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A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

ABSTRACT: BACKGROUND:This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) and paclitaxel (P). PATIENTS AND METHODS:Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m(2)) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m(2) in combination with standard doses of C (AUC6) and P (200 mg/m(2)) for six cycles. S was administered as a continuous intravenous infusion (CIVI) over 72 h in 21-day treatment cycles. Study end points included safety and toxic effect, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. RESULTS:Treatment with S was well tolerated, and toxic effects were mostly hematological in the phase II study. Two (11%) partial responses were observed with a median PFS of 5.7 months and median OS 16.1 months. Pharmacodynamic analysis did not demonstrate an association with response. CONCLUSION:The combination of S (10 mg/m(2)/day 72-h CIVI) administered with C and P every 3 weeks exhibited a favorable safety profile but failed to demonstrate an improvement in response rate in advanced NSCLC. CLINICAL TRIAL NUMBER:NCT01100931.

SUBMITTER: Kelly RJ

PROVIDER: S-EPMC3784336 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

Kelly R J RJ Thomas A A Rajan A A Chun G G Lopez-Chavez A A Szabo E E Spencer S S Carter C A CA Guha U U Khozin S S Poondru S S Van Sant C C Keating A A Steinberg S M SM Figg W W Giaccone G G

Annals of oncology : official journal of the European Society for Medical Oncology 20130714 10

<h4>Background</h4>This phase I/II study examined the safety and efficacy of Sepantronium Bromide (S), a small-molecule selective survivin suppressant, administered in combination with carboplatin (C) and paclitaxel (P).<h4>Patients and methods</h4>Forty-one patients were treated on study. Twenty-two patients received escalating doses of S (3.6-12 mg/m(2)) and 19 with untreated stage IV non-small-cell lung cancer (NSCLC) were treated with the maximum tolerated dose of 10 mg/m(2) in combination w ...[more]

PMID: 23857959

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Project description:PURPOSE:Sepantronium bromide (YM155) is a hydrophilic quaternary compound that cannot be administered orally due to its low oral bioavailability; it is furthermore rapidly eliminated via the kidneys. The current study aims at improving the pharmacokinetic profile of YM155 by its formulation in immunoliposomes that can achieve its enhanced delivery into tumor tissue and facilitate uptake in neuroblastoma cancer cells. METHODS:PEGylated YM155 loaded liposomes composed of DPPC, cholesterol and DSPE-PEG2000 were prepared via passive film-hydration and extrusion method. Targeted (i.e. immuno-)liposomes were prepared by surface functionalization with SATA modified monoclonal anti-disialoganglioside (GD2) antibodies. Liposomes were characterized based on their size, charge, antibody coupling and YM155 encapsulation efficiency, and stability. Flow cytometry analysis and confocal microscopy were performed on IMR32 and KCNR neuroblastoma cell lines. The efficacy of developed formulations were assessed by in-vitro toxicity assays. A pilot pharmacokinetic analysis was performed to assess plasma circulation and tumor accumulation profiles of the developed liposomal formulations. RESULTS:YM155 loaded immunoliposomes had a size of 170 nm and zeta potential of -10 mV, with an antibody coupling efficiency of 60% andYM155 encapsulation efficiency of14%. Targeted and control liposomal formulations were found to have similar YM155 release rates in a release medium containing 50% serum. An in-vitro toxicity study on KCNR cells showed less toxicity for immunoliposomes as compared to free YM155. In-vivo pharmacokinetic evaluation of YM155 liposomes showed prolonged blood circulation and significantly increased half-lives of liposomal YM155 in tumor tissue, as compared to a bolus injection of free YM155. CONCLUSIONS:YM155 loaded immunoliposomes were successfully formulated and characterized, and initial in-vivo results show their potential for improving the circulation time and tumor accumulation of YM155.

Project description:BackgroundThis study was performed to assess the efficacy and feasibility of definitive chemoradiotherapy consisting of weekly doses of combined paclitaxel and carboplatin concurrent with radiation therapy, followed by 2 cycles of consolidation chemotherapy for advanced esophageal carcinoma.MethodsEligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; Eastern Cooperative Oncology Group (ECOG) score ≤ 2; and adequate organ function. Patients received concurrent chemoradiation therapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m2) and carboplatin (area under the curve, AUC = 2) on days 1, 8, 15, 22 and 29. The two-cycle consolidation chemotherapy protocol was paclitaxel (175 mg/m2) plus carboplatin (AUC = 5) administered on days 57 and 85, after concurrent chemoradiotherapy.ResultsBetween August 2013 and February 2015, 65 patients with oesophageal carcinoma were enrolled in the study; 34 (52.3%) were newly diagnosed and 31 (47.6%) had postoperative local regional lymph node metastasis. The median overall survival time was 21.7 months (95% confidence interval [CI] 16.7-26.6), and the median progression-free survival time was 12.1 months (95% CI 9.0-15.3). A total of 96.9% (63/65) and 67.6% (44/65) patients completed ≥5 cycles and all 7 cycles of chemotherapy, respectively. A total of 93.8% (61/65) patients completed radiation therapy. The 1- and 2-year overall survival rates were 73.7 and 42.0%, respectively. The 1- and 2-year progression-free survival rates were 50.6 and 31.1%, respectively. Grade 3-4 toxicity during chemoradiotherapy included neutropenia (24.5%), thrombocytopenia (4.6%), fatigue (1.5%), anaemia (1.5%), radiation dermatitis (1.5%), pneumonitis (1.5%), oesophagitis (4.6%) and vomiting (1.5%).ConclusionsIn patients with locally advanced oesophageal cancer, the combination of weekly doses of paclitaxel and carboplatin was well tolerated and produced comparable results. A three-arm randomised phase III trial (NCT02459457) comparing paclitaxel in combination with cisplatin, carboplatin or 5-fluorouracil with concurrent radiotherapy is on-going at our hospital.

Dataset Information

A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

Publications

A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

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