Safety and Efficacy of Low-dose Nanoparticle Albumin-bound Paclitaxel for HER2-negative Metastatic Breast Cancer

Takashima, Tsutomu; Kawajiri, Hidemi; Nishimori, Takeo; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Tokunaga, Shinya; Mizuyama, Yoko; Sunami, Takeshi; Tezuka, Kenji; Ikeda, Katsumi; Ogawa, Yoshinari; Kashiwagi, Shinichiro; Noda, Shinichi; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei; Ohira, Masaichi

doi:10.21873/anticanres.12233

Cited by 8 publications

(6 citation statements)

References 12 publications

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“…In the current study, we observed grade 3 or higher neutropenia at a rate of 38%, febrile neutropenia at 3%, and grade 3 or higher CIPN at 13%, whereas previous trials in AGC evaluating tri-weekly nab-PTX at 260 mg/m 2 showed grade 3 or higher neutropenia and CIPN at rates of 49.1–64.8% and 20.1–23.6%, respectively. These results suggest that tri-weekly nab -PTX at 220 mg/m 2 achieved the expected reduction of adverse events, consistent with previous trials in MBC [ 21 , 22 ]…”

Section: Discussionsupporting

confidence: 90%

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A phase II trial of dose-reduced nab-paclitaxel for patients with previously treated, advanced or recurrent gastric cancer (OGSG 1302)

Tamura

Taniguchi²,

Nishikawa

et al. 2020

Int J Clin Oncol

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Background For unresectable or recurrent advanced gastric adenocarcinoma (AGC), tri-weekly administration of nanoparticle albumin-bound paclitaxel (nab-PTX) at 260 mg/m2 achieved a response rate of 27.8% in a phase II trial in Japan. However, frequent neutropenia and peripheral neuropathy limit its use in clinical settings. We, thus, conducted a single-arm phase II trial to investigate the efficacy and safety of a reduced dose (220 mg/m2) of tri-weekly nab-PTX. Methods Eligible patients included those with AGC and ECOG performance status of 0–2 who had received one or more prior chemotherapy containing fluoropyrimidine regimens. A reduced dose of nab-PTX (220 mg/m2) was administered tri-weekly. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity (RDI) and proportion of patients receiving subsequent chemotherapy. Results Among 33 patients enrolled, 32 were treated with protocol therapy. RR was 3.1% [95% confidence interval (CI), 0–16.2%], which did not reach the protocol-specified threshold (p = 0.966). DCR was 37.5% (95% CI, 21.1–56.3%). Median OS and PFS were 6.3 (95% CI, 4.4–14.2) and 2.2 (95% CI, 1.8–3.1) months, respectively. RDI was 97.8%. Twenty (62.5%) patients received subsequent chemotherapy. Toxicity was relatively mild with the most common grade ≥ 3 adverse events being neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). Conclusion Tri-weekly nab-PTX with a reduced dose (220 mg/m2) is not recommended for AGC in a second-line or later setting, despite demonstrating less toxicity than at 260 mg/m2. Clinical trial registration The OGSG1302 trial was registered with UMIN-CTR as UMIN000000714.

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Section: Discussionsupporting

confidence: 90%

“…This study also identified grade 3 or higher CIPN as a considerable adverse event of nab -PTX [ 15 ]. To reduce such toxicity, low-dose tri-weekly nab -PTX (160–175 mg/m 2 ) was examined in several phase II studies for MBC, showing good overall RR (23–39.5%) without CIPN of grade 3 or higher [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

A phase II trial of dose-reduced nab-paclitaxel for patients with previously treated, advanced or recurrent gastric cancer (OGSG 1302)

Tamura

Taniguchi²,

Nishikawa

et al. 2020

Int J Clin Oncol

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“…[4][5][6][7] Polyoxyethylene castor oil and absolute ethanol are used clinically (50:50, v/v) as a vehicle for intravenous PTX injections. 8,9 The solvent significantly increases the solubility of PTX, however, it has been reported to cause allergic reactions, neurotoxicity, nephrotoxicity, and other toxic side effects, [10][11][12] greatly limiting the clinical application of PTX. Additionally, like other broad-spectrum anticancer drugs, PTX has several limitations that seriously affect its clinical efficacy; it is not selectively distributed in vivo, has a short circulation halflife, and causes damage to normal cells while killing cancer cells.…”

Section: Introductionmentioning

confidence: 99%

<p>Preparation, Characterization, and Pharmacokinetic Study of a Novel Long-Acting Targeted Paclitaxel Liposome with Antitumor Activity</p>

Han

Yang

Chen

et al. 2020

IJN

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Background: Breast cancer is the leading cause of cancer death in women. Chemotherapy to inhibit the proliferation of cancer cells is considered to be the most important therapeutic strategy. The development of long-circulating PEG and targeting liposomes is a major advance in drug delivery. However, the techniques used in liposome preparation mainly involve conventional liposomes, which have a short half-life, high concentrations in the liver and spleen reticuloendothelial system, and no active targeting. Methods: Four kinds of paclitaxel liposomes were prepared and characterized by various analytical techniques. The long-term targeting effect of liposomes was verified by fluorescence detection methods in vivo and in vitro. Pharmacokinetic and acute toxicity tests were conducted in ICR mice to evaluate the safety of different paclitaxel preparations. The antitumor activity of ES-SSL-PTX was investigated in detail using in vitro and in vivo human breast cancer MCF-7 cell models. Results: ER-targeting liposomes had a particle size of 137.93±1.22 nm and an acceptable encapsulation efficiency of 88.07±1.25%. The liposome preparation is best stored at 4°C, and is stable for up to 48 hrs. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. We used the near-infrared fluorescence imaging technique to confirm that ES-SSL-PTX was effectively targeted and could quickly and specifically identify the tumor site. Pharmacokinetics and acute toxicity in vivo experiments were carried out. The results showed that ES-SSL-PTX could significantly prolong the half-life of the drug, increase its circulation time in vivo, improve its bioavailability and reduce its toxicity and side effects. ES-SSL-PTX can significantly improve the pharmacokinetic properties of paclitaxel, avoid allergic reaction of the original solvent, increase antitumor efficacy and reduce drug toxicity and side effects. Conclusion: ES-SSL-PTX has great potential for improving the treatment of breast cancer, thereby improving patient prognosis and quality of life.

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“… 19 On the basis of these findings, we designed and developed a novel active targeting delivery system by modifying PTX-loaded PEGylation BSA-NPs with the dual-functional ligand AMD3100 (AMD-NP-PTX). It is well known that albumin-based NPs have been widely used for delivery of drugs with low solubility, 28 , 29 and PEGylation strategy for NPs has become necessary to avoid their hydrophobic nature, slow degradation and rapid uptake by Reticuloendothelial System (RES). 30 , 31 Herein, we chemically modified AMD3100 to Mal-PEG-NHS followed by reacting with BSA, synthesized PTX-loaded AMD-PEG-BSA NPs by biomineralization.…”

Section: Discussionmentioning

confidence: 99%

<p>CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer</p>

Xue

Gao

et al. 2020

IJN

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Introduction: Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes. Methods: AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied. Results: AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial-mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway. Conclusion: The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.

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Safety and Efficacy of Low-dose Nanoparticle Albumin-bound Paclitaxel for HER2-negative Metastatic Breast Cancer

Abstract: Nab-PTX 175 mg/m/3wks regimen has a good safety profile and less frequent CIPN. This regimen can contribute to the strategy of MBC treatment.

Cited by 8 publications

References 12 publications

A phase II trial of dose-reduced nab-paclitaxel for patients with previously treated, advanced or recurrent gastric cancer (OGSG 1302)

A phase II trial of dose-reduced nab-paclitaxel for patients with previously treated, advanced or recurrent gastric cancer (OGSG 1302)

<p>Preparation, Characterization, and Pharmacokinetic Study of a Novel Long-Acting Targeted Paclitaxel Liposome with Antitumor Activity</p>

<p>CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer</p>

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