Response Rate Following Albumin-Bound Paclitaxel Plus Gemcitabine Plus Cisplatin Treatment Among Patients With Advanced Pancreatic Cancer: A Phase 1b/2 Pilot Clinical Trial.

Published on Jan 1, 2020in JAMA Oncology22.416
· DOI :10.1001/JAMAONCOL.2019.3394
Gayle S. Jameson14
Estimated H-index: 14
(TGen: Translational Genomics Research Institute),
Erkut Borazanci10
Estimated H-index: 10
(TGen: Translational Genomics Research Institute)
+ 13 AuthorsDaniel D. Von Hoff86
Estimated H-index: 86
(TGen: Translational Genomics Research Institute)
Importance Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations, indicating a DNA repair deficiency associated with sensitivity to DNA damaging agents, such as platinum. Objective To determine response rate following treatment with nab-paclitaxel plus gemcitabine plus platinum-based cisplatin for patients with metastatic pancreatic ductal adenocarcinoma (PDA). Design, Setting, and Participants This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus cisplatin treatment in which 25 patients with previously untreated metastatic PDA were enrolled. The trial was conducted from December 2013 to July 2016 at 3 US sites, with the last patient receiving study treatment at the end of October 2016, and the study closing January 2018. Interventions Patients were treated with nab-paclitaxel plus gemcitabine plus various doses of cisplatin, 25 mg/m2, 37.5 mg/m2, and 50 mg/m2, on days 1 and 8 of a 21-day cycle. Main Outcomes and Measures Primary end point was complete response rate as assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and levels of carbohydrate antigen 19-9 (or in nonexpressers, carbohydrate antigen 125 or carcinoembryonic antigen). Efficacy analysis included evaluable patients (those who received at least 1 dose of study treatment and had at least 1 postbaseline tumor assessment). Results Of 25 patients enrolled in the study, the median (range) age was 65.0 (47.0-79.0) years, 14 (56%) were men, and most (24) were white (96%). The maximum tolerable dose of cisplatin was 25 mg/m2. The most common treatment-related adverse events grade 3 or higher were thrombocytopenia (17 patients [68%]), anemia (8 patients [32%]), and neutropenia (6 patients [24%]). Fatal events occurred for 3 patients (12%); 2 were related to study participation. A median (range) of 8 (1-15) cycles was completed. The RECIST responses in 24 evaluable patients included 2 complete responses (8%), which was below the primary end point of 25%, 15 partial responses (62%), 4 stable disease (17%), and 3 progressive disease (12%), with median overall survival of 16.4 (95% CI, 10.2-25.3) months; 16 patients (64%) were alive at 1 year, 10 (40%) at 2 years, 4 (16%) at 3 years, and 1 (4%) at 4 plus years. Overall survival ranged from 36 to 59 months. Median progression-free survival was 10.1 (95% CI, 6.0-12.5) months. Thus, the overall response rate was 71%, and the disease control rate was 88%. Conclusions and Relevance This triple drug regimen showed substantial clinical activity in this small study. Although the primary end point was not reached, the high overall response rate, disease control rate, and median survival time among patients with advanced PDA treated with this combination are encouraging. The regimen is being studied in patients with PDA in the neoadjuvant setting and in patients with advanced biliary cancers. Trial Registration identifier:NCT01893801
  • References (14)
  • Citations (4)
#1Rachna T. Shroff (UA: University of Arizona)H-Index: 20
#2Milind Javle (University of Texas MD Anderson Cancer Center)H-Index: 30
Last. Mitesh J. Borad (Mayo Clinic)H-Index: 34
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Importance Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed. Objective To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)–paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced bi...
8 CitationsSource
#1Michele ReniH-Index: 49
#2Silvia ZanonH-Index: 8
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Summary Background Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. Methods This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled pat...
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#1Michael T. Barrett (Mayo Clinic)H-Index: 18
#2Ray DeiotteH-Index: 1
Last. Daniel D. Von Hoff (TGen: Translational Genomics Research Institute)H-Index: 86
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Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enr...
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#1Gayle S. JamesonH-Index: 14
#2Erkut BorazanciH-Index: 10
Last. Daniel D. Von HoffH-Index: 86
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341Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stag...
10 CitationsSource
#1Michele Reni (UniSR: Vita-Salute San Raffaele University)H-Index: 49
#2Gianpaolo Balzano (UniSR: Vita-Salute San Raffaele University)H-Index: 39
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Phase 1B trial of Nab -paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma
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#1E. G. Chiorean (UW: University of Washington)H-Index: 2
#2D. D. Von Hoff (TGen: Translational Genomics Research Institute)H-Index: 8
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#1Nicola Waddell (UQ: University of Queensland)H-Index: 27
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Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (var...
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#1Daniel D. Von Hoff (TGen: Translational Genomics Research Institute)H-Index: 86
#2Thomas J. ErvinH-Index: 28
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BACKGROUND In a phase 1–2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performan...
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Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, eva...
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Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, with systemic therapy being the mainstay of treatment. Survival continues to be limited, typically less than 1 year. The PDAC microenvironment is characterized by a paucity of malignant epithelial cells, abundant stroma with predominantly immunosuppressive T cells and myelosuppressive-type macrophages (M2), and hypovascularity. The current treatment options for metastatic PDAC are modified (m)FOLFIRINOX /FOLFIRI...
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Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years. Improving quality of life and survival amongst these patients will require new ideas and novel therapies in a multidisciplinary approach. This review will cover the most recent advances in the comprehensive treatment of pancreatic cancer and place them within a historical context when necessary. Treatment of all disease stages will ...