Bendamustine in Metastatic Breast Cancer: An Old Drug in New Design

Pîrvulescu, Cristina; Minckwitz, Gϋnter von; Loibl, Sibylle

doi:10.1159/000154105

Cited by 6 publications

(5 citation statements)

References 22 publications

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“…Bendamustine hydrochloride (BDM), synthesized in Germany in the 1960s, is an anticancer drug with alkylating and antimetabolite properties [1][2][3][4]. BDM has shown efficacy for hematologic malignancies and solid tumors [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan

Ishizawa

Yokoyama

Kato

et al. 2022

Cancer Chemother Pharmacol

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Purpose This phase I/II clinical study was conducted to examine the safety, tolerability, pharmacokinetics, and efficacy of 10-min dosing of bendamustine in patients with previously untreated indolent B-cell non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL) (Group 1) and patients with relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) (Group 2). Methods Rituximab 375 mg/m2 was administered intravenously every 28 days to Group 1 patients on day 1 and every 21 days to Group 2 patients on day 1. Bendamustine 90 mg/m2/day was administered to the former on days 1 and 2; bendamustine 120 mg/m2/day was administered to the latter on days 2 and 3. Each regimen was delivered up to six cycles for both groups. The primary endpoints were safety and tolerability in Groups 1 and 2, respectively. Results Among 37 enrolled patients, safety was assessed in 36. In Group 1 (n = 30), 27 patients (90%) had follicular lymphoma. Adverse events (AEs) were observed in all 30 patients in Group 1. Dose-limiting toxicities were observed in two of six patients in Group 2. Common AEs included lymphocyte count decreased (86.7%, 100%). In Group 1, overall response and complete response rates were 93.1% (95% confidence interval [CI] 77.2–99.2%) and 75.9% (95% CI 56.5–89.7%), respectively. The Cmax and AUC of bendamustine tended to be higher in Group 2 than in Group 1. Conclusions This study showed that bendamustine is safe, well-tolerated and effective for patients with previously untreated iNHL, MCL or rrDLBCL. Pharmacokinetic data were equivalent to those obtained outside of Japan. Registration numbers Registration NCT03900377; registered April 3, 2019.

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Section: Introductionmentioning

confidence: 99%

A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan

Ishizawa

Yokoyama

Kato

et al. 2022

Cancer Chemother Pharmacol

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“… 2 Bendamustine is also a well-tolerated agent that has already shown anticancer activity in breast cancer. 3 …”

Section: Introductionmentioning

confidence: 99%

“…It is currently approved by the US Food and Drug Administration (FDA) as well as the European Medicine Agency (EMA) for the treatment of chronic lymphocytic leukaemia (CLL) and indolent B-cell non-Hodgkin’s lymphoma (NHL). The evidence of bendamustine in the treatment of MBC has previously been reviewed by Pirvulescu et al 3 published in Breast Care in 2008. As monotherapy for pre-treated patients (one pilot trial 4 and three phase II trials), 5 – 7 bendamustine revealed an overall response rate (ORR) ranging from 20% up to 48%, accompanied by a moderate toxicity profile.…”

Section: Introductionmentioning

confidence: 99%

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Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)

et al. 2021

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Background: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin lymphoma, has already shown anticancer activity in metastatic breast cancer (MBC). Here, we present the results of a phase II trial of bendamustine in combination with capecitabine in pre-treated patients with MBC. Patients and methods: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in HER2-negative MBC. All patients were pre-treated with anthracyclines and/or taxans and had measurable disease. Patients received per os 1000 mg/m2 capecitabine twice daily on days 1 to 14 in combination with 80 mg/m2 bendamustine intravenously on days 1 and 8 of a 3-week cycle for a maximum of eight cycles, followed by a capecitabine maintenance therapy. The primary endpoint was overall response rate (ORR). Results: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centres. The median age was 60 years (range 29–77). Twenty-five per cent of patients had triple-negative breast cancer (TNBC) and 93% showed visceral involvement. With 17 partial and one complete remission, ORR was 46%. Median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI) 6.1–10.7]. The most common non-haematological adverse events (AEs) of grade 3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea (8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4 haematological AEs (neutropenia) were observed. One patient died of restrictive cardiomyopathy, in which a relationship to capecitabine cannot be excluded, but seems unlikely. Conclusion: The combination of capecitabine and bendamustine shows promising efficacy and moderate toxicity. Further evaluation of this drug combination is warranted. The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov , ( https://clinicaltrials.gov/ ; identifier: NCT01891227).

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“…Bendamustine was originally synthesized at Jena University in Germany in 1963. Multiple clinical trials confirm that this bifunctional alkylating agent has anti-tumor activity in MM, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and breast cancer [6][7][8][9]. A Phase III clinical trial indicated that treatment of bendamustine plus prednisone in patients with newly diagnosed MM leads to superior complete response rate and has a more lasting effect as compared with treatment with melphalan plus prednisone [7].…”

Section: Introductionmentioning

confidence: 99%

Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins

Lü¹,

Li²,

Pan³

et al. 2013

ABBS

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Bendamustine is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers. We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines (RPMI8226 and MM1.S) and primary MM cells. Our results demonstrated a synergistic effect of these drugs, which was effective for both p53-wild-type and p-53-deleted MM cells, but was minimal in mononuclear cells from a healthy donor. Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin-V/PI staining, caspase-3 degradation, and PARP cleavage. Cell death was associated with the up-regulation of the pro-apoptotic protein Bax and the down-regulation of the anti-apoptotic proteins Mcl-1 and survivin. The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the mTOR pathway, p70s6k, and 4EBP-1, as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1.S cells. p21 was also down-regulated upon treatment with the two drugs, suggesting a mechanism of sensitization through the release of cell cycle arrest. Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine, and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and mTOR inhibitors in future clinical practice.

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Bendamustine in Metastatic Breast Cancer: An Old Drug in New Design

Cited by 6 publications

References 22 publications

A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan

A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan

Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)

Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins

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