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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. [ABSTRACT FROM AUTHOR]

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 [ 18 F]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/m 2 plus gemcitabine 1000 mg/m 2 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/m 2 and 125 mg/m 2 cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m 2 had a 4-month survival advantage over those who received 100 mg/m 2 . All patients in the nab-paclitaxel 125 mg/m 2 cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m 2 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/m 2 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/m 2 plus gemcitabine 1000 mg/m 2 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.

Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

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.

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/m 2 on days 1, 8, and 15 or sb-P 200 mg/m 2 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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.

Background: The efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial., Patients and Methods: Chemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m(2) on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m(2) every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS)., Results: A total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631-0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738-1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm., Conclusions: nab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients., Methods: Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ⩾60 and ⩾70 years as cut points., Results: Among patients aged ⩾60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2-2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ⩾70 years age group, nab-PC showed similar, but non-significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL., Conclusion: Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (© 2014 by American Society of Clinical Oncology.)

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.

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.).

Background: This analysis compared the efficacy and safety outcomes by histology of nab-paclitaxel (nab-P) plus carboplatin (C) versus solvent-based paclitaxel (sb-P) plus C in patients with advanced non-small-cell lung cancer (NSCLC) based on preplanned stratification factors specified in the phase III trial protocol., Patients and Methods: Patients with untreated stage III/IV NSCLC received 100 mg/m(2) nab-P weekly and C (area under the curve, AUC = 6) every 3 weeks (q3w) or 200 mg/m(2) sb-P plus C (AUC = 6) q3w. Primary end point was objective overall response rate (ORR)., Results: nab-P/C versus sb-P/C produced a significantly higher ORR (41% versus 24%; response rate ratio [RRR] 1.680; P < 0.001) in patients with squamous cell (SCC) NSCLC. For nab-P/C versus sb-P/C, ORRs were 26% versus 27% (RRR 0.966; P = 0.814) in patients with adenocarcinoma, 33% versus 15% (RRR 2.167; P = 0.323) in patients with large cell carcinoma (LC), and 24% versus 15% (RRR 1.593; P = 0.372) in patients with not otherwise specified histology. Median overall survival for nab-P/C versus sb-P/C in patients with SCC was 10.7 versus 9.5 months (HR 0.890; P = 0.310), and 12.4 versus 10.6 months (HR 1.208; P = 0.721) for patients with LC. nab-P/C produced significantly (P < 0.05) less grade 3/4 neuropathy and arthralgia, whereas sb-P/C produced less thrombocytopenia and anemia., Conclusion(s): First-line nab-P/C demonstrated a favorable risk-benefit profile in patients with NSCLC regardless of histology.

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.

Background: This analysis evaluates safety and efficacy in elderly (≥ 70 years old) versus younger patients enrolled in a phase III advanced non-small-cell lung cancer (NSCLC) trial., Patients and Methods: Untreated stage IIIB/IV patients with PS 0/1 were randomly assigned (1:1) to carboplatin AUC6, day 1 every 3 weeks, and either nab-paclitaxel (Abraxane) 100 mg/m(2) weekly (nab-P/C) or solvent-based paclitaxel (Taxol) 200 mg/m(2) day 1 every 3 weeks (sb-P/C). The primary end-point was overall response rate (ORR)., Results: Fifteen percent of 1052 enrolled patients were elderly: nab-P/C, n = 74; sb-P/C, n = 82. In both age cohorts, the ORR was higher with nab-P/C versus sb-P/C (age ≥ 70: 34% versus 24%, P = 0.196; age <70: 32% versus 25%, P = 0.013). In elderly patients, progression-free survival (PFS) trended in favor of nab-P/C (median 8.0 versus 6.8 months, hazard ratio (HR) 0.687, P = 0.134), and overall survival (OS) was significantly improved (median 19.9 versus 10.4 months, HR 0.583, P = 0.009). In younger patients, PFS (median 6.0 versus 5.8 months, HR 0.903, P = 0.256) and OS (median 11.4 versus 11.3 months, HR 0.999, P = 0.988) were similar in both arms. Adverse events were similar in both age groups, with less neutropenia (P = 0.015), neuropathy (P = 0.001), and arthralgia (P = 0.029), and increased anemia (P = 0.007) with nab-P/C versus sb-P/C., Conclusions: In elderly NSCLC patients, nab-P/C as first-line therapy was well tolerated and improved the ORR and PFS, with substantially longer OS versus sb-PC.

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.

Purpose: Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell lung cancer (SCLC)., Patients and Methods: Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m(2)/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF)., Results: Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m(2)., Conclusion: Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.

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.

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.

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.

The outcome of patients with brain metastases is generally poor. Survival alone is not necessarily a good measure of clinical outcome. Measures of neurocognitive function and the impact of the disease and treatments on functional status also need to be considered. Although these parameters have been measured in patients with primary brain tumors, they have not been as thoroughly evaluated in patients with brain metastases. The Mini-Mental State Examination provides limited assessment of neurocognitive domains impaired in brain tumor patients. It is less sensitive to mild impairment, does not avoid memorized learning from repeat administration, and does not have validated alternative forms necessary for non-English speaking patients. To determine the feasibility of using a more comprehensive neurocognitive test battery, motor, verbal, executive, and daily functions were assessed in 30 patients with brain metastases. The test battery included the Hopkins Verbal Learning Tests, Controlled Oral Word Association Test, Grooved Pegboard Test, Trailmaking Tests A and B, and the Barthel Index. In this study, there was complete patient compliance, with average test completion time of 23 +/- 6 minutes. Despite high functional status, most patients demonstrated impairment in memory and fine motor domains. Neurocognitive test batteries can and should be used in patients with brain metastases enrolled in clinical trials.

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.

Purpose: Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival., Patients and Methods: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range., Results: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%., Conclusion: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.

Background: In photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis., Methods and Results: An open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect., Conclusions: This phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.

Purpose: Gadolinium texaphyrin (Gd-Tex, PCI-0120) is an expanded porphyrin that has demonstrated radiation enhancement. In this study, we evaluated the radiation enhancement and biolocalization of Gd-Tex in three animal tumor models., Methods and Materials: EMT6, SMT-F, and MCa tumors were established intramuscularly or subcutaneously. Gd-Tex and other metallotexaphyrins were administered prior to single or multiple fractions of radiation. 14C-labeled Gd-Tex was used for biolocalization studies., Results: Gd-Tex, in combination with radiation, produced significant tumor growth delay compared to irradiated control groups in both single and multifraction radiation studies. Gd-Tex radiation enhancement was observed only when the drug was given before, but not after irradiation. Several metallotexaphyrins, identical except for the metal ion, were studied in the EMT6 tumor model including gadolinium (Gd), lutetium (Lu), europium (Eu), yttrium (Y), and cadmium (Cd) texaphyrin complexes. Only Gd-Tex produced radiation enhancement. Biodistribution studies using 14C-labeled Gd-Tex demonstrated drug selectivity and retention in tumors growing intramuscularly compared to uninvolved muscle and plasma., Conclusions: Gd-Tex produces reproducible radiation enhancement in a variety of in vivo tumor models. This drug's unique radiochemistry, tumor selectivity, and in vivo activity suggests possible mechanisms of action not addressed by in vitro assay methods.

Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35-77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.

Synthetic peptide ligands specific for the surface immunoglobulin receptor of the human Burkitt's lymphoma cell line SUP-B8, previously identified using phage display libraries, induced apoptosis of the SUP-B8 cells in vitro when administered as dimers or tetramers. The use of synthetic peptide ligands is being explored for immunotherapy of B-cell lymphoma. It will be critical to identify which of the peptide ligands identified are the most active functionally. Using the Cytosensor microphysiometer, SUP-B8 cells and B-lymphoma cells obtained from patients were found to acidify their extracellular environment within minutes of specific activation by surrogate peptide ligands or by anti-idiotype antibodies. This signal was blocked by pretreatment of the lymphoma cells with the tyrosine kinase inhibitor genistein. Treatment of SUP-B8 cells with dimeric and tetrameric specific peptide ligands caused a rapid increase in extracellular acidification rate, which peaked after 10 min at approximately 15 and 20% above basal rates, respectively. These responses were blocked by excess monomeric peptide. To evaluate the ability of different peptide ligands to induce a signal directly on lymphoma cells, thereby establishing their relative affinity to the surface immunoglobulin receptor, acidification rate changes were measured at varying peptide concentrations. The microphysiometer signal correlated with the known relative affinities and antiproliferative potencies of the peptides. This approach is particularly useful for primary tumor cells that cannot be cultured. The signal may be predictive of the efficacy of treatment with synthetic peptide ligands and may be useful in the evaluation of ligands for other cell surface receptors with biological effects on B-lymphoma cells.

Peptide ligands for the antigen binding site of the surface immunoglobulin receptor of a human B-cell lymphoma cell line were identified with the use of filamentous phage libraries displaying random 8- and 12-amino acid peptides. Corresponding synthetic peptides bound specifically to the antigen binding site of this immunoglobulin receptor and blocked the binding of an anti-idiotype antibody. The ligands, when conjugated to form dimers or tetramers, induced cell death by apoptosis in vitro with an IC50 between 40 and 200 nM. This effect was associated with specific stimulation of intracellular protein tyrosine phosphorylation.