Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients

Schmittel, Alexander; Knödler, Maren; Hortig, P.; Schulze, Karsten; Thiel, Eckhard; Keilholz, Ulrich

doi:10.1016/j.lungcan.2006.09.029

Cited by 49 publications

(28 citation statements)

References 11 publications

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“…benzimidazolyl} butyric acid hydrochloride, also known as Treanda (Cephalon, Inc.) and marketed in Germany as Ribomustin (Mundi Pharma Ltd.), is a purine analogue/alkylator hybrid cytotoxic with shown clinical activity against various human cancers including non -Hodgkin's lymphoma (1,2), chronic lymphocytic leukemia (3), multiple myeloma (4,5), breast cancer (6), and small-cell lung cancer (7,8). In addition, both preclinical (9 -11) and clinical (12) studies of bendamustine have shown activity in cancer cells that are resistant to conventional alkylating agents.…”

Section: Bendamustine 4-{5-[bis(2-chloroethyl)amino]-1-methyl-2-mentioning

confidence: 99%

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

Leoni¹,

Bailey

Reifert

et al. 2008

Clinical Cancer Research

317

315

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Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.

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Section: Bendamustine 4-{5-[bis(2-chloroethyl)amino]-1-methyl-2-mentioning

confidence: 99%

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

Leoni¹,

Bailey

Reifert

et al. 2008

Clinical Cancer Research

317

315

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“…Bendamustine has clinicalactivityinseveralhematologicalmalignanciesandwas firstusedclinicallyin1969inpatientswithmultiplemyeloma [1]. It is also active in the treatment of chronic lymphocytic leukemia (CLL) [2], Hodgkin's disease [3] and other lowgradenon-Hodgkin'slymphomas [4].Itisactiveindifferent solid tumors and proved to be an interesting alternative to otheralkylatingagents.Single-agentbendamustineisatreatmentoptionforpatientswithadvancedsmall-celllungcancer assecond-linetherapy [5].Someclinicalexperienceexistswith bendamustineasprimarytherapy,aswellasintheadvanced stage,formetastaticbreastcancer(MBC) [6,7].Recently,the resultsofaphaseIIstudywithbendamustineinpatientswith MBCwerepresentedbyReichmannetal. [8].…”

Section: Introductionmentioning

confidence: 99%

Phase II Study with 3rd- or 4th-Line Bendamustine (Flat Dose) Therapy in Patients with Metastatic Breast Cancer

Steinbild¹,

Frost²,

Häring³

et al. 2009

Onkologie

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Background: Bendamustine is a drug with a favorable side effect spectrum and it offers a chance to overcome tumor resistance in pretreated patients with metastatic breast cancer (MBC). Patients and Methods: Bendamustine was given as flat dose with 200 mg at days 1 + 2 in MBC patients pretreated with 2–3 different chemotherapies. Therapy was repeated at day 28 or fully recovered neutrophils. After 2 treatment cycles, a tumor response evaluation was performed. Toxicity was graded according to the National Cancer Institute common toxicity criteria (NCI-CTC) catalogue. Results: 22 patients were evaluated for toxicity. 4 patients dropped out before the first tumor response evaluation; thus, 18 patients were evaluable for anticancer efficacy evaluation. 3/18 patients reached a partial remission (PR), 4 stable disease and 11 showed progression after 2 treatment cycles. The time to progression (TTP) was 5 months in patients with PR and 4 months in patients with no change (NC). In patients with progressive disease (PD), TTP was < 2 months. The main toxicities were nausea, weight loss and fatigue. Conclusions: Bendamustine can be given with a fixed flat dose, which simplifies the drug preparation. 2/5th of all treated patients responded to this therapy whereas bendamustine showed no anticancer effect in 3/5th of all patients. Bendamustine is definitely a drug with anticancer potential.

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“…Bendamustine is also actively investigated in multiple myeloma where the combination with prednisone proved to be more efficacious than the standard treatment: melphalan and prednisone (time to treatment failure: 14 vs 10 months, P ¼ 0.02) (Pönisch et al, 2006). In solid tumours, BM's lack of cross-resistance with other alkylating agents, its favourable toxicity profile, and the fact that it shows anticancer activity in second line and in the salvage setting in patients with pretreated metastatic breast cancer (MBC) (Höffken et al, 1998;Zulkowski et al, 2002), non-small cell lung cancer (NSCLC) (Reck et al, 1998), and small cell lung cancer (SCLC) (Schmittel et al, 2007) make it a valuable addition to the armamentarium of active anticancer drugs. Recently, a randomised phase III study compared cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with a comparable schedule in which cyclophosphamide was replaced by BM (BMF).…”

mentioning

confidence: 99%

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

et al. 2007

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The aim of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and the pharmacokinetic profile (P k ) of bendamustine (BM) on a day 1 and 2 every 3 weeks schedule and to recommend a safe phase II dose for further testing. Patients with solid tumours beyond standard therapy were eligible. A 30-min intravenous infusion of BM was administered d1 þ d2 q 3 weeks. The starting dose was 120 mg m À2 per day and dose increments of 20 mg m À2 were used. Plasma and urine samples were analysed using validated high-performance liquid chromatography/fluorescence assays. Fifteen patients were enrolled. They received a median of two cycles (range 1 -8). The MTD was reached at the fourth dose level. Thrombocytopaenia (grade 4) was dose limiting in two of three patients at 180 mg m À2 . One patient also experienced febrile neutropaenia. Lymphocytopaenia (grade 4) was present in every patient. Nonhaematologic toxicity including cardiac toxicity was not dose limiting with this schedule. Mean plasma P k values of BM were t max 35 min, t 1/2 49.1 min, V d 18.3 l m À2 , and clearance 265 ml min À1 m À2 . The mean total amount of BM and its metabolites recovered in the first micturition was 8.3% (range 2.7 -26%). The MTD of BM in the present dose schedule was 180 mg m À2 on day 1 þ 2. Thrombocytopaenia was dose limiting. The recommended dose for future phase II trials with this schedule is 160 mg m À2 per day.

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Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients

Cited by 49 publications

References 11 publications

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

Phase II Study with 3rd- or 4th-Line Bendamustine (Flat Dose) Therapy in Patients with Metastatic Breast Cancer

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

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