Effectiveness Of Nab-paclitaxel Research Articles

Efficacy and safety of second-line treatment for advanced gastric cancer: A network meta-analysis of randomized controlled trials.

e16018 Background: To evaluate the difference of curative effect between different treatment regimens in patients with advanced gastric cancer (AGC) who have previously received fluorouracil based first-line chemotherapy. Methods: We searched PubMed, PMC and EMBASE databases for published randomized controlled trials (RCTs). The number of people who reached the objective response rate (ORR) and the hazard ratio (HR) and its 95% confidence interval (CI) of progression-free survival (PFS) and overall survival (OS) were extracted. R (version 4.0.5) and R Studio were used to conduct meta-analysis of relevant data based on the Bayesian framework. Gemtc software package facilitates statistical analysis. To provide a ranking for each treatment regimen, surface under the cumulative ranking curve (SUCRA) was calculated. Survival analysis was conducted based on WinBUGS 14. STATA17.0 was used to draw the network diagram and funnel plot. Results: A total of 17 RCTs were included in this meta-analysis, and a total of 15 treatment regimens were used in the second-line treatment of AGC. There was no publication bias or other bias in the studies. Ramucirumab combined with paclitaxel and nab-paclitaxel weekly regimens have obvious advantages in efficacy and safety. Among them, ramucirumab combined with paclitaxel (83.6%) has great advantages in ORR, while the probability of anemia (36.6%) and anorexia (22.7%) is low, and the probability of leucopenia (66.6%) is high. However, the ORR of nab-paclitaxel weekly regimen (71.4%) is only second to that of ramucirumab combined with paclitaxel, and the probability of anemia (46.3%) and anorexia (44%) is also low, and the probability of leucopenia (53.8%) is high. In terms of OS and PFS, ramucirumab combined with paclitaxel has the best effect according to the probabilistic settlement table. Pembrolizumab and 5-Fu have poor therapeutic effects in terms of PFS. Conclusions: Ramucirumab combined with paclitaxel and nab-paclitaxel can significantly improve the survival outcome of patients with AGC. The effect of ramucirumab combined with paclitaxel is significantly better than that of paclitaxel, and the effect of nab-paclitaxel is only second to that of ramucirumab combined with paclitaxel. The safety of multi-drug combination should also be carefully considered. These findings may help clinicians better choose the second-line treatment strategy for patients with AGC.

Study on the intake and efficacy of nab-paclitaxel in patients with advanced cervical cancer

Cervical cancer is the second most common malignant tumor in women. This study aimed to investigate the intake and effect of nab-paclitaxel in chemotherapy for patients with advanced cervical cancer, to collect more evidence for clinical medication. A total of 96 patients with advanced cervical cancer who received chemotherapy treatment in Wuhan Third Hospital from July 2021 to July 2022 were randomly divided into observation group (treated with nab-paclitaxel + cisplatin) and control group (treated with paclitaxel + cisplatin) by envelope method. The short-term efficacy, tumor markers, immune function indicators, adverse reactions and quality of life of both groups were observed and compared with each other. After treatment, serum tumor markers were notably decreased, while cluster of differentiation 4 (CD4)+ and CD4+/cluster of differentiation 8 (CD8)+ were clearly increased in both groups. The observation group showed the improvement effect of each index in a statistically significant manner (p < 0.05) than the control group. The effective disease control rate of observation group was higher than that of the control group while the incidence of treatment-related adverse reactions in the observation group was higher than that of the control group. The observation group indicated improved effective rate of Karnofsky Performance Scale (KPS) than the control group (p < 0.05). In conclusion, nab-paclitaxel has significant advantages in chemotherapy for patients suffering from advanced cervical cancer, which can strengthen immune function, improve the effectiveness of disease control, and promote the improvement of functional status.

The effectiveness of nab-paclitaxel plus gemcitabine and gemcitabine monotherapy in first-line metastatic pancreatic cancer treatment: A real-world evidence.

Pancreatic cancer is one of the most lethal malignancies with a rise in mortality rates. FOLFIRINOX and nab-paclitaxel plus gemcitabine demonstrated a survival benefit compared to gemcitabine alone. Both protocols are now considered the standard of first-line treatment with no significant difference between them, primarily based on observational studies. Although new therapeutic options have emerged recently, the prognosis remains poor. We conducted a retrospective single-center study on 139 patients treated for metastatic pancreatic adenocarcinoma (mPDAC) with gemcitabine monotherapy (Gem) or nab-paclitaxel + gemcitabine (Nab-P/Gem) in the first line. The aim of our study was to evaluate the effectiveness in terms of overall survival (OS) and progression-free survival (PFS) as well as the influence of patient and disease characteristics on outcomes. Nab-P/Gem resulted in OS of 13.87 months compared to 8.5 months in patients receiving Gem. The same trend was achieved in PFS, 5.37 versus 2.80 months, respectively, but without reaching statistical significance. Furthermore, the 6-month survival in the Nab-P/Gem group was also higher, 78.1% versus 47.8%. In terms of survival, the group of elderly patients, patients of poorer performance, with higher metastatic burden and liver involvement, benefited the most from combination therapy. In our analysis ECOG performance status (p.s.), previous primary tumor surgery, and liver involvement were found to be independent prognostic factors. The addition of nab-paclitaxel to gemcitabine resulted in a significant improvement in the OS of patients with mPDAC. Subgroup analysis demonstrated that patients with some unfavorable prognostic factors benefited the most.

Abstract 2624: Methadone hydrochloride blocks epinephrine-induced proliferation and enhances apoptotic effects of nab-paclitaxel in esophageal adenocarcinoma

Abstract Introduction: Esophageal adenocarcinoma (EAC) is an aggressive form of cancer with 5-year survival rates under 20%. The low survival rate is due largely to advanced stage upon diagnosis. Improved treatment options remain essential in combating the disease and bolstering patient outcomes. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a chemotherapeutic receiving attention for its potential in EAC treatment. The taxane has exhibited greater specificity for targeting cancer cells while decreasing cytotoxic effects to adjacent healthy populations. Unfortunately, chemoresistance remains an issue surrounding adequate treatment regimes. Epinephrine and its receptor, β2 adrenergic, have been shown to dysregulate various oncogenic pathways and reduce chemotherapeutics efficacy. Typically associated with pain management and addiction treatment, Methadone hydrochloride has been investigated for its potential to block the oncogenic effects of epinephrine and strengthen the impact of chemotherapeutics. In this study, we evaluated the enhancement of apoptosis by combination of nab-paclitaxel and methadone, and we demonstrated the ability of methadone to block epinephrine-induced chemoresistance. Method: We utilized PCR to elucidate EAC cell lines with the greatest expression of Mu opioid and β2 adrenergic receptors. Next, we investigated adequate dosages of methadone and epinephrine for the EAC cell lines by WST-1 assay. WST-1 assays were also utilized to determine cell growth under co-administration of nab-paclitaxel and methadone as well as methadone and epinephrine. Propidium iodine cell viability flow cytometry assay was used to detect cell death. Annexin V staining was utilized to further distinguish between apoptotic and necroptotic cells. Result: OE19 and OE33 cell lines showed increased expression of Mu and β2 adrenergic receptors, ensuring the cells were capable of binding to methadone or epinephrine. WST-1 assays established 100 nM of epinephrine and 200 nM of methadone as optimal dosages for both cell lines. Our previous studies demonstrated that about 5.85 uM of nab-paclitaxel (5ug/mL) induces apoptosis in OE19 and OE33. Propidium iodide staining showed the enhancement of cell death under combination treatment of nab-paclitaxel and methadone. Annexin V staining confirmed that the effect was via apoptosis. Conclusion: The current study demonstrated methadone’s ability to block epinephrine-induced cell proliferation and showed an enhanced effect on apoptosis when combining nab-paclitaxel with methadone in EAC treatment. Citation Format: Nicholas Cwidak, Sazzad Hassan, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. Methadone hydrochloride blocks epinephrine-induced proliferation and enhances apoptotic effects of nab-paclitaxel in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2624.

Phase II trial of nab-paclitaxel in metastatic breast cancer patients with visceral metastases

BackgroundVisceral metastases account for 48–67% of metastatic breast cancer (MBC) patients and presage a worse overall survival. Previous study suggested potential effect of nab-paclitaxel on patients with visceral metastases subgroups. This phase II trial was conducted to explore the efficacy and safety of nab-paclitaxel in such a high-risk group of patients.MethodsIn this prospective, single-center, open-label, phase II study, MBC patients with visceral metastases (N = 80) received nab-paclitaxel (Abraxane, 125 mg/m2, D1, D8, D15 every 28 days).ResultsThe median PFS was 5.1 months (95% CI: 4.2–6.0 months), with an ORR of 33.8% (95% CI 21.3–43.8%) and CBR of 66.2% (95% CI 56.3–75.0%). In univariate analysis, patients with premenopausal status had a trend of better treatment outcome. Multivariate analysis demonstrated non brain metastasis (adjusted HR 0.31, 95% CI 0.12–0.83, P = 0.019) and first line treatment (adjusted HR 0.37, 95% CI 0.17–0.81, P = 0.013) as independent predictors of longer PFS. The overall safety was acceptable with most common treatment-related, grade ≥ 3 toxicities of neutropenia (16.3%) and sensory neuropathy (3.7%).ConclusionsThis phase II trial documented satisfactory efficacy and safety of nab-paclitaxel in MBC patients with visceral metastases, providing evidence for relative clinical practice. Patients in first line therapy had better treatment outcome. For patients with premenopausal status or brain metastasis, further alternatives (for example, combined chemotherapy or targeting therapy) might be required. This study also demonstrated the efficacy and safety of 125 mg/m2 nab-paclitaxel among Asian patients.Trial registrationThis research is registered under clinicaltrials.gov (NCT 02687490, February 22, 2016).

Real-world effectiveness of nab-paclitaxel plus carboplatin as first-line therapy for patients with advanced NSCLC: Results of the second interim analysis of the NEPTUN study.

e21611 Background: Collecting real-world evidence is required not only to evaluate effectiveness and safety in routine clinical practice, but to improve clinical cancer outcomes. Methods: NEPTUN is a prospective, multicenter, non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of first-line nab-Paclitaxel plus carboplatin in patients (pts) with advanced or metastatic non-small cell lung carcinoma (NSCLC) in the real-world setting in Germany. The primary endpoint was 6-months progression free survival rate (PFSR). Descriptive statistics were used to analyze data. Results: Between August 2016 and June 2019, 408 pts were enrolled at 75 active sites, 373 pts started treatment according to label. The cut-off date for this interim analysis (07 Dec 2019) was after all pts were observed for at least 6 months. The 6-months PFSR was 40.8% (95% CI, 35.3-46.2), median PFS 5.2 months (95% CI, 4.5-5.7). Overall response rate was 41.5% (95% CI, 36.3-46.8) with a complete response documented in 6 pts (1.7%) and a partial response in 142 pts (39.8%). Disease control rate was 61.6% (95% CI, 56.4-66.7). Employing a multivariable cox regression model for PFS adjusted for ECOG, histology, age group, renal impairment, and smoking status, elderly patients and patients with squamous histology were identified as being of favorable risk (HR squamous vs. non-squamous histology 0.76 (95% CI, 0.58-1.01); HR for ≥70 vs. < 70 years of age 0.80 (95% CI, 0.59-1.08)). Median overall survival (OS) was 10.5 months (95% CI, 9.2-11.6) with 9.6 months (95% CI, 7.7-11.2) for non-squamous and 11.8 months (95% CI, 9.2-13.8) for squamous histology. 12-months OS rate was 43.1% (95% CI, 37.3-48.7). The most common treatment-emergent AEs (TEAEs) were anemia (26.5%), leukopenia (25.7%) and thrombocytopenia (16.6%). Polyneuropathy was documented for 11.3% of pts. 54.2% of pts developed TEAE grade 3/4 including leukopenia (10.2%), anemia (8.6%) and pneumonia (5.1%). 9.9% pts discontinued nab-paclitaxel due to nab-paclitaxel-related TEAEs. EQ-5D-5L visual analogue scale and FACT-L total score remained stable during therapy. Conclusions: nab-Paclitaxel plus carboplatin given first-line according to German SmPC in advanced NSCLC patients in a real-world clinical setting is an effective and safe therapy commonly applied. These results were similar to those reported in the phase iii clinical trial setting. QoL scores remained stable during first-line treatment. No new safety signals emerged. Clinical trial information: NCT02799862.

Abstract P2-15-07: Real-world multicenter, prospective study of the effects of nab-paclitaxel on clinical outcomes and quality of life of patients with metastatic breast cancer in Greece. The ‘ABReast’ study

Abstract Introduction: Nanoparticle albumin-bound (nab)-paclitaxel (nab-P) is approved for the treatment of patients with metastatic breast cancer (MBC) who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. Real-world evidence on the effectiveness of nab-P is sparse. From this perspective, this non-interventional study was designed to assess the impact of nab-P on the clinical outcomes and the quality of life of patients with MBC in the routine care of Greece. Materials and methods: This multicenter prospective study enrolled consented females with MBC initiated (≤7 days prior to enrollment) on nab-P according to physicians decision. Clinicopathologic parameters and patient-reported outcomes [Functional Assessment of Cancer Therapy-Breast (FACT-B)] were collected at approximately 9-week intervals during the first 12 months of study participation and approximately every 18 weeks thereafter, until the end of the study observation period (maximum 30 months). Results: Between April 2016 and October 2017, 150 eligible patients (99.3% Caucasian) were enrolled in the study in 16 oncology centers. The patients’ median age was 64.5 years (range: 30.7-84.0) and ECOG performance status was 0 in 66.4% and 1 in 26.2%. 45.3% of patients had ≥1 comorbidity (21.3% cardiovascular diseases). The median time elapsed since MBC diagnosis was 22.4 months, while 36.0% of patients were de novo metastatic. The distribution of hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) status was 74.6% HR+/HER2-, 11.9% HR-/HER2-, 11.2% HR+/HER2+, and 2.2% HR-/HER2+. Most commonly occurring metastatic sites were the bones (55.3%), lung (50.0%), and liver (40.0%). Prior taxane-based therapy was annotated in 40.0% of patients. Of the patients, 11.3% received nab-P as first, 36.0% as second, 23.3% as third, and 29.3% as fourth or further treatment line. A median of 6 cycles (range: 1-33) was administered; 42.7% of the patients completed >6 and 22.0% >8 cycles. Dose reductions were required for 26.0% of the patients, mainly due to toxicity. The objective response rate was 26.7% and the clinical benefit rate was 44.0%. After a median follow-up of 19.3 months, 92 patients had progressed and 57 had died (14 without progression). The median progression-free survival (PFS) was 6.2 months [95% confidence interval (CI): 5.2-7.3]. The 6- and 12-month PFS rates were 50.6% and 30.5%, respectively. The median overall survival was 21.1 months (95% CI: 17.2-not estimable). Liver [hazard ratio (HR): 1.81; 95% CI: 1.24-2.66] and lung (HR: 1.53; 95% CI: 1.04-2.25) metastases were associated with a higher risk of progression or death. No statistically significant change in the patients’ baseline FACT-B total score (median: 93.0) was observed. The serious and non-serious adverse event (AE) incidence rates were 12.7% and 48.0%, respectively with a total of 37 grade ≥3 AEs (not including disease progression) reported. Conclusion: This study generated real-world evidence on the effectiveness of nab-paclitaxel; no new safety signals emerged. Citation Format: Anna Koumarianou, Paris Makrantonakis, Flora Zagouri, Christos Papadimitriou, Athina Christopoulou, Epaminontas Samantas, Christos Christodoulou, Amanda Psyrri, Dimitris Bafaloukos, Gerasimos Aravantinos, Pavlos Papakotoulas, Sofia Baka, Charalampos Andreadis, Athanasios Alexopoulos, Iliada Bombolaki, Katerina Kampoli, Sofia Liori, Kiki Karvounis, Alexandros Ardavanis. Real-world multicenter, prospective study of the effects of nab-paclitaxel on clinical outcomes and quality of life of patients with metastatic breast cancer in Greece. The ‘ABReast’ study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-07.

Abstract 2208: Targeted inhibition of FGF/PDGF/VEGF signaling enhances nanoparticle taxane response in preclinical gastric cancer models

Abstract Background: Gastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Most available systemic chemotherapy options for advanced GAC have limited efficacy. Nab-paclitaxel (NPT), a nanoparticle albumin-bound taxane formulation, has shown significant activity in preclinical GAC studies. Overexpression of multiple growth factors and their receptors such as FGF/FGFR, PDGF/PDGFR and VEGF/VEGFR, promote angiogenesis in several cancers including GAC that leads to tumor progression and metastasis. Dovitinib is a small molecule RTK inhibitor that potentially inhibits the activity of FGFR, PDGFR and VEGFR. We evaluated the antitumor efficacy of dovitinib and its ability to enhance nab-paclitaxel response in preclinical GAC models. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and Immunoblotting. In vivo tumor growth and animal survival studies were performed in NOD/SCID mice using human GAC MKN-45 cells. Results: Nab-paclitaxel and dovitinib had in vitro growth inhibitory effect on several GAC associated cell lines tested, with additive effects in combination. Immunoblot analysis revealed that dovitinib treatment caused a decrease in the expression of phospho-FGFR, phospho-AKT, phospho-ERK; and an increase in the expression of apoptosis-related proteins cleaved PARP-1 and cleaved caspase-3. Nab-paclitaxel activity correlated with the increased expression of phospho-stathmin. In subcutaneous GAC xenografts, NPT and dovitinib demonstrated inhibition in tumor growth, while NPT+dovitinib had an additive effect. Net tumor growth was 533.7 mm3 in controls, 394.8 mm3 after oxaliplatin, 135.8 mm3 after NPT, 128 mm3 after dovitinib, 98.9 mm3 after oxaliplatin+dovitinib and -41.8 mm3 (tumor regression) after NPT+dovitinib. Tumor tissue analysis revealed that dovitinib reduced tumor vasculature, while nab-paclitaxel reduced tumor cell proliferation. In a peritoneal dissemination model, animal survival compared to controls (23 days) remained unchanged after monotherapy with oxaliplatin (24 days) or dovitinib (25 days) but increased significantly after NPT monotherapy (42 days, a 83% increase). Combination of dovitinib with NPT exhibited a further increase in animal survival (66 days, a 187% increase), while the combination of dovitinib with oxaliplatin had no survival benefit (25 days). Conclusion: These findings demonstrate that the antitumor effect of nab-paclitaxel can be significantly enhanced by the FGFR/PDGFR/VEGFR pathway inhibitor dovitinib in preclinical GAC models. The data support the clinical relevance of this therapeutic combination for advanced GAC patients. Citation Format: Niranjan Awasthi, Kate Crawford, Erin Bontrager, Sazzad Hassan, Urs von Holzen, Margaret A. Schwarz, Roderich E. Schwarz. Targeted inhibition of FGF/PDGF/VEGF signaling enhances nanoparticle taxane response in preclinical gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2208.

Augmentation of Nab-Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models.

Gastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC; however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, whereas tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts. The mechanistic evaluation involved IHC and Immunoblot analysis in tumor samples. Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib. Nab-paclitaxel combination with nintedanib was most effective in improving animal survival, always greater than 300% over control. In cell-derived subcutaneous xenografts, nab-paclitaxel reduced tumor growth while all three antiangiogenic agents enhanced this effect, with nintedanib demonstrating the greatest inhibition. Furthermore, in GAC patient-derived xenografts the combination of nab-paclitaxel and nintedanib reduced tumor growth over single agents alone. Tumor tissue analysis revealed that ramucirumab and cabozantinib only reduced tumor vasculature, whereas nintedanib in addition significantly reduced tumor cell proliferation and increased apoptosis. Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy. Mol Cancer Ther; 17(11); 2353-64. ©2018 AACR.

347 (PB-142) - Real-World multicenter Austrian analysis of the safety and effectiveness of nab-paclitaxel in young and elderly patients with metastatic breast cancer

347 (PB-142) - Real-World multicenter Austrian analysis of the safety and effectiveness of nab-paclitaxel in young and elderly patients with metastatic breast cancer

Abstract GS3-06: Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-Paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC)

Abstract Background: CALGB 40502/NCCTG N063H (Alliance) compared weekly NP or Ix to P; most patients received bevacizumab. Ix was inferior to P, and NP was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms compared to P (Rugo et al, JCO 2015). We report long-term follow-up (FU) of this trial with an unplanned subset analysis in hormone receptor positive (HR+) and triple negative (TNBC) breast cancer. Methods: Patients were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 week (wk) on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all patients, but became optional in 3/2011 and was added to stratification. The primary endpoint was progression-free survival (PFS); secondary endpoints included safety and overall survival (OS). With a target N=900 patients, the study was powered to detect a hazard ratio of 1.36 (median PFS 10 vs 13.6 months). Eligibility included no prior chemotherapy for MBC, >12 mo from adjuvant P and measurable disease. Results: 799 patients were randomized between 11/08 and11/11 (283 to P, 271 to NP, 245 to Ix); 98% received bevacizumab. 68% (546) had HR+ disease, 25% (201) had TNBC. Median FU is 5 years. Median PFS is unchanged at 10.8, 9.2 and 7.4 mo for P, NP and Ix with hazard ratios (95% CIs) of 1.13 (0.94-1.34) and 1.44 (1.2-1.72) for NP and Ix to P, respectively. Median OS was 27.1, 24.2 and 23.6 months for P, NP and Ix with hazard ratios of 1.10 (0.91-1.34) and 1.3 (1.07-1.57) for NP and Ix to P, respectively. The effects of NP vs P on PFS and OS were significantly modified by subtype (interaction p=0.0018 and 0.0073), whereas Ix vs P was unchanged (interaction p's > 0.9, Table). More patients discontinued treatment due to adverse events in the experimental arms (14 vs 27 vs 23% for P, NP and Ix). Table P (mo)NP (mo)NP to P; HR (95% CI)Ix (mo)Ix to P, HR (95% CI)TNBC, PFS6.47.40.79 (0.55-1.12)15.61.39 (0.99-1.96)3HR+, PFS12.29.61.29 (1.04-1.59)181.5 (1.21-1.86)3TNBC, OS15.3210.74 (0.51-1.07)215.11.28(0.9-1.82)4HR+, OS33.226.61.25 (0.99-1.58)225.41.35(1.07-1.714Interaction tests: 1. p=0.0018; 2. p=0.0073; 3. p=0.96; 4. p=0.92 mo: months; HR: hazard ratio·· Conclusion: In patients with chemotherapy-naive MBC, Ix was inferior to P for PFS, and P was better tolerated than either NP or Ix. In this retrospective subset analysis, Ix and NP were inferior to P in HR+ disease, with a suggestion of improved PFS and OS with NP in patients with TNBC. Further investigation is required to explain and validate the subtype specificity seen in this exploratory analysis. Support: U10CA180820, U10CA180821, U10CA180882, U10CA180888. ClinicalTrials.gov Identifier: NCT00785291 Citation Format: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss A, Huebner L, Mayer EL, Naughton M, Layman RM, Carey LA, Somer RA, Toppmeyer D, Velasco M, Perez EA, Hudis CA, Winer E. Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-Paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-06.

Abstract 4202: Trametinib, a MEK inhibitor, augments nab-paclitaxel based chemotherapy response in preclinical models of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer related deaths in the USA with a 5-year survival less than 6%. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, NPT) has demonstrated 8.5 months median survival in combination with gemcitabine, and now represents a standard of care for PDAC patients. Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated in many human cancers. In PDAC, activating K-ras mutations occur at a frequency of 90%, rendering this a potential therapeutic target. Efforts to develop drugs that directly target mutant KRAS protein remain challenging due to target specificity issues. Alternative strategies therefore focus towards inhibition of downstream targets in the RAS-MAPK cascade such as MEK. Trametinib (Tra) is a potent and highly selective small molecule inhibitor of MEK1/2 kinase activity. We evaluated efficacy of trametinib to enhance antitumor response of nab-paclitaxel based chemotherapy regimens in preclinical models of PDAC using K-ras mutant cell lines. In subcutaneous PDAC xenografts using AsPC-1 cells, net tumor growth in different therapy groups was 432.6 mm3 in controls, 105.3 mm3 after NPT (p=0.0023), 184 mm3 after Tra (p=0.0018), 81 mm3 after NPT+Tra (p=0.0003), 37.3 mm3 after NPT+Gem (p=0.0025) and -8.1 mm3 (tumor regression) after NPT+Gem+Tra (p<0.0001). In another subcutaneous PDAC xenografts using Panc-1 cells, net tumor growth in different therapy groups was: 274.1 mm3 in controls, 80.8 mm3 after NPT (p=0.0002), 150.6 mm3 after Tra (p=0.0047), 75.1 mm3 after NPT+Tra (p=0.0002), 48.4 mm3 after NPT+Gem (p=0.0004) and 3.8 mm3 after NPT+Gem+Tra (p<0.0001). In PDAC peritoneal dissemination model using AsPC-1 cells, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase, p=0.0004), Tra (31 days, a 55% increase, p=0.0004), NPT+Tra (37 days, a 85% increase, p=0.0001), NPT+Gem (39 days, a 95% increase, p=0.0001) and NPT+Gem+Tra (49 days, a 145% increase, p<0.0001). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. In vitro studies demonstrated inhibition in PDAC cell (AsPC-1, Panc-1, Mia PaCa-2, CFPAC) proliferation by NPT+Gem, Tra, and combination. Immunoblot analysis revealed that trametinib effects were specifically accompanied by decrease in phospho-ERK expression and increase in the expression of apoptosis-related cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel based chemotherapy regimens can be enhanced through specific inhibition of MEK1/2 kinase activity, which clinically could lead to improved PDAC therapy effects. Citation Format: Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A. Schwarz, Roderich E. Schwarz. Trametinib, a MEK inhibitor, augments nab-paclitaxel based chemotherapy response in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4202. doi:10.1158/1538-7445.AM2017-4202

241P - Safety and effectiveness of nab-paclitaxel in young and elderly patients with metastatic breast cancer: a prospective, multicenter non-interventional study

241P - Safety and effectiveness of nab-paclitaxel in young and elderly patients with metastatic breast cancer: a prospective, multicenter non-interventional study

Prospective phase I study of nab-paclitaxel plus gemcitabine with concurrent MR-guided IMRT in patients with locally advanced or borderline resectable pancreatic cancer.

TPS480 Background: Radiotherapy (RT) for locally advanced and borderline resectable pancreatic cancer (LABPC) is controversial as potential local control benefits are often obscured by high rates of distant progression. However, local failure remains a significant cause of morbidity among patients without distant progression after initial chemotherapy, although toxicity concerns may limit delivery of optimal systemic therapy concurrent with RT. Given known systemic efficacy and radiosensitization effects of nab-paclitaxel (A) with gemcitabine (G), we initiated a phase I study of nab-paclitaxel with gemcitabine (AG) and concurrent intensity modulated radiation therapy with magnetic resonance guidance (MR-IMRT) for LABPC. Methods: A planned 24 patients with LABPC will be enrolled to a phase I dose escalation trial using the Time-to-Event Continual Reassessment Method (TITE-CRM) design. Following one lead-in cycle of GA, MR-IMRT is administered daily with concurrent weekly GA for a total of 25 fractions in 5 weeks. The initial dose levels for RT and AG, respectively, are: 40 Gy MR-IMRT, 75 mg/m2 A and 600mg/m2 G. The maximum possible dose level is 60 Gy MR-IMRT, 100mg/m2 A and 1000mg/m2 G. To reduce toxicity risk, MR-IMRT volumes include the primary tumor only, with cine-MR used for intra-fraction tumor tracking in place of fiducial markers. The primary endpoint is determination of the maximum tolerated dose level, with secondary endpoints including rate of conversion to resectable disease, progression- free survival, overall survival, and patient reported quality of life. Clinical trial information: NCT02283372.

P205 The relationship between dose intensity and pathological effect of nab-paclitaxel as neoadjuvant

P205 The relationship between dose intensity and pathological effect of nab-paclitaxel as neoadjuvant

Nab-paclitaxel salvage chemotherapy for metastatic ocular melanoma.

e19042 Background: Metastatic ocular melanoma is an incurable malignancy characterised by liver predominant involvement. Conventional systemic chemotherapy using drugs such as fotemustine or dacarbizine have low response rates. In liver only disease hepatic arterial infusion of fotemustine has reported a higher response rate. Methods: We report four prospectively followed patients who all received salvage treatment with Nab-paclitaxel after previous intra-arterial fotemustine for metasatic ocular melanoma. Results: One patient who did not respond to to intra-arterial chemotherapy had a radiological response to Nab-paclitaxel with a duration of six months (5 cycles of treatment) with subsequent progression inliver and CNS. Another patient had rapidly progressing liver, peritoneal and nodal metastases with elevated bilirubin. He received dose reduced Nab-paclitaxel sith significant biochemical, radiological and functional improvement. He continues on Nab-paclitaxel in ongoing partial remission and remains clinically improved after six months. Two patients with similarly advanced disease, including one with abnormal bilirubin, did not respond. Subsequent treatments for the three patients progressing after Nab-paclitaxel have been SIR-Spheres followed by Ipilumumab, Ipilumumab and palliation respectively. Typical side effects of Nab-paclitaxel have occurred including alopecia, fatigue, peripheral neuropathy and neutropenia. Conclusions: In summary we have seen clinically useful responses in two of four patients treated. We continue to recruit further patients to better understand the role of Nab-paclitaxel as salvage chemotherapy for metastatic ocular melanoma.

Nanoparticle albumin-bound (nab) IDN5404: a novel vascular disrupting agent with potent antitumor and antiangiogenic effects.

Abstract Abstract #2138 Background: The tumor vasculature is an established target for the therapy of solid tumors. IDN5404 is a thiocolchicine dimer with antitubulin and topisomerase 1 inhibitor properties. In this study, nab-formulated IDN5404 was examined for antitumor effects in three xenograft models and for antiangiogenic as well as vascular disrupting activity (VDA) in the avian embryonic chorioallantoic membrane (CAM) assays.
 Materials and Methods: Subcutaneous human breast (MX-1 and MDA-MB-231), colon (HT29), and prostate (PC3) tumors were grown in athymic nude mice and treated intravenously (IV) with nab-5404 alone at 10, 20, 30, or 40 mg/kg (q3dx4 or q4dx3) and in combination with IV or intraperitoneal (IP) nab-paclitaxel (Abraxane; 10, 15 or 30 mg/kg, qdx5 or q4dx3). The effect of dose, schedule, and sequence of combination regimen was tested. Nab-5404 was administered 24-hr before, concurrently or 24-hr after Abraxane administration. The effect of nab-5404 on embryonic angiogenesis was examined in vivo using the standard chick CAM assay with 3-day old embryos (n = 18). The quail CAM assay was used to determine the time course of VDA. Quail embryos (n = 36) were exposed to nab-5404 (1 to 16 µg/ml) on day 7 and digital CAM images were acquired over a 60 min period for scoring VDA.
 Results: Significant dose-dependent tumor growth inhibition (TGI) was observed in all xenograft models. In the MX-1 and HT29 models, nab-5404 (30 mg/kg, q3dx4) exhibited potent antitumor activity (P < 0.0001, ANOVA, vs. saline) alone and in combination with Abraxane (TGI for MX-1: 65% and 76%; TGI for HT29: 44% and 74% respectively). Nab-5404 was similarly effective with the q4dx3 schedule. In addition, when Nab-5404 (20 mg/kg, q4dx3) was administered 24-hr before, concurrently or 24-hr after Abraxane (5 mg/kg, q4dx3), the combination resulted in TGI of >99%, 88%, and 72% respectively. Using the in vivo chick CAM assay, nab-5404 inhibited embryonic angiogenesis by over 90% at 5 µg/CAM without affecting viability. Furthermore, rapid collapse of blood vessels was observed within 30 min in the viable quail CAM assay when embryos were exposed to nab-5404 at 4-16 µg/ml.
 Discussion: Nab-5404 alone and in combination with Abraxane demonstrated significant TGI in xenograft models of human breast, colon or prostate cancer. This effect was shown to be due to the rapid VDA of nab-5404. Maximum antitumor activity was seen when nab-5404 was administered 24 hr before Abraxane. Nab-5404, a microtubule-destabilizing vascular disruptive agent, potentiates the cytotoxic effects of nab-paclitaxel, a microtubule-stabilizing agent and the data suggest that these two agents may be utilized effectively in combination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2138.