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Thoracic Cancer Jun 2021Treatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe...
BACKGROUND
Treatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe cardiac toxicities. Amrubicin (AMR) is a next-generation anthracycline that is commonly used to treat lung cancer. Here, we conducted a phase II trial of this drug in patients with previously treated MPM.
METHODS
Eligible patients with MPM having adequate organ function and a performance status of 0-2 were enrolled after disease progression following pemetrexed/platinum therapy. Patients received 35 mg/m AMR on days 1-3 every three weeks until tumor progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. Median progression-free survival (PFS), overall survival (OS), number of treatment cycles, and adverse events were evaluated as secondary endpoints.
RESULTS
This trial was discontinued because of low accrual. From September 2013 to July 2018, five patients with MPM were enrolled. Stable disease (SD) was observed in three patients (60%), and progressive disease was noted in two patients (40%). The median PFS was 2.4 (range, 1.2-11.2) months, and the median OS was 9.1 (range, 6.2-22.0) months. The median number of treatment cycles was three (range, 2-11). Grade 1/2 toxicities were observed in all patients. Grade 3/4 neutropenia was observed in four patients (80%), but there were no cases of febrile neutropenia.
CONCLUSIONS
Despite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM.
Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Female; Humans; Male; Mesothelioma, Malignant; Middle Aged; Palliative Care; Pleural Neoplasms; Young Adult
PubMed: 33830645
DOI: 10.1111/1759-7714.13892 -
Investigational New Drugs Apr 2021Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study...
Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (C) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the C of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.
Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival
PubMed: 33159674
DOI: 10.1007/s10637-020-01031-z -
In Vivo (Athens, Greece) 2020Concurrent chemoradiotherapy (CCRT) is the gold standard for limited-stage small-cell lung cancer (LS-SCLC); however, most patients inevitably experience relapse. We...
BACKGROUND
Concurrent chemoradiotherapy (CCRT) is the gold standard for limited-stage small-cell lung cancer (LS-SCLC); however, most patients inevitably experience relapse. We hypothesized consolidation amrubicin following CCRT to be a potential treatment for LS-SCLC.
PATIENTS AND METHODS
All enrolled patients were treated using induction CCRT consisting of four cycles of etoposide and cisplatin plus concurrent thoracic radiotherapy. Eligible patients then received three cycles of amrubicin as consolidation therapy (consolidation population). The primary endpoint was the 2-year progression-free survival rate in the consolidation population.
RESULTS
Of the 36 intention-to-treat patients, 28 (78%) received amrubicin and 24 (67%) completed all planned treatments. The 2-year progression-free survival rate and overall response rate were 35.7% and 86%, respectively. The median progression-free and overall survival were 14.3 and 60.9 months, respectively. There were no treatment-related deaths in the intention-to-treat population.
CONCLUSION
This study was terminated due to slow patient accrual; however, this treatment strategy was feasible and demonstrated promising efficacy.
Topics: Aged; Anthracyclines; Antineoplastic Agents; Chemoradiotherapy; Combined Modality Therapy; Consolidation Chemotherapy; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Small Cell Lung Carcinoma; Treatment Outcome
PubMed: 32111801
DOI: 10.21873/invivo.11855 -
Japanese Journal of Cancer Research :... Oct 1998It has been reported that the 9-aminoanthracycline amrubicin shows good efficacy in human tumor xenograft models. We studied the disposition and metabolism of amrubicin...
It has been reported that the 9-aminoanthracycline amrubicin shows good efficacy in human tumor xenograft models. We studied the disposition and metabolism of amrubicin in mice, in comparison with those of doxorubicin. Amrubicinol, a 13-hydroxy metabolite of amrubicin, which is 10 to 100 times more cytotoxic than amrubicin, was detected as a major metabolite in blood and tissues, and aglycones of amrubicin were also detected. A pharmacokinetic study revealed that amrubicin had a smaller distribution volume and a shorter half-life than doxorubicin. In several normal tissues, the levels of amrubicin and amrubicinol were lower than those of doxorubicin. In contrast, the tumor levels of amrubicinol in the mice treated with amrubicin were higher than those of doxorubicin in the mice treated with that drug, in tumors that are sensitive to amrubicin. These results suggest that the potent therapeutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Doxorubicin; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Stomach Neoplasms; Tissue Distribution; Transplantation, Heterologous
PubMed: 9849586
DOI: 10.1111/j.1349-7006.1998.tb00497.x -
Medicine Jun 2020The aim of this study is to examine the efficacy of weekly amrubicin (WA) for treating refractory or relapsed non-small cell lung cancer (RRNSCLC).
BACKGROUND
The aim of this study is to examine the efficacy of weekly amrubicin (WA) for treating refractory or relapsed non-small cell lung cancer (RRNSCLC).
METHODS
The literature search will be performed using the Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, Scopus, Chinese Biomedical Literature Database, WANGFANG, VIP database, and China National Knowledge Infrastructure from inception onwards up to the March 1, 2020. No language limitation will be implemented. Randomized controlled trials that examined the efficacy and safety of WA for the treatment of RRNSCLC will be included. Literature selection, data extraction, and methodological quality assessment will be handled by 2 independent authors. We will invite a third author to disentangle any divergences between 2 authors. We will carry out statistical analysis using RevMan 5.3 software.
RESULTS
This study will summarize current evidence to assess the efficacy and safety of WA for the treatment of RRNSCLC.
CONCLUSIONS
The findings of this study will provide helpful evidence for the clinician, and will promote further studies, as well as clarify the direction of research on WA for the management of RRNSCLC.Study registration number: INPLASY202040168.
Topics: Anthracyclines; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Meta-Analysis as Topic; Neoplasm Recurrence, Local; Systematic Reviews as Topic
PubMed: 32569168
DOI: 10.1097/MD.0000000000020454 -
Investigational New Drugs Apr 2016Amrubicin is a third generation synthetic 9-aminoanthracycline that specifically inhibits topoisomerase II. Amrubicin preferentially concentrates in tumor cells leading...
Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable soft tissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation.
PURPOSE
Amrubicin is a third generation synthetic 9-aminoanthracycline that specifically inhibits topoisomerase II. Amrubicin preferentially concentrates in tumor cells leading to tumor cell death without causing cardiac toxicity. This phase II multicenter study was done to evaluate the efficacy and tolerability of amrubicin in advanced soft tissue sarcoma (STS).
PATIENTS AND METHODS
24 eligible patients with chemotherapy-naive metastatic or unresectable STS were treated with amrubicin 40 mg/m(2) intravenously daily for three consecutive days in 21 days cycles with growth factor support. Patients continued to receive treatment, as long as it was tolerated, in the absence of significant disease progression. The disease was followed on imaging scans every 6 weeks. The primary endpoint of the study was the best overall response rate.
RESULTS
The best overall response rate was 13% in 23 evaluable patients. Median progression-free survival was 5.8 months, and median overall survival was 26 months. Grade 3 to 4 toxicities of febrile neutropenia and anemia occurred in 21% of treated patients. One patient with metastatic myxoid liposarcoma with TLS-CHOP translocation had a durable response and received 40 cycles of amrubicin. There was no significant cardiac toxicity.
CONCLUSIONS
Amrubicin has efficacy comparable to doxorubicin in adult STS, is well tolerated and has no significant cardiac toxicity up to a cumulative dose of 4800 mg /m(2). Topoisomerase II inhibition with amrubicin warrants further study as a potential 'targeted therapy' for TLS-CHOP-translocated myxoid liposarcoma. Results from this trial favor the use of amrubicin for the treatment of STS.
Topics: Adult; Aged; Anthracyclines; Demography; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Kaplan-Meier Estimate; Liposarcoma, Myxoid; Male; Middle Aged; Oncogene Proteins, Fusion; RNA-Binding Protein FUS; Sarcoma; Tomography, X-Ray Computed; Transcription Factor CHOP; Translocation, Genetic; Treatment Outcome
PubMed: 26897615
DOI: 10.1007/s10637-016-0333-z -
Anticancer Research Mar 2021We evaluated the efficacy of primary prophylaxis with pegfilgrastim (PEG) for febrile neutropenia (FN) in small cell lung cancer (SCLC) patients receiving amrubicin...
BACKGROUND/AIM
We evaluated the efficacy of primary prophylaxis with pegfilgrastim (PEG) for febrile neutropenia (FN) in small cell lung cancer (SCLC) patients receiving amrubicin (AMR).
PATIENTS AND METHODS
A retrospective cohort study was conducted in patients with SCLC receiving AMR as second-line therapy.
RESULTS
A total of 33 patients were treated with AMR (no PEG group), while 13 patients were treated with AMR plus prophylactic administration of PEG (PEG group). The severity of neutropenia was significantly reduced in the PEG group compared to the no PEG group (p=0.02). The incidence of FN in the no PEG and PEG groups was 27.3% and 7.7%, respectively. The time to development of FN tended to be longer in the PEG group compared to the no PEG group (p=0.132).
CONCLUSION
Primary prophylaxis with PEG may be beneficial in reducing the risk of FN in patients with SCLC receiving AMR.
Topics: Aged; Anthracyclines; Antineoplastic Agents; Febrile Neutropenia; Female; Filgrastim; Humans; Lung Neoplasms; Male; Polyethylene Glycols; Retrospective Studies; Small Cell Lung Carcinoma
PubMed: 33788757
DOI: 10.21873/anticanres.14923 -
Journal of Thoracic Oncology : Official... Sep 2010Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small cell lung cancer (SCLC), but the adverse pulmonary effects of...
BACKGROUND
Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small cell lung cancer (SCLC), but the adverse pulmonary effects of amrubicin are less well known. We investigated the incidence of acute interstitial lung disease (ILD) in SCLC patients who had been treated with amrubicin.
METHODS
Medical records were used to retrospectively investigate a total of 100 cases of SCLC patients treated with single-agent amrubicin therapy at the National Cancer Center Hospital East between June 2003 and March 2008. The patients' radiographic records and clinical data were reviewed to identify patients who had developed acute ILD after being treated with amrubicin.
RESULTS
After receiving amrubicin, seven of the 100 SCLC patients subsequently developed pulmonary infiltrates, and they were identified as cases of acute ILD associated with amrubicin. Of the seven patients who developed ILD, six were treated with corticosteroids, and the ILD improved in three of them, but the other three patients died of respiratory failure. The incidence of ILD was 33% (4/12) among the patients with pre-existing pulmonary fibrosis (PF) and 3% (3/88) among the patients without PF, and the difference between the two groups was statistically significant (P = 0.0036).
CONCLUSIONS
The results of this study indicated that amrubicin may cause severe ILD and that pre-existing PF was associated with a higher rate of ILD among SCLC patients treated with amrubicin. We recommend not administering amrubicin in the treatment of SCLC patients with pre-existing PF.
Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Female; Humans; Incidence; Lung Diseases, Interstitial; Lung Neoplasms; Male; Medical Records; Middle Aged; Neoplasm Staging; Retrospective Studies; Small Cell Lung Carcinoma; Survival Rate; Treatment Outcome
PubMed: 20683210
DOI: 10.1097/JTO.0b013e3181e369a8 -
Cancer Chemotherapy and Pharmacology Apr 2012Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of...
PURPOSE
Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of amrubicin, a third-generation synthetic anthracycline and potent topoisomerase (topo)-II inhibitor with little or no observed cardiotoxicity to other anthracyclines and the topo-II inhibitor etoposide in drug-resistant tumor models in order to elucidate its potential mechanisms of action.
METHODS
Amrubicin activity was assessed in multi-drug-resistant cell lines and human tumor explants using cytotoxicity assays, confocal microscopy, fluorescence time-lapse imaging, flow cytometry, immunoblotting, and gene expression profiling techniques.
RESULTS
We demonstrate that both doxorubicin-resistant tumor cell lines and several drug-resistant human ovarian and breast tumor explants retain sensitivity to amrubicin. In addition, we observed similar levels of amrubicin uptake and accumulation in doxorubicin-sensitive versus doxorubicin-resistant cell lines. Although amrubicin is a weak P-glycoprotein substrate, transport and retention of amrubicin were not solely modulated by P-glycoprotein in the resistant cell lines overexpressing drug efflux pumps. The cellular retention of amrubicin is likely to be a result of rapid influx due to its high intrinsic permeability and lipophilic properties, and this may explain why amrubicin overcomes pleiotropic drug resistance. Consistent with drug accumulation studies, amrubicin induced DNA damage, G(2)-M cell cycle arrest, and apoptosis in both doxorubicin-sensitive and doxorubicin-resistant lines. Using gene expression profiling studies, several classes of genes were significantly and uniquely regulated following amrubicin, but not doxorubicin or etoposide, treatment.
CONCLUSIONS
Amrubicin appears to have a distinct mode of action that overcomes typical anthracycline resistance mechanisms. Therefore, amrubicin may be useful in the treatment of anthracycline-refractory or anthracycline-resistant tumors.
Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Caspase 3; Cell Growth Processes; Cell Line, Tumor; DNA Damage; Doxorubicin; Drug Resistance, Neoplasm; Epirubicin; Female; G2 Phase Cell Cycle Checkpoints; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; M Phase Cell Cycle Checkpoints; Ovarian Neoplasms; Topoisomerase II Inhibitors; Uterine Neoplasms
PubMed: 22120960
DOI: 10.1007/s00280-011-1782-x -
Japanese Journal of Clinical Oncology Oct 2015Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to...
OBJECTIVE
Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer.
METHODS
Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate.
RESULTS
From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia.
CONCLUSIONS
While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited.
Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Pneumonia; Small Cell Lung Carcinoma; Survival Rate; Thrombocytopenia; Young Adult
PubMed: 26232449
DOI: 10.1093/jjco/hyv107