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

Abstract

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: ClinicalTrials.gov identifier: NCT01893801.

Conflict of interest statement

Conflict of Interest Disclosures: Mrs Jameson reports receiving grants from Seena Magowitz Foundation, Stand Up to Cancer, TGen Foundation, Lustgarten Foundation, and HonorHealth Foundation during the conduct of the study; receiving grants and personal fees from Celgene; and receiving personal fees from Ipsen, outside the submitted work. Dr Borazanci reports receiving grants and personal fees from Fujifilm; personal fees from Corcept Therapeutics and from Ipsen; receiving grants from Bristol-Myers Squibb, Samumed, Merck & Co, Ambry Genetics, MabVax Therapeutics, Eli Lilly and Company, and Minneamrita Therapeutics, outside the submitted work; and receiving grants from the Seena Magowitz Foundation, Stand Up to Cancer, TGen Foundation, Lustgarten Foundation, and HonorHealth Foundation during the conduct of the study. Dr Babiker receives personal fees from Celgene and Endocyte outside of the submitted work. Dr Niewiarowska reported receiving grants from BERG outside the submitted work. Dr Gordon reported receiving grants from Seena Magowitz Foundation, TGen Foundation, Stand Up to Cancer, and Lustgarden Foundation during the conduct of the study; and receiving personal fees from Agenus, TRACON Pharmaceuticals, Deciphera Pharmaceuticals, and Imaging Endpoints, outside the submitted work. Ms Amy Stoll-D’Astice reports receiving grants from TGen Foundation during the conduct of the study and grants from Celgene outside the submitted work. Dr Korn reports consulting for ImaginAb, Dracen Pharmaceuticals, Merrimack Pharmaceuticals, Halozyme Therapeutics, and Globavir outside the submitted work. Dr Ramanathan reports receiving grants from Celgene during the conduct of the study; receiving personal fees from Pharmacyclics; receiving grants from Celgene, Ipsen, Merck & Co, Novartis, and Boston Biomedical outside the submitted work; and reports becoming an employee of Merck Research labs with stock options after the conduct of this study. Dr Von Hoff reports receiving grants from Seena Magowitz Foundation, Stand Up to Cancer, TGen Foundation, Lustgarten Foundation, and HonorHealth Foundation during the conduct of the study; owning shares of stock in McKesson, Medtronic, CerRx, SynDevRx, UnitedHealthcare, Anthem Inc, Capella Therapeutics, Stromatis Pharma, Systems Oncology, and Cell Therapeutics; receiving grants and personal fees from Five Prime Therapeutics, Aduro Biotech, Eli Lilly and Company, and Celgene; receiving personal fees from DNAtrix, Esperance Pharmaceuticals, FORMA Therapeutics, Imaging Endpoints, Immodulon Therapeutics, Insys Therapeutics, Medical Prognosis Institute, mRNA Therapeutics, Senhwa Biosciences, Tolero Pharmaceuticals, TrovaGene, Alethia Biotherapeutics, Alpha Cancer Technologies, Arvinas, Bellicum Pharmaceuticals, CanBas, Horizon Discovery, Innate Pharma, Lixte Biotechnology Holdings, Oncolyze, RenovoRx, Translational Drug Development, Aadi Bioscience, Aptose Biosciences, BioLineRx, CV6 Therapeutics, CytomX Therapeutics, EMD Serono, Evelo Biosciences, Fujifilm, Histogen, Intezyne Technologies, Kalos Therapeutics, Kura Oncology, Pharmamab, Phosplatin Therapeutics, Sotio, Strategia Therapeutics, Sun BioPharma, SynerGene Therapeutics, Systems Imagination, 7 Hills Pharma, Actinium Pharmaceuticals, ARMO BioSciences, Cancer Prevention Pharmaceuticals, Defined Health now known as Cello Health BioConsulting, Geistlich Pharma, HUYA Bioscience International, Immunophotonics, Novocure, Vertex Pharmaceuticals, ARIAD Pharmaceuticals, Boston Biomedical, Corrona, Genzada Pharmaceuticals, L.E.A.F. Pharmaceuticals, Oncology Venture A/S, RefleXion Medical, TP Therapeutics now known as Turning Point Therapeutics, Verily, Athenex, Fate Therapeutics, FibroGen, Jounce Therapeutics, Samus Therapeutics, Sumitomo Dainippon Pharma, Aeglea Biotherapeutics, 2X Oncology, Innokeys, Novita Pharmaceuticals, NuCana BioMed, Araxes Pharma, Ipsen, SciClone Pharmaceuticals, TargaGenix, TransMed Pharma, Veana Therapeutics, BioSpecifics Technologies, Riptide Bioscience, Vicus Therapeutics, Codiak Bioscience, Decoy Biosystems, OSI Pharmaceuticals, Agenus, Globe Life Sciences, Kelun-Klus Pharma, Radimmune Therapeutics, Samumed, Sobi, Adicet Bio, BioXcel Therapeutics, Bryologyx, Helix BioPharma, Sirnaomics; receiving grants from Genentech, Agios, Incyte, Merrimack Pharmaceuticals, Plexxikon, Minneamrita Therapeutics, 3-V Biosciences, AbbVie, ArQule, Baxalta, Cleave Biosciences, CytRx Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Endocyte, Exelixis, ESSA Pharma, Gilead Sciences, Merck & Co, miRNA Therapeutics, Pfizer, Pharmacyclics, Phoenix Biotechnology, ProdermIQ, Samumed, Strategia Therapeutics, TrovaGene, Verastem Oncology, Halozyme, outside the submitted work; and reports receiving travel, accommodations, and expenses paid or reimbursed by Genentech/Roche.

Figures

Figure 1.. Consort Diagram

CR indicates complete response; MTD, maximum tolerated dose; PD, progressive disease; PR, partial response; RECIST 1.1, Response Evaluation Criteria in Solid Tumors, version 1.1; and SD, stable disease.

Figure 2.. Patient Response to Treatment

CA19-9 indicates carbohydrate antigen 19-9; PR, partial response.

Figure 3.. Kaplan-Meier Curves for Overall Survival and Progression-Free Survival for All Patients