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      A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies

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          Abstract

          Purpose:

          AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers.

          Patients and Methods:

          A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m 2, BEV 30–70 mg/m 2). Pharmacokinetic analyses were performed.

          Results:

          No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m 2, BEV 60 mg/m 2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies.

          Conclusions:

          The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m 2, BEV 60 mg/m 2).

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          Most cited references44

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          Delivering nanomedicine to solid tumors.

          Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.
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            Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.

            In platinum-resistant ovarian cancer (OC), single-agent chemotherapy is standard. Bevacizumab is active alone and in combination. AURELIA is the first randomized phase III trial to our knowledge combining bevacizumab with chemotherapy in platinum-resistant OC. Eligible patients had measurable/assessable OC that had progressed two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end point was progression-free survival (PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < .001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = .001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients. Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.
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              Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240)

              On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events.
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                Author and article information

                Journal
                Clin Cancer Res
                Clin Cancer Res
                Clinical Cancer Research
                American Association for Cancer Research
                1078-0432
                1557-3265
                14 June 2024
                26 March 2024
                : 30
                : 12
                : 2623-2635
                Affiliations
                [1 ]Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
                [2 ]Department of Immunology, Mayo Clinic, Rochester, Minnesota.
                [3 ]Department of Pharmacy, Mayo Clinic, Rochester, Minnesota.
                [4 ]Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
                [5 ]Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
                Author notes
                [* ] Corresponding Author: Matthew S. Block, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: block.matthew@ 123456mayo.edu

                Clin Cancer Res 2024;30:2623–35

                Author information
                https://orcid.org/0009-0008-3614-5195
                https://orcid.org/0009-0004-2256-6715
                https://orcid.org/0000-0002-1117-0983
                https://orcid.org/0000-0002-9640-5189
                https://orcid.org/0000-0001-8844-4391
                https://orcid.org/0000-0001-7820-6138
                https://orcid.org/0000-0001-8922-2619
                https://orcid.org/0009-0003-3074-7682
                https://orcid.org/0009-0003-5723-5409
                https://orcid.org/0000-0003-3967-921X
                https://orcid.org/0009-0009-8040-1915
                https://orcid.org/0000-0001-9413-316X
                https://orcid.org/0009-0003-9533-3181
                https://orcid.org/0000-0002-1081-189X
                https://orcid.org/0009-0001-0815-4704
                https://orcid.org/0000-0002-1470-1305
                https://orcid.org/0000-0001-9361-8392
                https://orcid.org/0000-0002-8199-5040
                https://orcid.org/0000-0002-4752-7104
                https://orcid.org/0000-0002-7130-7259
                https://orcid.org/0000-0001-8981-4702
                https://orcid.org/0000-0003-2872-3123
                https://orcid.org/0000-0002-9238-4325
                https://orcid.org/0000-0001-5692-4219
                Article
                CCR-23-3196
                10.1158/1078-0432.CCR-23-3196
                11176914
                38530846
                276d21dc-e6b5-4a65-8d2f-68c66fdc9dec
                ©2024 The Authors; Published by the American Association for Cancer Research

                This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.

                History
                : 30 October 2023
                : 13 February 2024
                : 21 March 2024
                Page count
                Pages: 13
                Funding
                Funded by: Mayo Foundation for Medical Education and Research (MFMER), DOI https://doi.org/10.13039/100007048;
                Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
                Funded by: National Cancer Institute (NCI), DOI https://doi.org/10.13039/100000054;
                Award ID: P30 CA015083
                Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
                Categories
                Clinical Trial Results
                Phase I clinical trials
                Gynecological Cancers
                Endometrial Cancer
                Ovarian Cancer
                Nanoparticle Agents
                Clinical Trials: Targeted Therapy

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