Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

A proposed approach for analyzing post-study therapy effect in survival analysis.

Clinical trials that explore long-term endpoints may confound the analysis when post-study therapy effects are considered. This article introduces a procedure to mediate the effects of confounding and allow inferences of first-line experimental treatments in the presence of post-study therapy. The procedure is evaluated by intensive simulation analyses and applied to an analysis of a clinical cancer trial.

18F-FDG PET/CT response in a phase 1/2 trial of nab-paclitaxel plus gemcitabine for advanced pancreatic cancer.

BACKGROUND: Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine. METHODS: Tumors were measured by [18F]2-fluoro-2-deoxyglucose PET/computed tomography (CT) in patients who received nab-paclitaxel 100 (n = 13), 125 (n = 38), or 150 (n = 1) mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Lesion metabolic activity was evaluated at baseline and 6 and 12 weeks postbaseline. RESULTS: Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m2 and 125 mg/m2 cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m2 had a 4-month survival advantage over those who received 100 mg/m2. All patients in the nab-paclitaxel 125 mg/m2 cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m2 cohort, investigator-assessed objective response rates were 77% and 44% among patients with a CMR and PMR, respectively, with no correlation between PET and CT response (Spearman r s = 0.22; P = 0.193). Patients in the nab-paclitaxel 125 mg/m2 cohort with a CMR experienced a significantly longer overall survival vs those with a PMR (median, 23.0 vs 11.2 months; P = 0.011), and a significant correlation was found between best percentage change in tumor burden by PET and survival: for each 1% decrease in PET score, the risk of death decreased by 2%. CONCLUSIONS: The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 for treating mPC and the utility of PET for measuring treatment response. Treatment response by PET analysis may be considered when evaluating investigational agents in mPC. TRIAL REGISTRATION: NCT00398086.

Tumor Reduction in Primary and Metastatic Pancreatic Cancer Lesions With nab-Paclitaxel and Gemcitabine: An Exploratory Analysis From a Phase 3 Study.

OBJECTIVES: Results from the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to approval of nab-paclitaxel plus gemcitabine for first-line treatment of metastatic pancreatic cancer. The current analysis evaluated the effects of nab-paclitaxel plus gemcitabine versus gemcitabine on primary pancreatic and metastatic lesions. METHODS: In this analysis of the previously described MPACT trial, changes in pancreatic and metastatic tumor burden were assessed using independently measured diameters of lesions on computed tomography or magnetic resonance imaging scans. Changes in the sums of longest tumor diameters were summarized using descriptive statistics and were included in a multivariate analysis of overall survival. RESULTS: Primary pancreatic lesion measurement was feasible. Reductions in primary pancreatic tumor burden and metastatic burden from baseline to nadir were significantly greater with nab-paclitaxel plus gemcitabine versus gemcitabine. Baseline pancreatic tumor burden was independently predictive of survival. Both regimens elicited linear reductions in primary pancreatic and metastatic tumor burden through time. There was a high within-patient concordance of tumor changes between primary pancreatic lesions and metastatic lesions. CONCLUSIONS: This analysis of MPACT demonstrated significant tumor shrinkage benefit for nab-paclitaxel plus gemcitabine in both primary pancreatic and metastatic lesions, supporting ongoing evaluation of this regimen in locally advanced disease.

Weekly nab-Paclitaxel in Combination With Carboplatin as First-Line Therapy in Patients With Advanced Non-Small-Cell Lung Cancer: Analysis of Safety and Efficacy in Patients With Diabetes.

PURPOSE: To examine outcomes in a phase 3 trial of nab-paclitaxel plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C) in a subset of patients with advanced non-small-cell lung cancer (NSCLC) and diabetes. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC received nab-P 100 mg/m2 on days 1, 8, and 15 or sb-P 200 mg/m2 on day 1, both with C at an area under the curve of 6 mg·min/mL on day 1 every 3 weeks. Overall response rate (ORR) and progression-free survival (PFS) were determined by blinded, independent, centralized review. P values were based on chi-square test for ORR and log-rank test for overall survival (OS) and PFS. RESULTS: Of the 1052 randomized patients in the phase 3 trial, 61 had diabetes according to prespecified terms (nab-P/C, 31; sb-P/C, 30). ORR for nab-P/C versus sb-P/C in this subset was 52% versus 27% (relative risk ratio, 1.935; P = .046), median PFS was 10.9 versus 4.9 months (hazard ratio, 0.420; P = .016), and median OS was 17.5 versus 11.1 months (hazard ratio, 0.550; P = .057). Treatment differences in PFS remained significant (P ≤ .036) after adjusting for histology, region, stage, race, and age and also remained significant in OS for histology (P = .039). Patients with diabetes experienced lower rates of grade 3 or higher neutropenia and peripheral neuropathy and higher rates of thrombocytopenia and anemia with nab-P/C versus sb-P/C. CONCLUSION: nab-P/C demonstrated improved efficacy and manageable tolerability in patients with advanced NSCLC and diabetes.

Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial.

PURPOSE: To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. RESULTS: Four hundred one patients were enrolled (251 with non-small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P =.062) and improved neurologic function as assessed by a blinded events review committee (P =.048). CONCLUSION: Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.

PURPOSE: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS: Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points.

PURPOSE: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases. PATIENTS AND METHODS: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points. RESULTS: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium's tumor selectivity was established with MRI. CONCLUSION: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.

Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme.

The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.

Weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: analysis of safety and efficacy in patients with renal impairment.

INTRODUCTION: Renal impairment in cancer patients can affect treatment tolerability and outcomes. This analysis evaluated the safety and efficacy of nab-paclitaxel (nab-P) versus solvent-based paclitaxel (sb-P), both in combination with carboplatin (C), in patients with advanced non-small-cell lung cancer (NSCLC) and renal impairment. METHODS: Untreated patients with stage IIIB/IV disease with NSCLC and a performance status of 0/1 were randomly assigned (1:1) to receive 100 mg/m(2)nab-P weekly plus C (under the curve = 6, every 3 weeks) or 200 mg/m(2) sb-P plus C (under the curve = 6) every 3 weeks. The primary end point was overall response rate. RESULTS: Of 1038 treated patients in the phase III trial, 38% had mild renal impairment (creatinine clearance > 50 to ≤ 80 mL/min; n = 198 for nab-P/C and n = 206 for sb-P/C) and 5% had moderate renal impairment (creatinine clearance ≤ 50 mL/min: n = 26 for nab-P/C and n = 27 for sb-P/C). For nab-P/C versus sb-P/C, the treatment difference in efficacy in patients with either level of renal impairment was comparable to the overall population but did not reach statistical significance, with an overall response rate of 35% versus 27% (response rate ratio, 1.324; P = .060) in patients with mild renal impairment, and 31% versus 19% (response rate ratio, 1.662; P = .300) in patients with moderate renal impairment. Overall survival and progression-free survival were nonsignificantly longer for nab-P/C versus sb-P/C in these subsets. Patients with renal impairment experienced less grade 3 or higher neutropenia and sensory neuropathy, but more thrombocytopenia and anemia with nab-P/C versus sb-P/C. CONCLUSION: nab-P/C proved beneficial and tolerable in patients with advanced NSCLC and mild and moderate renal impairment.

Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial.

BACKGROUND: Triple-negative breast cancer is an aggressive disease with unmet clinical needs. In a phase III study of patients with metastatic triple-negative breast cancer, first-line gemcitabine/carboplatin resulted in a median progression-free survival of 4.6 months. nab-paclitaxel-based regimens (with gemcitabine or carboplatin±bevacizumab) also demonstrated efficacy and safety in first-line phase II trials of human epidermal growth factor receptor 2-negative metastatic breast cancer. TRIAL DESIGN: In this international, multicenter, open-label, randomized phase II/III trial, the efficacy and safety of first-line nab-paclitaxel with gemcitabine or with carboplatin will be compared with gemcitabine/carboplatin (control arm) for metastatic triple-negative breast cancer. METHODS: In the phase II portion, 240 patients with measurable metastatic triple-negative breast cancer and treatment-naive for metastatic disease will be randomized 1:1:1 (stratified by disease-free interval: ≤1 versus>1 year) to nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 plus carboplatin area under the curve 2 mg×min/mL, or gemcitabine 1000 mg/m2 plus carboplatin area under the curve 2 mg×min/mL, all given on days 1 and 8 of a 21-day cycle. Investigator-assessed progression-free survival (primary endpoint), overall response rate, overall survival, and safety will be assessed. A ranking algorithm of five efficacy and safety parameters will be used to pick the "winner" of the nab-paclitaxel regimens. In the phase III portion, 550 patients will be randomized 1:1 (stratified by disease-free interval: ≤1 versus >1 year, and prior adjuvant/neoadjuvant taxane use) to the nab-paclitaxel combination arm selected from the phase II portion or to the control arm. Patients in phase II will not be part of the phase III population. The phase III primary endpoint is blinded, independently-assessed progression-free survival; secondary endpoints include blinded, independently-assessed overall response rate, overall survival, disease control rate, duration of response, and safety. Biomarker and circulating tumor-cell exploratory analyses and quality-of-life assessments will also be performed. A list of approving ethical bodies was provided in Additional file 1. DISCUSSION: The tnAcity trial aims to identify a new standard cytotoxic chemotherapy regimen for first-line treatment of metastatic triple-negative breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01881230 . Date of registration: 17 June 2013.

The emerging role of reactive oxygen species in cancer therapy.

The generation of reactive oxygen species (ROS) can be exploited therapeutically in the treatment of cancer. One of the first drugs to be developed that generates ROS was procarbazine. It is oxidised readily in an oxic environment to its azo derivative, generating ROS. Forty years ago, Berneis reported a synergistic effect in DNA degradation when procarbazine was combined with radiation; this was confirmed in preclinical in vivo modes. Early uncontrolled clinical trials suggested an enhancement of the radiation effect with procarbazine, but two randomised trials failed to confirm this. The role of ROS in cancer treatments and in the development of resistance to chemotherapy is now better understood. The possibility of exploiting ROS as a cancer treatment is re-emerging as a promising therapeutic option with the development of agents such as buthionine sulfoximine and motexafin gadolinium.

Patient-reported neuropathy and taxane-associated symptoms in a phase 3 trial of nab-paclitaxel plus carboplatin versus solvent-based paclitaxel plus carboplatin for advanced non-small-cell lung cancer.

INTRODUCTION: nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non-small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nab-P/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. METHODS: Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. RESULTS: Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). CONCLUSION: In this trial of patients receiving first-line treatment for advanced non-small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C.

Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer.

PURPOSE: Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. PATIENTS AND METHODS: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m(2) intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m(2) IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. CONCLUSION: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.

Phase I study to assess the pharmacokinetics and the effect on cardiac repolarization of amrubicin and amrubicinol in patients with advanced solid tumors.

PURPOSE: To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. METHODS: Patients received amrubicin 40 mg/m(2)/day as a 5-min infusion on days 1-3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1-9 and time-matched triplicate electrocardiograms on the "off-drug" visit (1-5 days prior to start of treatment) and days 1-9. RESULTS: Twenty-four patients were treated. Amrubicinol reached peak concentration 2-4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline. CONCLUSIONS: Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.

Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial.

PURPOSE: This phase III trial compared the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In all, 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 mg/m(2) nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 once every 3 weeks (nab-PC) or 200 mg/m(2) sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks (sb-PC). The primary end point was objective overall response rate (ORR). RESULTS: On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-PC (33% v 25%; response rate ratio, 1.313; 95% CI, 1.082 to 1.593; P = .005) and in patients with squamous histology (41% v 24%; response rate ratio, 1.680; 95% CI, 1.271 to 2.221; P < .001). nab-PC was as effective as sb-PC in patients with nonsquamous histology (ORR, 26% v 25%; P = .808). There was an approximately 10% improvement in progression-free survival (median, 6.3 v 5.8 months; hazard ratio [HR], 0.902; 95% CI, 0.767 to 1.060; P = .214) and overall survival (OS; median, 12.1 v 11.2 months; HR, 0.922; 95% CI, 0.797 to 1.066; P = .271) in the nab-PC arm versus the sb-PC arm, respectively. Patients ≥ 70 years old and those enrolled in North America showed a significantly increased OS with nab-PC versus sb-PC. Significantly less grade ≥ 3 neuropathy, neutropenia, arthralgia, and myalgia occurred in the nab-PC arm, and less thrombocytopenia and anemia occurred in the sb-PC arm. CONCLUSION: The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious and resulted in a significantly improved ORR versus sb-PC, achieving the primary end point. nab-PC produced less neuropathy than sb-PC.

Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy.

PURPOSE: This phase II study evaluated the safety and efficacy of single-agent amrubicin versus topotecan in patients with small-cell lung cancer (SCLC) sensitive to first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned 2:1 to amrubicin (40 mg/m(2)/d in a 5-minute intravenous [IV] infusion, days 1 through 3, every 21 days) or topotecan (1.5 mg/m(2)/d in a 30-minute IV infusion, days 1 through 5, every 21 days). The primary efficacy end point was overall response rate (ORR) for amrubicin. Secondary end points included time to progression, median progression-free survival (PFS), and median overall survival (OS). RESULTS: Of 76 patients enrolled, 50 patients were randomly assigned to amrubicin, and 26 patients were randomly assigned to topotecan. Amrubicin treatment resulted in a significantly higher ORR than topotecan (44% v 15%; P = .021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. However, grade 3 or worse neutropenia and thrombocytopenia seemed to be more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively). CONCLUSION: Amrubicin shows promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Additional studies are ongoing.