Administration Of Nab-paclitaxel Research Articles

Adverse Event Profile for Nanoparticle Albumin-Bound Paclitaxel Compared With Solvent-Based Taxanes in Solid-Organ Tumors: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Background:Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an innovative form of taxane that has superior antitumor effects; however, the safety profile between nab-paclitaxel and traditional taxanes remains controversial.Objective:To determine the burden of adverse events (AEs) in patients with multiple malignancies receiving nab-paclitaxel compared with that in patients receiving traditional taxanes.Methods:Randomized clinical trials comparing nab-paclitaxel with traditional taxanes (solvent-based paclitaxel [sb-paclitaxel] or docetaxel) in the treatment of primary solid-organ malignancies were included if AEs were reported as an outcome. Statistical analyses were conducted to calculate the summary odds ratio (OR) of the relevant adverse outcomes related to nab-paclitaxel and traditional taxanes. Prespecified subgroup analyses based on intervention and doses, primary tumor sites, and different ethnic groups were also performed.Results:Twelve clinical trials were included in the meta-analysis. Grade 3/4 anemia, thrombocytopenia, and neurotoxicity were more frequent with nab-paclitaxel than with traditional taxanes. Nab-paclitaxel at 100 or 125 mg/m2/w dosage was associated with fewer or similar grade 3/4 specific AEs. Allergy was less common with nab-paclitaxel. The median recovery times of neurotoxicity were 25, 64, and 37 days in patients receiving nab-paclitaxel, sb-paclitaxel, and docetaxel, respectively. Elevated incidences of specific AEs were more common in breast cancer and non-Asian patients than in other malignancies and ethnic groups, respectively.Conclusion and Relevance:Nab-paclitaxel increased the risk of hematologic and non-hematologic AEs in general, but anaphylaxis was less common, and the recovery duration of neurotoxicity was shorter. Weekly administration of nab-paclitaxel at a lower dosage provided better tolerance.

Measuring Tumor Epichaperome Expression Using [124I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.

Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer.

To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for neutropenia following nab-paclitaxel administration and identify factors associated with drug disposition and changes in neutrophil counts in patients with solid cancer. PK/PD analysis by nonlinear mixed effects approach was performed using the data from 27 patients who participated in phase I studies of nab-paclitaxel monotherapy conducted in Japan. The patients were treated with either weekly (80, 100, or 125mg/m2) or every 3weeks (200, 260, or 300mg/m2). The observed paclitaxel concentrations in whole blood and neutrophil counts in the first cycle were used for PK/PD analysis. Covariate analysis was performed to identify factors affecting PK and the decrease in neutrophil counts. The developed 3-compartment, non-linear PK model described relationships of body surface area with total body clearance and volume of distribution for the peripheral compartment. Covariate factors affecting neutrophil counts were age and serum albumin level. Simulation based on the developed PK/PD model showed a substantial impact of age and serum albumin level on the time course of neutrophil counts after nab-paclitaxel administration. Advanced age was related to greater decrease in neutrophil counts, and serum albumin level, inversely related to change in neutrophil counts. We have developed a novel PK/PD model for nab-paclitaxel in which age and serum albumin level were considered clinically important covariate factors. This model needs to be further validated using a larger patient population.

Toxicity and efficacy of gemcitabine plus nab-paclitaxel (paclitaxel + albumin) in a Russian patient population: results of a multicenter retrospective study

Introduction. The results of randomized MPACT study have demonstrated that the addition of nab-paclitaxel to gemcitabine leads to a statistically significant increase in life expectancy. The main objective of this retrospective study was to obtain up-to-date efficacy and toxicity data for this drug combination in Russian real-world clinical setting. Materials and methods . The study enrolled patients with morphologically confirmed locally advanced or metastatic pancreatic cancer who had ECOG Performance Status scores of 0-2 and received treatment with gemcitabine and nab-paclitaxel. Immediate and long-term outcomes, as well as treatment toxicity and dose modifications, were assessed. Results. The study included 142 patients who received treatment from 2009 to 2019 at 17 centers in 11 regions of Russia. Full dose gemcitabine and nab-paclitaxel were administered at baseline in 74 % of the cases. The median number of chemotherapy cycles was 4 (range, from 1 to 16). Nab-paclitaxel dose was reduced in 32 % of the cases, and that of gemcitabine in 23 % of them. Regression analysis revealed no prognostic factors associated with increased toxicity of gemcitabine and nab-paclitaxel administration. However, previous use of two or more chemotherapy lines had an impact on decisions made by physicians, making them reduce the baseline dose of gemcitabine and/or nab-paclitaxel (OR=6.1, 95% CI 1.5-24.2, р =0.010). An objective response was assessed in 134 subjects with positive response observed in 34 cases (25.4 %). The median time to progression was found to be 6.1 months, and the median life expectancy was 14.2 months. Conclusions. The combination of gemcitabine and nab-paclitaxel exhibits comparatively high efficacy. The acceptable toxicity profile allows its use in selected patients even with ECOG 2 and in the presence of serious comorbidities.

Abstract P6-20-03: Tumor epichaperome expression using 124I PU-H71 PET (PU-PET) as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2 negative (HER2-) metastatic breast cancer (MBC)

Abstract Background: The epichaperome is a new cancer target required for tumor survival (Joshi et al. Nature Reviews Cancer 2018). PU-H71 is a synthetic, purine scaffold epichaperome inhibitor that binds to the ATP-binding site of HSP90 specifically when HSP90 is integrated into the epichaperome (Rodina et al. Nature 2016). It has demonstrated antitumor activity in multiple xenograft models. Furthermore, sequential administration of nab-paclitaxel and PU-H71 in TNBC xenograft models augmented epichaperome levels, and in turn resulted in super-synergistic drug action with ablation of xenografted tumors and cures in mice. Methods: This is an open label phase1b study of PU-H71 + nab-paclitaxel in pts with HER2- MBC. Pts received nab-paclitaxel at a standard dose of 260mg/m2 IV Q 3weeks. PU-H71 was administered IV 6 hrs (+/-1 hr) post nab-paclitaxel Q3weeks in 2 escalating dose levels (225mg/m2 and 300 mg/m2). All pts underwent FDG PET/CT every 6 weeks. Additionally, patients had the option to enroll on a separate diagnostic PU-PET protocol to measure epichaperome expression prior to initiating treatment on the phase 1b study, wherein they received a single dose of up to 11mci of 124I-PU-H71 IV and underwent imaging at 3-4hrs and 20-24 hrs. Primary objective was to establish the MTD/RP2D of this regimen. Secondary objectives were to assess PK of PU-H71 + nab-paclitaxel and clinical efficacy. Exploratory analysis included correlation of epichaperome expression at baseline using PU-PET with tumor response. Results: 12 patients (5 ER+/HER2- ; 7 TNBC) were enrolled (6 at 225mg/m2 of PU-H71 and 6 at 300mg/m2). Median Age: 54 yrs (range: 37-71). Median ECOG: 0. Median lines of therapy in the metastatic setting: 6 (range 1-11) including prior taxanes in 75% of pts. Most common toxicities included diarrhea G1 58%; G2 7%, G3 7%) that was easily managed with anti-diarrheal agents, G1 fatigue (25%), G1/2 peripheral neuropathy (17%), G1 hyperglycemia (67%), G1 increases in alk phos (58%), AST (50%) and ALT (42%). Hematological toxicities included G3 leukopenia (42%), G3/4 neutropenia (67%), G3 anemia (50%) and G2 thrombocytopenia (17%). There were no DLTs. 33% (4/12) had PR, 58% (7/12) achieved SD with only 1 PD at the time of first scan; 5 pts are currently ongoing including 2 TNBC pts with PR who have been on therapy > 7 months. PK data will be presented. 8/12 patients also underwent PU-PET at baseline. A higher tumor to muscle SUV ratio at 24 hrs on PU-PET predicted response and increased PU-H71 retention on PU-PET at 24 hrs correlated with a longer duration of response. Conclusion: The RP2D of PU-H71 was 300mg/m2 with 260mg/m2 of nab-paclitaxel administered IV every 3 weeks. The regimen is well tolerated with promising clinical activity in this heavily pre-treated cohort. Tumor epichaperome expression at baseline using PU-PET has the potential to serve as a predictive biomarker of response. A Phase 2 trial of this combination along with baseline PU-PET is currently planned. Citation Format: Jhaveri K, Dunphy M, Wang R, Comen E, Fornier M, Moynahan ME, Bromberg J, Ma W, Patil S, Taldone T, Rodina A, Sterlin V, Khoshi S, Lewis J, Norton L, Chiosis G, Modi S. Tumor epichaperome expression using 124I PU-H71 PET (PU-PET) as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-03.

A randomized phase II study evaluating different maintenance schedules of nab-paclitaxel in the first-line treatment of metastatic breast cancer: final results of the IBCSG 42-12/BIG 2-12 SNAP trial

BackgroundThe phase II SNAP trial was designed to evaluate the efficacy of alternative chemotherapy schedules for prolonged administration in HER2-negative metastatic breast cancer (MBC), after a short induction at conventional doses. Patients and methodsBetween April 2013 and August 2015, 258 women untreated with chemotherapy for MBC were randomly assigned to receive three different maintenance chemotherapy schedules after three cycles of identical induction chemotherapy: arm A, nab-paclitaxel 150mg/m2 days 1 and 15 Q28; arm B, nab-paclitaxel 100mg/m2 days 1, 8 and 15 Q28; arm C, nab-paclitaxel 75mg/m2 days 1, 8, 15 and 22 Q28. Induction was three cycles nab-paclitaxel 150/125mg/m2, days 1, 8 and 15 Q28. The primary objective was to evaluate the efficacy of each maintenance schedule, in terms of progression-free survival (PFS), as compared with the historical reference of 7-month median PFS reported by previous studies with first-line docetaxel. One-sample, one-sided log-rank tests were utilized. Quality-of-life (QoL) evaluation was carried out, and the global indicator for physical well-being was defined as the primary QoL end point; completion rates of QoL forms were >90%. ResultsIn total, 255 patients were assessable for the primary end point. After 18.2-month median follow-up, 182 PFS events were observed. Median PFS was 7.9months [90% confidence interval CI 6.8–8.4] in arm A, 9.0months (90% CI 8.1–10.9) in arm B and 8.5months (90% CI 6.7–9.5) in arm C. PFS in arm B was significantly longer than the historical reference of first-line docetaxel (P=0.03). Grade≥2 sensory neuropathy was reported in 37.9%, 36.1% and 31.2% of the patients in arm A, B and C, respectively (Grade≥3 in 9.1%, 5.6% and 6.6% of the patients, respectively). Noteworthy, the QoL scores for sensory neuropathy did not worsen with prolonged nab-paclitaxel administration in any of the maintenance arms. ConclusionThe SNAP trial demonstrated that alternative nab-paclitaxel maintenance schedules with reduced dosages after a short induction at conventional doses are feasible and active in the first-line treatment of MBC.Registration: ClinicalTrials.gov NCT01746225

The absence of class III β-tubulin is predictive of a favorable response to nab-paclitaxel and gemcitabine in patients with unresectable pancreatic ductal adenocarcinoma

The combined administration of nab-paclitaxel and gemcitabine (nab-P + Gem) is a standard chemotherapy for unresectable pancreatic ductal adenocarcinoma (UR-PDAC); thus, a predictive biomarker to identify patients best suited for nab-P + Gem therapy would be useful. Class III β-tubulin (TUBB3) has been reported to be a predictive marker for taxane resistance in various tumors. However, the correlation between TUBB3 expression and the response to nab-P + Gem in patients with UR-PDAC has not been evaluated. We retrospectively reviewed 75 patients with UR-PDAC who received nab-P + Gem. TUBB3 expression was examined immunohistochemically in specimens obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). From 67 analyzable specimens that were available for TUBB3 staining, 14 (21%) were negative for TUBB3 immunostaining and 53 (79%) were positive. Patients with negative TUBB3 expression showed a significantly higher disease control rate (100% vs. 64.2%; P = .008) and longer progression-free survival (PFS); (7.1 months vs. 3.7 months; log-rank test, P = .036) than those of patients with positive. Furthermore, negative TUBB3 expression was an independent predictive marker of a prolonged PFS on multivariate analysis (hazard ratio, 2.41; 95% confidence interval, 1.11-5.24; P = .026). Our data indicate that an absence of TUBB3 expression in specimens obtained by EUS-FNA may be a favorable predictive marker of the response to nab-P + Gem in patients with UR-PDAC, highlighting its use as a potential new biomarker for treatment optimization.

Anti-Cancer Drug Nab-Paclitaxel May Exacerbate Corneal Epithelial Disorder

Purpose: To report 2 cases of corneal disorder after cancer treatment with nab paclitaxel. Methods: Retrospective review of 2 cases. Case presentation: Case 1 was a 55-year-old female who presented with blurred vision. She underwent cancer treatment in the form of combination therapy with nab-paclitaxel, trastuzumab and pertuzumab for breast cancer 2 weeks before. An ophthalmoscopic examination showed an atypical corneal epithelium invasion in both eyes. The corneal disorder was resolved following discontinuation of nab-paclitaxel. Case 2 had a pancreatic cancer and she presented with an atypical corneal epithelium invasion in both eyes after treatment with S-1 and gemcitabine hydrochloride. The corneal disorder might be caused by S-1, so S-1 treatment was replaced by nab-paclitaxel. The corneal disorder improved temporarily, but it worsened 3 months after the administration of nab-paclitaxel. Finally, the corneal disorder was resolved following the discontinuation of nab-paclitaxel as well as in case 1. Conclusion: Our 2 cases suggest that cancer treatment including nab-paclitaxel may cause severe corneal disorders. Clinicians should consider the possibility of the corneal disorder being caused by the cancer therapy.

Universal tolerance of nab-paclitaxel for gynecologic malignancies in patients with prior taxane hypersensitivity reactions.

ObjectiveTo report on the incidence of nab-paclitaxel hypersensitivity reactions (HSRs) in patients with prior taxane HSR.MethodsFrom 2005 to 2015, all patients who received nab-paclitaxel for a gynecologic malignancy were identified. Chart abstraction included pathology, prior therapy, indication for nab-paclitaxel, dosing, response, toxicities including any HSR, and reason for discontinuation of nab-paclitaxel therapy.ResultsWe identified 37 patients with gynecologic malignancies with a history of paclitaxel HSR who received nab-paclitaxel. Six patients (16.2%) had a prior HSR to both paclitaxel and docetaxel while the other 31 patients had not received docetaxel. No patients experienced a HSR to nab-paclitaxel. Median number of cycles of nab-paclitaxel was 6 (range 2–20). Twelve patients received weekly dosing at 60 to 100 mg/m2. The remainder of patients received 135 mg/m2 (n=13), 175 mg/m2 (n=9), or 225 mg/m2 (n=3). Thirty four patients (91.9%) received nab-paclitaxel in combination with carboplatin (n=28, 75.7%), IP cisplatin (n=1, 2.7%), carboplatin and bevacizumab (n=3, 8.1%), or carboplatin and gemcitabine (n=2, 5.4%). Reasons for discontinuing nab-paclitaxel included completion of adjuvant therapy (n=16), progressive disease (n=18), toxicity (n=1), and death (n=1). There were no grade 4 complications identified during nab-paclitaxel administration. Grade 3 complications included: neutropenia (n=9), thrombocytopenia (n=4), anemia (n=1), and neurotoxicity (n=1).ConclusionNab-paclitaxel is well-tolerated with no HSRs observed in this series of patients with prior taxane HSR. Given the important role of taxane therapy in nearly all gynecologic malignancies, administration of nab-paclitaxel should be considered prior to abandoning taxane therapy.

Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel

Angiogenesis is critical to the growth of tumors. Vascularization-targeting agents, with or without cytotoxic drugs, are widely used for the treatment of several solid tumors including esophagogastric adenocarcinoma. However, little is known about the systemic effects of anti-angiogenic therapies and how this affects the pharmacokinetics and intratumoral delivery of cytotoxic agents. In this study, patient-derived xenograft mouse models of esophageal adenocarcinoma were used to identify the effects of DC101, a murine vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, on the pharmacokinetics and the intratumoral uptake of nab-paclitaxel (NPTX). We showed that DC101 had large systemic effects resulting in decreased vasculature of intraperitoneally located organs. As a consequence, after intraperitoneal administration of NPTX, plasma uptake (5.029 ± 4.35 vs. 25.85 ± 2.27 µM) and intratumoral delivery (5.48 ± 5.32 vs. 38.49 ± 2.805 pmol/mg) of NPTX were greatly impaired in DC101-treated animals compared to control animals. Additionally, routes of NPTX elimination were altered upon angiogenesis inhibition; unchanged renal clearance and intraperitoneal accumulation of NPTX were observed, but NPTX levels were significantly lower in the liver. Histological examination of the intestine revealed a reduced thickness of the intestinal wall following DC101 therapy and suggested seepage of intraperitoneally injected NTPX through the intestinal wall to explain its reduced uptake in liver, plasma, and tumor tissue. These data explain several adverse effects observed in the clinic when using anti-angiogenic therapies and also imply that the combined use of anti-angiogenesis and cytotoxic agents in both preclinical and clinical setting is still suboptimal.

Albumin-bound paclitaxel for the treatment of refractory or relapsed small-cell lung cancer.

Since nanoparticle albumin-bound (nab)-paclitaxel exerts clinically meaningful antitumor effects on various malignancies, including breast, gastric and non-small-cell lung cancer, we hypothesized that treatment with nab-paclitaxel may also be beneficial for patients with small-cell lung cancer (SCLC). We herein evaluated the safety and efficacy of weekly, single-agent nab-paclitaxel in patients with refractory or relapsed SCLC. Between May, 2013 and February, 2015, 9 patients with refractory or relapsed SCLC were treated with single-agent nab-paclitaxel at the Kyoto University Hospital. The medical records of the patients were retrospectively reviewed. All the patients had been previously treated with ≥2 lines of chemotherapy prior to receiving nab-paclitaxel. The median number of cycles of nab-paclitaxel was 2 (range, 1-4) and 3 partial responses were observed (response rate: 33%). The toxicity was generally mild and manageable: Grade 3/4 adverse events were only observed in 1 patient (grade 3 leukopenia). Thus, weekly administration of nab-paclitaxel may be a viable treatment option in patients with refractory or relapsed SCLC. Considering that treatment options are quite limited in this patient population, further evaluation of this regimen may prove valuable in the clinical setting.

Abstract P6-11-06: Time and value of chemotherapy administration burden in a Swedish hospital

Abstract Background Administration of treatment for cancer patients can require substantial health care resources and differences in administration burden between treatments are therefore important to take into account when comparing them. Besides the direct personnel and bed time, the administration can also have broader consequences on the organisation and process of care delivery, as well as on the patients. How to value differences in these parameters is however not straightforward. Nab-paclitaxel and paclitaxel are examples of two treatments with important differences in administration burden, and the objective of this study was to perform a time-motion study to compare time required for treatment administration. Material and methods Breast cancer patients vising the oncology day care unit at the department of oncology at Akademiska Hospital in Uppsala, Sweden, as part of their regular treatment-course with nab-paclitaxel (n=13) or paclitaxel (n=9) were included in the study. Time data collection was based on a questionnaire answered by hospital staff. Time for infusions and the total patient time in hospital were measured for each patient. Results Mean infusion times per administration of nab-paclitaxel and paclitaxel were 42.1 (Standard deviation (SD) 20.7) minutes and 104.3 (SD 43.3) minutes, respectively. Total patient times in clinic per infusion were 82.2 (SD 40.9) minutes and 183.9 (SD 34.8) minutes, respectively. A 12-week treatment course of nab-paclitaxel (every three weeks), nab-paclitaxel (weekly) and paclitaxel (weekly) would require in total 2.8, 8.4 and 20.9 hours of infusion time, respectively. The corresponding patient time in hospital would be 5.5, 16.4 and 36.8 hours, respectively. Conclusion There can be substantial differences in nurse and facility resources required for administration of chemotherapy, our data showed approximately a 7-fold difference in patient, personnel and facility time requirements between the compared treatments. In a time with shortage of both hospital personnel and facilities, the valuation of these resources is not easy and may have broader impact on the organisation and delivery of care. Monetary valuation using rent cost or salaries may in a time of resource shortage underestimate the true opportunity cost, and more research and discussions on how to prioritise use of these resources versus other costs are therefore needed. Citation Format: Nilsson A, Lundkvist J, Lindman H. Time and value of chemotherapy administration burden in a Swedish hospital. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-11-06.

Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations.

Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab-paclitaxel or Cremophor EL-paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel-carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab-paclitaxel and Cremophor EL-paclitaxel was attributed to rapid tissue distribution of the paclitaxel-carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab-paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL-paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel-time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel-carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration-time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its clinical outcome.

Albumin-bound paclitaxel: a review of its use for the first-line combination treatment of metastatic pancreatic cancer.

Nanoparticle albumin-bound paclitaxel (Abraxane(®)) [hereafter referred to as nab-paclitaxel] is an intravenously administered microtubule inhibitor. It was developed to avoid the toxicities associated with the polyoxyethylated castor oil solvent (Cremophor) and ethanol vehicles used to overcome paclitaxel's poor aqueous solubility. Nab-paclitaxel is indicated in the EU and the USA as first-line combination therapy with gemcitabine in adults with metastatic adenocarcinoma of the pancreas. Compared with gemcitabine alone, nab-paclitaxel plus gemcitabine significantly prolonged median overall survival, reflecting a 28% reduction in the risk of death, in adults with metastatic pancreatic cancer participating in a multinational phase III study. In addition, median progression-free survival was significantly prolonged and the objective response rate was significantly higher with nab-paclitaxel plus gemcitabine than with gemcitabine therapy. Nab-paclitaxel plus gemcitabine had a manageable tolerability profile; in general, adverse events in the phase III study were grade 3 or lower and resolved without specific therapy. Neutropenia and peripheral neuropathy were the most frequently reported adverse reactions leading to nab-paclitaxel dose reductions, or to delays in or the withholding of nab-paclitaxel dosing. Peripheral neuropathy was rapidly reversible in the majority of patients following interruptions in nab-paclitaxel administration and a subsequent reduction in the nab-paclitaxel dose. Current evidence indicates that nab-paclitaxel plus gemcitabine is a valuable option for the treatment of metastatic pancreatic cancer.

P0116 Safety of weekly administration of nanoparticle albumin-bound paclitaxel in patients with breast cancer

Background Nanoparticle albumin-bound (nab) paclitaxel is reported to be highly effective; however, in a Japanese Post-marketing Safety Evaluation of 943 patients a high incidence of myelosuppression, peripheral neuropathy, and myalgia was observed. In patients undergoing two cycles of continuous administration of nab-paclitaxel, the rates of dose reduction and treatment discontinuation were reported to be 27.3% and 24.6%, respectively. The objective of this study is to confirm the safety of weekly nab-paclitaxel in patients with breast cancer. Methods We enrolled 14 patients with breast cancer at our hospital, who received weekly nab-paclitaxel (80 mg/m 2 ) for 3 consecutive weeks followed by a 1-week wash-out period from May until December 2012. Findings The incidence of adverse events and the number of patients who experienced these events were as follows: leucopenia (G1/2, 42.8%; G3/4, 0%) in six patients, haemoglobin decreased (G1/2, 21.4%; G3/4, 0%) in three patients, thrombocytopenia (G1/2, 7.1%; G3/4, 0%) in one patient, hepatic dysfunction (G1/2, 28.6%; G3/4, 0%) in four patients, diarrhoea (G1/2, 28.6%; G3/4, 0%) in four patients, constipation (G1/2, 21.4%; G3/4, 0%) in three patients, nausea (G1/2, 35.7%; G3/4, 0%) in five patients, stomatitis (G1/2, 71.4%; G3/4, 0%) in 10 patients, anorexia (G1/2, 7.1%; G3/4, 7.1%) in four patients, oedema (G1/2, 28.6%; G3/4, 0%) in four patients, arthralgia (G1/2, 35.7%; G3/4, 0%) in five patients, myalgia (G1/2, 21.4%; G3/4, 0%) in three patients, peripheral neuropathy (G1/2, 57.2%; G3/4, 0%) in eight patients, malaise (G1/2, 64.3%; G3/4, 0%) in nine patients, and interstitial pneumonia (G1/2, 0%; G3/4, 7.1%) in one patient. No dose reductions were reported, and nab-paclitaxel treatment was only discontinued in one patient due to the occurrence of interstitial pneumonia. Interpretation In patients with breast cancer, weekly nab-paclitaxel was probably less toxic than those of the previously reported regimen of nab-paclitaxel once every 3 weeks.

Phase I and pharmacokinetic study of nab-paclitaxel, nanoparticle albumin-bound paclitaxel, administered weekly to Japanese patients with solid tumors and metastatic breast cancer

We conducted phase I and tolerability studies to determine the maximum tolerated dose (MTD) and recommended dose of nab-paclitaxel when administered weekly with solid tumors and to evaluate the tolerability of weekly administration at a dose of 150mg/m(2) with metastatic breast cancer (MBC) as a first-line therapy in Japanese patients. In this phase I study, patients with advanced solid tumors received nab-paclitaxel at dose levels of 80-125mg/m(2) as 30-min infusions once a week for three weekly doses repeated every 4weeks. In the tolerability study, patients received 150mg/m(2) nab-paclitaxel. Blood samples at the first dose of nab-paclitaxel were collected for pharmacokinetic analysis. Fifteen patients were treated for a median of five cycles in the phase I study. The MTD was 125mg/m(2); the dose-limiting toxicity was neutropenia requiring skipping of the second or third weekly administration in the first cycle. In the tolerability study, six patients were treated for a median of six cycles; no intolerable toxicities were observed in the first cycle. Grade 3 sensory and motor neuropathy was observed in four and one patients, respectively. Ocular toxicities were observed in two patients (keratopathy and macular hole). Maximum paclitaxel concentration and area under the curve increased linearly with the dose. Weekly administration of nab-paclitaxel was well tolerated up to 100mg/m(2) by heavily pretreated patients. For MBC patients, 150mg/m(2) nab-paclitaxel as a first-line therapy was well tolerated. Dose reduction due to neuropathy allows multiple cycles of treatment.

Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m2 with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over 30 minutes infusion without premedication every 3 weeks) mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hour injection with standard premedication). The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nabpaclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer in terms of clinical usefulness including efficacy and safety of this new agent.

Randomized Crossover Pharmacokinetic Study of Solvent-Based Paclitaxel and nab-Paclitaxel

Abraxane (ABI-007) is a 130-nm albumin-bound (nab) particle formulation of paclitaxel, devoid of any additional excipients. We hypothesized that this change in formulation alters the systemic disposition of paclitaxel compared with conventional solvent-based formulations (sb-paclitaxel; Taxol), and leads to improved tolerability of the drug. Patients with malignant solid tumors were randomized to receive the recommended single-agent dose of nab-paclitaxel (260 mg/m(2) as a 30-minute infusion) or sb-paclitaxel (175 mg/m(2) as a 3-hour infusion). After cycle 1, patients crossed over to the alternate treatment. Pharmacokinetic studies were carried out for the first cycle of sb-paclitaxel and the first two cycles of nab-paclitaxel. Seventeen patients were treated, with 14 receiving at least one cycle each of nab-paclitaxel and sb-paclitaxel. No change in nab-paclitaxel pharmacokinetics was found between the first and second cycles (P = 0.95), suggesting limited intrasubject variability. Total drug exposure was comparable between the two formulations (P = 0.55) despite the dose difference. However, exposure to unbound paclitaxel was significantly higher after nab-paclitaxel administration, due to the increased free fraction (0.063 +/- 0.021 versus 0.024 +/- 0.009; P < 0.001). This study shows that paclitaxel disposition is subject to considerable variability depending on the formulation used. Because systemic exposure to unbound paclitaxel is likely a driving force behind tumoral uptake, these findings explain, at least in part, previous observations that the administration of nab-paclitaxel is associated with augmented antitumor efficacy compared with solvent-based paclitaxel.

Systemic Nanoparticle Paclitaxel (nab‐Paclitaxel) for In‐stent Restenosis I (SNAPIST‐I): A First‐in‐Human Safety and Dose‐finding Study

Paclitaxel-eluting stents inhibit restenosis; however, this technology has drawbacks (e.g., stent thrombosis, requirement for long-term antiplatelet therapy, and cost--particularly for patients with multivessel disease). Systemic treatment with a novel 130-nm, albumin-bound particle form of paclitaxel (nab-paclitaxel) has been shown to reduce restenosis in animals. This study was designed to establish the safety and optimal dose of systemic nab-paclitaxel for reducing in-stent restenosis in humans. If well tolerated, systemic nab-paclitaxel may be used with any available bare-metal stent and at potentially lower cost than drug-eluting stents. Patients received nab-paclitaxel 10, 30, 70, or 100 mg/m(2) intravenously after stenting of a single de novo lesion >or= 3 mm in diameter. Study endpoints included safety and major adverse cardiac events (MACE) at 2 and 6 months. Data were obtained for all 23 enrolled patients (mean age 66 +/- 10 years, 74% men, 26% with diabetes). No significant adverse events (AE) were attributable to nab-paclitaxel at 10 or 30 mg/m(2). Moderate neutropenia, moderate sensory neuropathy, and mild to moderate, reversible alopecia occurred only at doses of 70 and 100 mg/m(2); therefore, doses of 70 mg/m(2) or higher were considered unacceptable in this patient population. No MACE were reported at 2 months. At 6 months, 4 target lesion revascularizations (TLR) for restenoses were reported (2 each in the 10- and 100-mg/m(2)-dose groups). Systemic nab-paclitaxel was well tolerated at doses below 70 mg/m(2) in this group of patients; no unexpected AE were noted. Additional studies are under way to explore intravenous and intracoronary administration of nab-paclitaxel.