins are overexpressed on the cell surface of primary USPC cell lines. Intetumumab may significantly inhibit USPC cell adhesion and migration pathways and may therefore represent a novel treatment option for patients harboring this rare but highly aggressive variant of endometrial cancer.

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“…Other integrin inhibitors that have been studied in clinical trials in prostate cancer include cilengitide, intetumumab, and MK-0429 (36)(37)(38)(39)(40). These agents target various av integrins: cilengitide, integrins avb3 and avb5 (37); intetumumab, av integrins (38); and MK-0429, integrin avb3 (40).…”

Section: Discussionmentioning

confidence: 99%

“…These agents target various av integrins: cilengitide, integrins avb3 and avb5 (37); intetumumab, av integrins (38); and MK-0429, integrin avb3 (40). Both cilengitide and intetumumab were well tolerated, but there was no evidence of activity in phase II trials of these agents (36)(37)(38)(39). MK-0429 caused a reduction in bone turnover, leading the authors to hypothesize that it may have a role in the treatment of metabolic bone disease (40).…”

Section: Discussionmentioning

confidence: 99%

Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer

Hussain

Moulec

Gimmi

et al. 2016

Clinical Cancer Research

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on behalf of the PERSEUS Study Group Abstract Purpose: Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-av integrin inhibitor abituzumab in chemotherapy-na€ ve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.Experimental Design: PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS).Results: The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR ¼ 0.89; 95% confidence interval (CI), 0.57-1.39; abituzumab 1,500 mg, 4.3 months, HR ¼ 0.81; 95% CI, 0.52-1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms.Conclusions: Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancerassociated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192-200. Ó2016 AACR.

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A phase 1, multicenter, open-label study of the safety of two dose levels of a human monoclonal antibody to human αv integrins, intetumumab, in combination with docetaxel and prednisone in patients with castrate-resistant metastatic prostate cancer

Abstract: Intetumumab was generally safe and well tolerated in combination with docetaxel, with a higher incidence of TEAEs in the 10 mg/kg dose cohort. The efficacy of 10 mg/kg intetumumab in combination with docetaxel appears to warrant further study.

Cited by 28 publications

References 15 publications

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

Expression of αV-Integrins in Uterine Serous Papillary Carcinomas; Implications for Targeted Therapy With Intetumumab (CNTO 95), a Fully Human Antagonist Anti-αV-Integrin Antibody

Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer

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