Amrubicin In Patients Research Articles

Influencing factors of efficacy and long‐term use of amrubicin in patients with small cell lung cancer

Amrubicin (AMR) has become the standard of care for post-relapse small cell lung cancer (SCLC). It has also been reported to achieve long-term disease control in patients with good treatment response. However, the optimal patient population for whom AMR is effective and the factors associated with long-term disease control are yet to be identified. The aim of the study was to identify the clinical characteristics and factors associated with long-term disease control in patients with recurrent SCLC who would benefit from AMR therapy. The clinical records of 33 patients diagnosed with recurrent SCLC and treated with AMR were retrospectively reviewed. Clinical information was compared between patients who achieved disease control (effective group) and who developed disease progression (noneffective group) on the first efficacy assessment after AMR and between patients who continued AMR for more than seven cycles (maintenance group) and those who terminated treatment after 1-6 cycles (discontinuation group). The noneffective group included significantly more patients with AMR dose reductions after the second cycle (p = 0.006). AMR dose reduction was an independent risk factor for disease progression. The maintenance group had significantly lower pretreatment lactate dehydrogenase (LDH) levels than the discontinuation group (p = 0.046). A high LDH level was an independent risk factor for short AMR discontinuation. Overall survival was significantly longer in the effective group than in the noneffective group (p < 0.001). In AMR therapy for patients with relapsed SCLC, continuation of AMR without dose reduction after the second cycle may contribute to disease control and prolonged survival.

Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study.

BackgroundTopoisomerase is an essential enzyme for deoxyribonucleic acid replication, and its inhibitors suppress tumor progression. Amrubicin, a topoisomerase II inhibitor, is mainly used in the second-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). However, the impact of different types of topoisomerase inhibitors for first-line chemotherapy on the efficacy of amrubicin remains unclear. In the present study, we aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors.MethodsThis study retrospectively analyzed patients with ES-SCLC who experienced recurrence and were treated with amrubicin at 22 institutions in Japan between April 2015 and November 2020. The progression-free survival of amrubicin monotherapy was investigated using the Kaplan-Meier method.ResultsA total of 320 patients were enrolled in this study, with 59 (18%) receiving platinum plus topoisomerase I inhibitor irinotecan and 261 (82%) receiving platinum plus topoisomerase II inhibitor etoposide as first-line treatment. The progression-free survival of amrubicin was significantly longer in the irinotecan group than in the etoposide group (3.2 vs. 2.5 months; P=0.034).ConclusionsThese results showed that different types of topoisomerase inhibitors could affect the efficacy of amrubicin monotherapy in the second-line treatment of patients with relapsed ES-SCLC.

EP1.01-64 Effect of Amrubicin in Patients with Previously Treated Non-Small-Cell Lung Cancer

EP1.01-64 Effect of Amrubicin in Patients with Previously Treated Non-Small-Cell Lung Cancer

Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies

ObjectivesThere are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor. Materials and methodsThis was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1–3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients. ResultsA total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%–32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient. ConclusionAmrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.

501P - Phase II study of nedaplatin plus amrubicin in patients with untreated, advanced or relapsed squamous cell lung cancer

501P - Phase II study of nedaplatin plus amrubicin in patients with untreated, advanced or relapsed squamous cell lung cancer

A phase 2 randomized study of TAS-102 versus topotecan or amrubicin in patients requiring second-line chemotherapy for small cell lung cancer refractory or sensitive to frontline platinum-based chemotherapy

ObjectivesTAS-102 is an oral combination treatment comprised of an antimetabolite, trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, at a molar ratio of 1:0.5. This antimetabolite has demonstrated efficacy in clinical trials, including a global phase 3 trial in metastatic colorectal cancer. As this agent has shown activity greater than cisplatin in small cell lung cancer xenograft mouse models, the objective of this study was to evaluate TAS-102 in the second-line treatment of small cell lung cancer. MethodsThis was a multicenter, open-label, two-arm, randomized phase 2 study designed to compare oral TAS-102 (35mg/m2/dose twice daily) versus control (topotecan or amrubicin). Patients requiring second-line chemotherapy for treatment of small cell lung cancer, either refractory or sensitive to frontline platinum-based chemotherapy, were enrolled. ResultsEighteen patients were enrolled. Eight of nine patients receiving TAS-102 discontinued treatment due to progressive disease and one patient died due to clinical progression during the safety follow-up. Unplanned interim futility considerations were made, and the study was terminated early because it was unlikely that superiority of TAS-102 versus comparator could be demonstrated. Six control patients discontinued therapy due to progressive disease and one due to an adverse event. Median progression-free survival was 1.4 months (range 0.9–1.8) versus 2.7 months (range 1.0–6.8) for TAS-102 and control, respectively, with a hazard ratio of 3.76 (80% CI, 1.68–8.40) favoring control. The most common adverse events with TAS-102 were neutropenia, diarrhea, anemia, anorexia, and fatigue, each in three patients. ConclusionTAS-102 showed no evidence of activity in second-line small cell lung cancer.

Pharmacokinetics of amrubicin in lung cancer patients with impaired hepatic function

ObjectiveThe pharmacokinetics of amrubicin in patients with impaired hepatic function have not been reported. The aim of this study was to compare the pharmacokinetics of amrubicin and its major metabolite, amrubicinol, and to assess the safety of amrubicin in lung cancer patients with impaired hepatic function and those with normal hepatic function. Materials and methodsFive patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) with small or non-small cell lung carcinoma were enrolled. Liquid chromatography with tandem mass spectrometry was used to determine the amrubicin and amrubicinol concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. ResultsThe terminal half-lives of amrubicin and amrubicinol in whole blood and plasma were slightly longer in arm I than in arm N. The area under the concentration–time curve (AUC0–24h) values of amrubicin in plasma and AUC0–120h of amrubicinol in whole blood in arm I were not larger than those in arm N because of dose adjustments based on prior treatment history and baseline values of total bilirubin, aspartate aminotransferase and alanine aminotransferase. The dose-normalized AUCs (dose 40mg/m2) of amrubicin and amrubicinol in arm I were slightly larger than those in arm N. There were two deaths in arm I, one related to disease progression and one from an unknown cause. ConclusionIf an adjusted dose of amrubicin is used in patients with impaired hepatic function, the exposure of amrubicin and amrubicinol would be within the range of variation observed in patients with normal hepatic function.

Oral 1.01: Phase II trial of amrubicin in patients with previously treated advanced thymic malignancies

Background Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM patients in this trial.

Phase I and Pharmacokinetic Study of Erlotinib Administered in Combination With Amrubicin in Patients With Previously Treated, Advanced Non–small Cell Lung Cancer

We conducted a phase I trial of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose, the dose-limiting toxicities (DLTs), and the pharmacokinetics of this combination in patients with non-small cell lung cancer who had received previous chemotherapy. A total of 9 patients with stage IV disease were treated at 3-week intervals with erlotinib once daily on days 1 through 21 plus a 5-minute intravenous injection of amrubicin on days 1 through 3. The dose levels evaluated were erlotinib (mg/body)/amrubicin (mg/m): 100/30 (n=3), 100/35 (n=3), and 150/30 (n=3). The maximum tolerated dose of erlotinib and amrubicin was 100 mg/body and 35 mg/m because 2 of the 3 patients experienced DLTs during the first cycle of treatment at the third dose level of 150 mg/body and 30 mg/m. Cessation of erlotinib administration for 8 days because of grade 3 leukopenia and grade 3 skin infection (erysipelas) were the DLTs. No drug-drug interactions between erlotinib and amrubicin were observed in this study. The overall response rate was 33%, including 3 partial responses, in the 9 patients. The median progression-free survival for all patients was quite long, 11.3 months, and the median overall survival has not yet been reached. Combined erlotinib plus amrubicin therapy seems to be highly effective, with acceptable toxicity, against non-small cell lung cancer. The recommended dose for phase II studies was erlotinib 100 mg once daily on days 1 through 21, and amrubicin 35 mg/m on days 1 through 3 administered every 21 days.

A phase II trial of novel anthracycline amrubicin in advanced soft tissue sarcoma.

10587 Background: Amrubicin is a 9-aminoanthracycline with significantly less cardiotoxicity than doxorubicin, a current standard against soft tissue sarcoma, and may represent an appealing alternative first line therapy. We report findings in a phase II study investigating tolerability and efficacy of amrubicin in patients with advanced STS. Methods: We enrolled adult patients in a single-arm open label study with locally advanced or metastatic soft tissue sarcoma, no prior systemic treatment, measurable disease, an ECOG PS &lt;2, and adequate organ function. We administered amrubicin (40 mg/m2 IV over 10’) on D#1-3 of a 21D cycle with GCSF support. Six cycles were planned with continuation at clinician discretion. We used RECIST 1.1 to radiologically assess response to therapy. Toxicities were assessed using CTCAE 4.0. The primary objective was overall response rate (CR+PR), and clinical benefit (CR+PR+SD). We employed a 2- stage design, with 15 patients treated in the first stage. Error rates were α=5% for accepting a poor regimen and β=10% for rejecting a promising regimen, with planned enrollment of 30 patients through the second stage if activity was observed. Results: 15 of 15 planned patients enrolled in the first stage of this phase II clinical trial; 10 males and 5 females, with median age 59 (range 30-73). Of the 13 evaluable patients, at 6 cycles 3 patients achieved a PR, with best response of 78% reduction of target lesions; 4 patients demonstrated minor response/stable disease (SD), ranging from 11-28% reduction of target lesions, and 4 patients had minor progression/SD (less than 20% progression). Two patients progressed &gt;20%. Clinical benefit is currently 85.7% (12/14). Amrubicin has been well tolerated, with primarily grade I and II AEs. A single dose adjustment has occurred but no treatment delays. No cardiac complications, ECG or significant echocardiogram changes have been noted. Conclusions: Amrubicin is a novel anthracycline with encouraging activity against STS and an extremely well tolerated side effect profile. Further study of amrubicin in STS is warranted. With minor treatment-related morbidity, amrubicin would also be a good candidate for combination therapy with other standard or experimental therapeutics. Clinical trial information: NCT01259375.

Risk Factors for Predicting Severe Neutropenia Induced by Amrubicin in Patients with Advanced Lung Cancer

Background: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3–4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m². The incidence of grade 3–4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01–134.15; p = 0.049), higher AMR doses (40 mg/m² or more) (OR = 5.98; 95% CI 1.77–23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04–4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.

Efficacy and safety of amrubicin in patients with advanced or recurrent thymoma.

e17513 Background: Thymoma is rare thoracic tumor, which is chemoresponsive with anthracycline or cisplatin-containing regimen in advanced or recurrent setting. Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small-cell lung cancer. The purpose of this study was to determine the efficacy and safety of amrubicin in patients with advanced or recurrent thymoma. Methods: We reviewed 11 consecutive patients with advanced or recurrent thymoma treated with single-agent amrubicin therapy at our institution from May 2006 to September 2010, retrospectively. Amrubicin was administered intravenously at 40 or 45 mg/m2 on day 1 to 3 of 3-4 weeks until disease progression or development of intolerance. Results: Profile of patients included: median age was 57 years (range 25–74); Male/Female=5/6; PS 0/1= 7/4; and Masaoka stage IVA/IVB/recurrence=7/2/2. All patients had received no prior chemotherapy. The median number of treatment cycles was 4 (range 3-6). A partial response was achieved in 1 patient and 10 patients exhibited stable disease. The overall response rate was 9%, but 3 patients had at least a 20% reduction in tumor size with amrubicin. The median reduction rate in tumor size was 13% (range 0-40). The median progression-free survival period was 5.4 months (range 2.3-15.8 months). The median overall survival has not been reached although a median follow-up time was 2.5 years. Based on the Kaplan-Meier method, the estimated 3-year survival rate was 83%. The most common adverse events were hematological toxicities. Five patients had grade 3/4 neutropenia, but febrile neutropenia was not observed. Non-hematological grade 3 toxicities were less frequent. There were no treatment-related deaths. Conclusions: Single-agent amrubicin showed modest activity and acceptable safety profile as chemotherapy for advanced or recurrent thymoma. Additional testing of amrubicin combined with cisplatin in this disease is warranted.

Phase II study of irinotecan and amrubicin in patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 0402

Background. The survival advantage achieved by existing anti-cancer agents as second-line therapy for relapsed non-small cell lung cancer (NSCLC) is modest and further improvement of treatment outcome is desired. Combination chemotherapy with irinotecan and amrubicin for advanced NSCLC has not been fully evaluated. Methods. The primary endpoint of this phase II clinical trial was objective response. Patients with NSCLC who had been treated previously with one or two chemotherapy agents were enrolled. Irinotecan and amrubicin were both administered on Days 1 and 8 of a 21-day cycle, at doses of 100 mg/m2 and 40 mg/m2, respectively. Results. Between 2004 and 2006, 31 patients received a total of 101 courses; the median number of courses administered was three (range, one to six). Objective response was obtained in nine of the 31 patients (29.0% response rate; 95% confidence interval (CI), 12.1–46.0%). With a median follow-up time of 43.9 months, median survival time and the median progression-free survival time were 14.2 and 4.0 months, respectively. Myelosuppression was the most frequently observed adverse event, with grade 3/4 neutropenia in 51% of patients. Febrile neutropenia developed after nine courses (9%) and resulted in one treatment-related death. Cardiac toxicity and diarrhea, possibly specific for both agents, were infrequent and manageable. Conclusion. Combination chemotherapy with irinotecan and amrubicin is effective in patients with NSCLC but showed moderate toxicities in second- or third-line settings.

Phase I and pharmacologic study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial

To evaluate the safety and tolerability of amrubicin (AMR), determine its maximum tolerated dose (MTD), its dose-limiting toxicities (DLTs), and its recommended dose (RD), and to conduct a pharmacokinetic study of weekly AMR administrations in patients with chemotherapy-refractory or recurrent small cell or non-small cell lung cancer. Patients with refractory or relapsed non-small cell and small cell lung cancer after 1 or 2 regimens of chemotherapy were eligible. AMR was initiated at 45 mg/m(2) weekly (repetition of dose on 1st and 8th day with a rest on day 15). The dose level was increased by 5 mg/m(2) by modified Fibonacci dose escalation scheme. Seven patients had small cell lung cancer and 9 had non-small cell lung cancer. Fifty-four courses (median: 3, range: 1-6) were administered at 5 dose levels. At 65 mg/m(2), 3 patients had DLTs as follows: 1 was grade 3 (CTCAE v3.0) in AST/ALT, 1 was grade 3 febrile neutropenia, and 1 was grade 4 neutropenia. Leukocytopenia and neutropenia were correlated with amrubicinol (AMR-OH) C (max) (P = 0.042, P = 0.047, respectively). The AUC (area under the curve of plasma concentration versus time extrapolated to concentration zero) of AMR and AMR-OH did not depend on the dose levels. In the present phase I study of AMR administered weekly to previously treated lung cancer patients, the maximum tolerated dose and RD were 65 and 60 mg/m(2), respectively. The best response rate was 15.4%, and adverse events with this schedule were tolerable.

Phase I study to assess pharmacokinetics (PK), QT/QTc effect, and safety of amrubicin in patients (pts) with advanced solid tumors.

7073 Background: Amrubicin (AMR), a 3rd-generation synthetic anthracycline has shown promising activity in solid tumors, including small cell lung cancer (SCLC) without cardiotoxicity. This intensi...

Phase II Study of Sequential Triplet Chemotherapy, Irinotecan and Cisplatin Followed by Amrubicin, in Patients with Extensive-Stage Small Cell Lung Cancer: West Japan Thoracic Oncology Group Study 0301

Combination chemotherapy of irinotecan, a topoisomerase I inhibitor, and cisplatin is a standard treatment in patients with extensive-stage small cell lung cancer (SCLC). Amrubicin, a novel 9-aminoanthracycline, inhibits topoisomerase II. We investigated a sequential triplet chemotherapy consisting of irinotecan and cisplatin followed by amrubicin in patients with extensive-stage SCLC. Eligible patients were aged 20 to 70 years and had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable lesions, and adequate organ functions. Chemotherapy consisted of irinotecan 60 mg/m on days 1 and 8 plus cisplatin 60 mg/m on day 1 every 3 weeks for three cycles and then amrubicin 40 mg/m alone on days 1 to 3 every 3 weeks for three cycles. From September 2004 to September 2006, 45 patients were enrolled, 43 were evaluable for response and survival, and 44 were evaluable for toxicity. Twenty-eight patients (64%) completed the full planned chemotherapy. One patient achieved complete response and 33 had partial response for an overall response rate of 79%. Median progression-free survival was 6.5 months. Median overall survival was 15.4 months. Major toxicity was myelosuppression. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia occurred in 57%, 7%, 0%, and 7% of patients during irinotecan/cisplatin cycles and in 91%, 27%, 9%, and 15% of patients during amrubicin cycles, respectively. The sequential triplet chemotherapy, irinotecan and cisplatin followed by amrubicin, is an effective and well-tolerated treatment in patients with extensive-stage SCLC. Further investigation of this treatment is warranted.

Plasma concentration of amrubicinol in gamma phase in patients treated for 3 days with amrubicin and hematological toxicities

e14606 Background: Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-amino-anthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we performed a PK/PD study of AMR in patients with lung cancer treated with AMR alone or the combination of AMR + cisplatin (CDDP). Methods: AMR was given at a dose of 30 or 40 mg/m2 on days 1 to 3. Plasma samples were collected at pretreatment, 24 hours after the 1st injection (day 2), and 24 hours after the 3rd injection (day 4). Plasma concentrations of AMR, AMR-OH, and CDDP were determined by HPLC and AAS. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid Emax model. Results: A total of 35 patients with a median age of 65 years (range 40–78), including 10 with small cell lung cancer (SCLC), 23 with non-small cell lung cancer (NSCLC), 1 with thymic cancer, and 1 with neuroblastoma were enrolled. A total of 107 plasma samples were available for study. Mean concentrations of AMR on day 2, AMR on day 4, AMR-OH on day 2, and AMR-OH on day 4 were 8.52ng/mL+4.63, 16.55ng/mL+11.92, 7.28 ng/mL+3.56 SD, and 13.35ng/mL+5.56 (mean ± SD), with significant increase from day 2 to day 4 for both AMR (p&lt;0.0001) and AMR-OH (p&lt;0.0001). Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (p=.018, p=.012, and p=.025). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (p = .081). No relationships were observed between drug concentrations and responses. The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients with co-administration with CDDP using a sigmoid Emax model. Conclusions: The plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. Assessment of plasma concentration of AMR-OH at one time point might enable prediction of hematological toxicities. No significant financial relationships to disclose.

A dose finding and PK/PD study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial

e13517 Background: Amrubicin (AMR) is a potent topoisomerase II inhibitor, and a promising agent for both small cell and non-small cell lung cancer. AMR is usually administered on days 1–3 intravenously. However, it causes severe, occasionally fatal, toxicity of leucopenia and neutropenia. The purpose of this study was to evaluate the safety and tolerability of AMR, to determine the recommended weekly dose, and to conduct a PK/PD study in patients with chemotherapy-refractory or recurrent lung cancer. Methods: Refractory or relapsed non-small cell and small cell lung cancer patients after 1 or 2 regimens, younger than 80 and with adequate main organ functions were eligible. AMR was initiated 45 mg/m2 given weekly (on day 1 and 8 q3wks). The dose level was increased by 5 mg/m2 by modified Fibonacci dose escalation scheme. Dose limiting toxicity (DLT) was assessed on the 1st cycle. Results: 16 patients were enrolled. Patients were 7 small cell lung cancer and 9 non-small cell lung cancer. 54 cycles (median: 3, range: 1–6) were administered in 5 dose levels. In 65 mg/m2 level, 3 patients had DLTs. The maximum tolerated dose was 65 mg/m2. The recommended weekly AMR dose was determined to be 60 mg/m2. Leucocytopenia, neutropenia, thrombocytopenia, and the dose level were correlated (p&lt;0.001, p=0.0012, p=0.043) respectively. Leucocytopenia, neutropenia, and amrubicinol (AMR-OH) Cmax were correlated (p=0.042, p=0.047) respectively. AUC (AUC extrapolated to concentration-zero) of AMR and AMR-OH did not depend on the dose levels. The pharmacokinetic results are shown in the Table. [Table: see text] [Table: see text]

Phase II study of irinotecan plus cisplatin followed by amrubicin in patients with extensive-stage small-cell lung cancer (WJTOG 0301)

19039 Background: The combination chemotherapy of irinotecan (CPT-11), that is a topoisomerase (topo) I inhibitor, and cisplatin (CDDP) is one of the standard treatments in patients with extensive-stage small-cell lung cancer (SCLC). Amrubicin (AMR), that is a novel 9-aminoanthracycline, inhibits topo II. Some preclinical studies reported that a combination of topo I and II inhibitors shows a synergistic cytotoxicity. We investigated the sequential chemotherapy that consisted of CPT-11 plus CDDP followed by AMR in patients with extensive- stage SCLC. Methods: Eligible patients had an ECOG performance status of 0 or 1, an age of ≤ 70 years, measurable lesions, and adequate organ functions. Treatment consisted of CPT-11 60 mg/m2 on days 1 and 8 plus CDDP 60 mg/m2 on day 1 every three weeks for three cycles, and then AMR 40 mg/m2 on days 1 to 3 every three weeks for three cycles. We evaluated the efficacy and toxicity of this treatment. Results: From Sep. 2004 to Sep. 2006, 45 patients were enrolled, of whom, 43 patients were assessable for response and survival, and 44 patients were assessable for toxicity. Twenty-eight (64%) patients received full planned chemotherapy. One patient achieved a CR and 33 patients had a PR, with a response rate of 79% (95% CI, 64% to 90%). The median overall survival time was 15.4 months and the median progression-free survival was 6.5 months. The major toxicity was myelosuppression. Grade 3 or 4 neutropenia, neutropenic fever, and anemia occurred in 57%, 7%, and 7% of patients during the CPT-11 plus CDDP phase, and 91%, 15%, and 27% of patients during the AMR phase, respectively. No treatment-related death was observed. Conclusions: CPT-11 plus CDDP followed by AMR is an effective and well-tolerated treatment in patients with extensive-stage SCLC. It is likely that the sequential AMR prolongs the survival. No significant financial relationships to disclose.

Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC)

7061 Background: Amrubicin, a totally synthetic 9-amino-anthracycline, has been shown to have excellent antitumor activity as a single agent against previously untreated extensive-stage SCLC. The objective of this study was to assess the efficacy and safety of amrubicin in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving first- or second- line chemotherapy were eligible for the study. Amrubicin (45mg/m2/day) was administered on Days 1–3 every 3 weeks for four to six courses. The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 33 patients (Simon’s two-stage minimax design). Results: From June 2003 to January 2005, 35 patients (26 males/9 females, median age, 64 years) were enrolled, and 34 of these patients were treated with the study drug. Four courses or more were administered in 59% (20/34) of the patients, and dose reduction was required in 52% (15/29) of the patients who had received 2 courses or more. Four complete responses and 14 partial responses were observed among the 34 treated patients, yielding a RR of 53% (95% confidence interval: 35.1%–70.2%). The median survival duration in the patients was 8.8 months, and the 1-year survival rate was 26%. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia were observed in 76%, 97% and 38% of the patients, respectively. Febrile neutoropenia occurred in 12 patients (35%), and one patient died from treatment related pneumonia. Conclusion: Amrubicin (45mg/m2/day) was effective in patients with previously treated advanced SCLC, however, severe hematological toxicities occurred in some patients. No significant financial relationships to disclose.