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

Abstract

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.

RXDX-107, A Dodecanol Alkyl Ester of Bendamustine, Demonstrates Greater Stability and Broad Antitumor Activity in Multiple Pre-Clinical Models of Solid Tumor

“…Bendamustine is an alkylating agent in used to treat various hematological malignancies, but it has never demonstrated objective in patients with solid tumors likely due to very short half-life [1,12,13]. This report demonstrates single agent antitumor activity of RXDX-107 in solid tumor preclinical models with enhanced pharmacodynamics and pharmacokinetic properties.…”

“…However, the activity of bendamustine in the treatment of solid tumor malignancies has been less impressive, possibly due to the pharmacokinetic and biodistribution properties of bendamustine. Bendamustine displays very short half-life, approximately 40 mins in human [1,[11][12][13].…”

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

“…In this regard, when two conditioning regimens with alkylating agents were prospectively compared by a Spanish Group a higher response rate was found with busulfan/melphalan than with melphalan alone. 17,18,44 We decided to use a fixed dose of 200 mg/m 2 because of the reported cardiotoxicity in previous series at higher doses of BENDA 42,43 and to reduce the risk of synergistic toxicity between the BENDA and HDM and keeping in mind that all patients performed, in the previous 6 months, a first ASCT. Moreover, the association between BENDA at 200 mg/m 2 +plus HDM at 140 mg/m 2 was investigated in lymphoma patients in the context of BeEAM chemotherapy regimen with an extremely low-toxicity profile.…”

“…In our study, the choice of BENDA was based on the documented sensitivity of myeloma cells to the drug in the context of resistance to previous treatments; 24,41,42 and the decision was made to explore the association between a pure alkylating agent (melphalan) with an agent (BENDA) that combines the alkylating properties of a mustard group with the antimetabolic activity of a purine analog and can induce responses in disease resistant in a distinct way from standard alkylator mechanisms of action. 43 We believe that the use of a preparative regimen that combines two agents in the second ASCT could have a key role in long-term results.…”

Visible Spectrophotometric Determination of Bendamustine Hydrochloride in Formulation Sample

“…[3] WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES HPLC, [4][5][6] LC-MS. [7,8] No visible spectrophotometric method for determination of bendamustine complexing with 1:10 phenanthroline in bulk drug samples and formulations was reported. [9,10] The present study describes simple, sensitive, accurate, rapid and economical spectrophotometric methods for the estimation of bendamutsine hydrochloride in bulk samples & injection dosage forms.…”