Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial.

PURPOSE: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

BACKGROUND: nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. PATIENTS AND METHODS: Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). RESULTS: Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. CONCLUSIONS: nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. EUDRACT: 2013-000144-26.

nab-Paclitaxel plus gemcitabine in metastatic pancreatic adenocarcinoma: Australian subset analyses of the phase III MPACT trial.

AIM: The phase III MPACT trial (N = 861) demonstrated superior overall survival (OS) with first-line nab-paclitaxel plus gemcitabine versus gemcitabine alone (median, 8.7 months vs 6.6 months; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.83; P < 0.001) in patients with metastatic pancreatic cancer. The efficacy benefit of the combination over gemcitabine alone was observed across patient subgroups, including those based on region. This subset analysis was designed to examine the safety and efficacy of nab-paclitaxel plus gemcitabine in patients treated in Australia to understand whether differences in patient population or regional variations in patient care had any impact on clinical outcomes. METHODS: Patients with metastatic pancreatic cancer received first-line nab-paclitaxel plus gemcitabine or gemcitabine alone in the MPACT study; this analysis focused on those treated in Australia. RESULTS: In the Australian cohort, 120 patients were randomized to receive nab-paclitaxel plus gemcitabine (n = 61) or gemcitabine alone (n = 59). Median OS was 9.4 months with nab-paclitaxel plus gemcitabine versus 6.7 months with gemcitabine alone (HR, 0.64; 95% CI, 0.44-0.94; P = 0.022). Progression-free survival (median, 5.5 months vs 3.6 months; HR, 0.65; 95% CI, 0.42-1.00; P = 0.049) and the overall response rate (23% vs 2%; P < 0.001) were significantly improved with the combination. No new safety signals were observed. CONCLUSIONS: The results of this subset analysis confirm the efficacy and manageable safety profile of nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer treated in Australia.

Enhanced photoinduced antibacterial activity of a BODIPY photosensitizer in the presence of polyamidoamines.

Photosensitizers belonging to the boron-dipyrromethenes (BODIPYs) class were recently found endowed with good efficacy in the antibacterial photodynamic therapy (aPDT) against both Gram-positive and Gram-negative bacteria. In this paper, we report on the remarkable adjuvant effect exerted in this respect by linear polyamidoamines (PAAs), a family of moderately basic polymers obtained by Michael-type polyaddition of amines to bisacrylamides. Three different PAAs (AGMA1, BP-AGMA, and BP-DMEDA) were studied, testing for each two different molecular weight samples (8000 and 24000 Da). At nontoxic concentrations (1 or 10 µg mL-1) all PAAs remarkably improved the killing efficacy of BODIPY upon irradiation with a green LED device (range: from 480 to 580 nm with λmax = 525 nm) up to an energy rate of 16.6 J cm-2. A 6-7 log unit decrease in bacteria survival was observed with concentrations of BODIPY of 1.0 and 0.1 µM in the case of Escherichia coli and Staphylococcus aureus, respectively. The one-way analysis of variance (ANOVA) was used to evaluate the statistical significance of different treatments (n ≥ 3). Thus, the PAA-photosensitizer combination warrants potentially as a new, effective, and mild method of killing bacteria. Moreover, the antibacterial treatment here reported might be successfully applied to defeat the bacterial resistance often encountered with many antibacterial drugs owing to the double action of this two-component treatment.

nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: a subgroup analysis of the Western European cohort of the MPACT trial.

PURPOSE: The global Phase III MPACT trial demonstrated superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone as first-line treatment for metastatic pancreatic cancer. Region was a randomization stratification factor in the MPACT trial. This subgroup analysis of MPACT examined efficacy and safety of patients treated in Western Europe. PATIENTS AND METHODS: Patients received nab-paclitaxel plus gemcitabine or gemcitabine alone as first-line treatment for metastatic pancreatic cancer as previously described. A total of 76 patients were included in this analysis (n=38 for each arm). RESULTS: Differences between the overall Western European cohort and the intention-to-treat population included lower percentages of male patients (46% and 58%, respectively) and patients with biliary stents (8% and 17%), and higher percentages of patients with Karnofsky performance status of 90-100 (78% and 60%) and primary tumors in the body of the pancreas (48% and 31%). The median overall survival was 10.7 months with nab-paclitaxel plus gemcitabine vs 6.9 months with gemcitabine alone (hazard ratio [HR]: 0.82 [95% confidence interval (CI): 0.48-1.40]; P=0.471). Median progression-free survival was 5.3 vs 3.7 months, respectively (HR: 0.70 [95% CI: 0.37-1.33]; P=0.277). The independently assessed overall response rate was 18% vs 5% (response rate ratio, 3.50 [95% CI: 0.78-15.78]; P=0.076). The most common grade ≥3 adverse events with nab-paclitaxel plus gemcitabine and gemcitabine alone were neutropenia (46% vs 33%, respectively), leukopenia (35% vs 19%), anemia (22% vs 0%), asthenia (21% vs 6%), thrombocytopenia (14% vs 3%), and peripheral neuropathy (13% vs 3%). CONCLUSION: Although a statistically significant difference between the treatment arms was not reached for efficacy endpoints, this study does report treatment benefit and a manageable safety profile associated with nab-paclitaxel plus gemcitabine in patients treated in Western Europe with metastatic pancreatic cancer.

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.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT).

BACKGROUND: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS: Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS: In the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤ I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS: nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤ I in many patients (median ≈ 1 month) NCT00844649.

Prognostic factors of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer.

BACKGROUND: nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. MATERIALS AND METHODS: Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. RESULTS: Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. CONCLUSION: The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.

Pharmacokinetic interactions between omeprazole/pantoprazole and clarithromycin in health volunteers.

The association omeprazole/clarithromycin is of current wide use in the treatment of Helicobacter pylori associated gastroduodenal ulcer. This combination may result in increased levels of omeprazole with potential interactions with commonly associated drugs. Kinetic/metabolic changes occurring after omeprazole/clarithromycin were compared to those occurring after pantoprazole/clarithromycin in healthy volunteers. Eight healthy volunteers, all males, age 25-34 years, all EM for CYP2C19, participated in a randomized, double blind crossover study in two periods of 7 days, separated by a 14-day washout. In each treatment period, subjects took either omeprazole 20mg b.i.d. together with clarithromycin 500 mg b.i.d., or pantoprazole 40 mg b.i.d. with the same dose of the antibiotic. The pharmacokinetic parameters of omeprazole and pantoprazole were compared to those after intake of both agents alone. Kinetics of unchanged clarithromycin was evaluated at the end of the two periods. The mean value of the area under the plasma concentration versus time curve (AUC) of unchanged omeprazole increased almost two-fold after concomitant administration of clarithromycin; the average 5-OH-omeprazole AUC was instead significantly reduced by 42%. Omeprazole clearance and volume of distribution were reduced significantly by 75 and 56%, respectively, after administration of the drug with clarithromicyn. No significant changes of the kinetic of pantoprazole and metabolites were observed. Kinetics of clarithromycin did not differ after the two associated treatments. The administration of clarithromycin with two different proton pump inhibitors indicates that the antibiotic can markedly increase omeprazole, not pantoprazole, levels. This observation may result in a better therapeutic response to omeprazole, but it may also potentially affect either the metabolism of CYP3A4 substrates or interfere with the absorption of drugs requiring an intact gastric digestion system.