Response Rate Following Albumin-Bound Paclitaxel Plus Gemcitabine Plus Cisplatin Treatment Among Patients With Advanced Pancreatic Cancer: A Phase 1b/2 Pilot Clinical Trial | Gastroenterology | JAMA Oncology | JAMA Network
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Figure 1.  Consort Diagram
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
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
Kaplan-Meier Curves for Overall Survival and Progression-Free Survival for All Patients
Table 1.  Patient Demographic and Disease Characteristics
Patient Demographic and Disease Characteristics
Table 2.  Treatment-Related Adverse Events Occurring in More Than 5% of Patientsa
Treatment-Related Adverse Events Occurring in More Than 5% of Patientsa
1.
Siegel  RL, Miller  KD, Jemal  A.  Cancer statistics, 2018.  CA Cancer J Clin. 2018;68(1):7-30. doi:10.3322/caac.21442PubMedGoogle ScholarCrossref
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Barrett  MT, Deiotte  R, Lenkiewicz  E,  et al.  Clinical study of genomic drivers in pancreatic ductal adenocarcinoma.  Br J Cancer. 2017;117(4):572-582. doi:10.1038/bjc.2017.209PubMedGoogle ScholarCrossref
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Waddell  N, Pajic  M, Patch  AM,  et al; Australian Pancreatic Cancer Genome Initiative.  Whole genomes redefine the mutational landscape of pancreatic cancer.  Nature. 2015;518(7540):495-501. doi:10.1038/nature14169PubMedGoogle ScholarCrossref
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Von Hoff  DD, Ramanathan  RK, Borad  MJ,  et al.  Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.  J Clin Oncol. 2011;29(34):4548-4554. doi:10.1200/JCO.2011.36.5742PubMedGoogle ScholarCrossref
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Von Hoff  DD, Ervin  T, Arena  FP,  et al.  Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.  N Engl J Med. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369PubMedGoogle ScholarCrossref
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Liang  WS, Craig  DW, Carpten  J,  et al.  Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing.  PLOS One. 2012;7(10):e43192. doi:10.1371/journal.pone.0043192PubMedGoogle Scholar
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Conroy  T, Desseigne  F, Ychou  M,  et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.  N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923PubMedGoogle ScholarCrossref
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Reni  M, Balzano  G, Zanon  S,  et al.  Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma.  Br J Cancer. 2016;115(3):290-296. doi:10.1038/bjc.2016.209PubMedGoogle ScholarCrossref
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Reni  M, Zanon  S, Peretti  U,  et al.  Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.  Lancet Gastroenterol Hepatol. 2018;3(10):691-697. doi:10.1016/S2468-1253(18)30196-1PubMedGoogle ScholarCrossref
10.
Jameson  G, Borazanci  E, Poplin  E,  et al. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [abstract LB-003]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; April 19, 2015; Philadelphia (PA). Cancer Res. 2015;75(15 suppl):Abstract LB-003. doi:10.1158/1538-7445.AM2015-LB-003
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Jameson  G, Borazanci  E, Babiker  H,  et al.  A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer  [abstract 341].  J Clin Oncol. 2017;35(suppl 4):341.Google ScholarCrossref
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World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
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Eisenhauer  EA, Therasse  P, Bogaerts  J,  et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026PubMedGoogle ScholarCrossref
14.
Shroff  RT, Javle  MM, Xiao  L,  et al.  Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial.  JAMA Oncol. 2019;5(6):824-830. doi:10.1001/jamaoncol.2019.0270PubMedGoogle ScholarCrossref
15.
Chiorean  EG, Von Hoff  DD, Reni  M,  et al.  CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer.  Ann Oncol. 2016;27(4):654-660. doi:10.1093/annonc/mdw006PubMedGoogle ScholarCrossref
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ClinicalTrials.gov. Pre-operative Treatment for patients with untreated pancreatic cancer: ClinicalTrials.gov identifier, NCT03138720. https://clinicaltrials.gov/ct2/show/NCT03138720. Accessed August 22, 2019.
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ClinicalTrials.gov. Gemcitabine, cisplatin, and abraxane in advanced biliary cancers: ClinicalTrials.gov identifier, NCT02392637. https://clinicaltrials.gov/ct2/show/NCT02392637. Accessed August 22, 2019.
Original Investigation
October 3, 2019

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

Author Affiliations
  • 1HonorHealth Research Institute, Scottsdale, Arizona
  • 2Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, Arizona
  • 3Comprehensive Cancer Center, The University of Arizona, Tucson
  • 4Rutgers Cancer Institute of New Jersey, New Brunswick
  • 5Vita Medical Associates, Bethlehem, Pennsylvania
  • 6Mayo Clinic, Scottsdale, Arizona
  • 7Cancer Research And Biostatistics, Seattle, Washington
  • 8Imaging Endpoints, Scottsdale, Arizona
JAMA Oncol. 2020;6(1):125-132. doi:10.1001/jamaoncol.2019.3394
Key Points

Question  Is adding cisplatin to nab-paclitaxel and gemcitabine treatment associated with increased overall survival and complete response potential among patients with metastatic pancreatic adenocarcinoma?

Findings  In this single-arm, phase 1b/2 clinical trial of 25 patients, the combination of cisplatin, nab-paclitaxel, and gemcitabine for the treatment of patients with previously untreated stage IV pancreatic adenocarcinoma was associated with an overall response rate of 71%, including a complete response rate of 8%. The median overall survival was 16.4 months, and the median progression-free survival was 10.1 months.

Meaning  Adding cisplatin to nab-paclitaxel and gemcitabine in this pilot study was associated with substantially increased clinical activity; thus, further investigation of this triple-drug combination in larger studies is warranted.

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

Introduction

Current treatment regimens for patients with advanced pancreatic ductal adenocarcinoma (PDA) offer modest improvements in progression-free survival and overall survival (OS). Owing to a lack of adequate screening guidelines and delayed onset of symptoms, greater than 80% of patients at the time of diagnosis present with unresectable, advanced disease.1 Standard treatment options for patients with inoperable, locally advanced, or metastatic PDA have been quite limited.

In recent years, greater insight into the biology of PDA has prompted new treatment strategies and some optimism. It is well known that many pancreatic tumors possess numerous molecular signatures, including DNA repair deficiencies, and are potentially vulnerable to new targeted therapies and DNA damaging agents.2,3 We hypothesized that the addition of a platinum-based agent to the approved regimen of nab-paclitaxel plus gemcitabine for patients with advanced PDA could improve treatment efficacy and patient outcomes.4,5

In a previous whole-genome/transcriptome sequencing analysis, some members of our team found that abnormal repair pathways were a feature of all of the pancreatic cancers that were sequenced.6 Cisplatin prevents cellular DNA repair by binding to and causing crosslinking of DNA, triggering apoptosis. Although a platinum-based drug has been examined with oxaliplatin within the FOLFIRINOX combination (fluorouracil, irinotecan, and oxaliplatin) for treatment of PDA,7 cisplatin has been rarely described in combination with nab-paclitaxel plus gemcitabine. Recently reported phase 1b and phase 2 trials combining nab-paclitaxel, gemcitabine, and cisplatin with or without capecitabine for treatment of patients with metastatic PDA noted a 74% progression-free rate at 6 months in the combination arm (42 patients) compared with 46% in the nab-paclitaxel plus gemcitabine arm (41 patients).8,9 Here, we conducted a phase 1b/2 open-label, multi-institution, prospective study evaluating the preliminary efficacy and safety of nab-paclitaxel plus gemcitabine plus cisplatin (NABPLAGEM) in patients with previously untreated metastatic PDA.10,11

Methods
Study Participants

The study protocol in Supplement 1 and all amendments were approved by the institutional review boards or independent ethics committee at each participating institution. All patients provided written informed consent in a manner consistent with the Declaration of Helsinki12 prior to participation in the study. Patients were invited to participate in the optional collection of archived tumor tissue for comparative genomic hybridization and next-generation sequencing (eAppendix 1 in Supplement 2). No one received compensation or was offered any incentive for participating in this study.

Eligible patients were 18 years or older, had histologically or cytologically confirmed metastatic PDA that was measurable according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1,13 a Karnofsky Performance Status score of 70% or higher, life expectancy of 12 weeks or longer, and adequate hematologic, hepatic, and renal function. Additional eligibility criteria are listed in the trial protocol in Supplement 1.

Study Design and Treatment

This pilot, open-label, single-arm, phase 1b/2 clinical study evaluated the preliminary efficacy and safety of nab-paclitaxel, 125 mg/m2, gemcitabine, 1000 mg/m2, and cisplatin, 25 mg/m2, 37.5 mg/m2, or 50 mg/m2, all administered intravenously (IV) on days 1 and 8 every 21 days until development of unacceptable toxicity or disease progression. The doses of the nab-paclitaxel and gemcitabine were obtained from the original phase 1b/2 trial, which was further evaluated in a phase 3 trial.4,5 A 3 × 3 dose escalation schema was used in phase 1b at a starting dose of cisplatin 25 mg/m2 to determine the maximum tolerated dose (MTD) that would be administered in phase 2. The study design is given in detail in Supplement 1.

Patients received IV premedication of dexamethasone, 12 mg, palonosetron, 0.25 mg, and fosaprepitant, 150 mg, followed by oral dexamethasone, 4 mg, and ondansetron, 8 mg, twice daily for 2 days after each chemotherapy. The sequence of drug administration was IV hydration followed by nab-paclitaxel, then cisplatin, and then gemcitabine (trial protocol in Supplement 1). Patients received additional IV hydration on days 2 and 9 and received pegfilgrastim, 6 mg, subcutaneously on day 9 of each cycle.

Assessments

Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, by the National Cancer Institute. Hematology and serum chemistry measurements were performed weekly during treatment. Grade 3 or higher AEs were collected.

Tumor response was assessed every 9 weeks by spiral computed tomography or magnetic resonance imaging per RECIST 1.1. Serial measurements of the carbohydrate antigen 19-9 (CA19-9) levels or of carbohydrate antigen-125 (CA-125) or carcinoembryonic antigen (CEA) levels in patients who were not expressers of CA19-9 were performed at baseline and at the beginning of every treatment cycle thereafter. Patients were followed up for survival until death or study closure.

Study End Points

The primary end point was complete response (CR) rate as defined by RECIST 1.1 criteria and by CA19-9 normalization (or by CA-125 or CEA in CA19-9 nonexpressers). Once documented, a CR was to be confirmed by positron emission tomography (PET). Secondary end points included disease control rate, partial response (PR), stable disease, treatment-related toxicities, and change in CA19-9 (or CA-125, or CEA in nonexpressers) measured at 9 weeks. Treatment-related AEs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, and were coded and summarized according to the preferred terms in the Medical Dictionary for Regulatory Activities, version 15.0.

Statistical Analysis

The full statistical analyses are described in the trial protocol in Supplement 1. The sample size of 25 patients was based on a test of a null hypothesis of 5% or less CR (as defined by our strict criteria) vs an alternative hypothesis of 25% CR or higher. The initial cohort was 10 patients, and if there were no CRs, the trial would be closed. One or more CRs in 10 would be required to proceed to the total enrollment of 25 patients. Four or more CRs among 25 patients would be sufficient evidence for rejection of the null hypothesis of insufficient activity of the regimen. This design had a power of 87% at a 1-sided type I error rate of 3%.

Safety analyses included any patient who received at least 1 dose of drug. Efficacy analyses included only the evaluable population, defined as a patient who had received at least 1 dose of treatment with NABPLAGEM and had at least 1 tumor assessment after baseline.

Final data analyses were performed using SAS, version 9.4 (SAS Institute Inc), with a data cutoff date of December 5, 2018. Data from patients who were alive as of that date were censored for the survival analysis.

Results
Patient Characteristics

In total, 25 patients provided consent and were enrolled across 3 US sites from December 2013 through July 2016. The median (range) age was 65.0 (47.0-79.0) years, 14 (56%) were males, and the majority (24) were white (96%). Nine patients were enrolled in the phase 1b dose escalation portion, and 16 in the phase 2 cohort expansion (Figure 1). The last patient received study treatment at the end of October 2016, and the study was closed January 2018 although 3 patients continued to be followed up for survival status.

All patients received at least 1 dose of study treatment and were included in the safety analyses and time to event end point analyses, including progression-free survival and OS. Patients were not evaluable for overall response by RECIST 1.1 if a radiologic assessment could not be made. One patient died of a serious AE prior to postbaseline tumor assessment. Therefore, 24 patients were evaluable for efficacy. Patient demographic and disease characteristics for the treated population are summarized in Table 1 and eTable 1 in Supplement 2.

Treatment Exposure and MTD

Three patients tolerated the starting dose of cisplatin, 25 mg/m2, without a dose-limiting toxic effect. Therefore, the dose of cisplatin was increased to 50 mg/m2. The first patient in this cohort with the higher dose experienced dose-limiting toxicities of grade 4 neutropenic fever and pneumonia. It was determined unsafe to treat additional patients at the cisplatin 50 mg/m2 dose level. Three additional patients were treated safely at the cisplatin 25 mg/m2 dose level without dose-limiting toxicity. The investigators then selected an intermediary dose of cisplatin for dose escalation at 37.5 mg/m2. Two patients were treated at the cisplatin 37.5 mg/m2 dose level. Both patients experienced dose-limiting toxicities: 1 patient experienced grade 4 clostridium difficile colitis and the other had grade 4 thrombocytopenia.

Based on the unacceptable toxicities at 37.5 mg/m2, the MTD and the recommended phase 2 dose, were established as nab paclitaxel, 125 mg/m2, cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2, administered IV on days 1 and 8 every 21 days. Sixteen patients were treated in phase 2 at this dose level. Patients in phase 1b and phase 2 were combined so that 22 began therapy at the MTD of cisplatin, 25 mg/m2. Of the 3 patients in the dose escalation cohorts who received cycle 1 at the higher doses of cisplatin (2 patients at 37.5 mg/m2, 1 patient at 50 mg/m2), all were able to resume and continue therapy at the 25 mg/m2 dose level. The median (range) duration of treatment was 8 (1-15) cycles, with 8 patients (32%) receiving treatment for at least 6 months. Median (range) doses (body surface area) were nab paclitaxel, 113.8 (77.9-125.0) mg/m2, cisplatin 25.0 (24.4-33.3) mg/m2, and gemcitabine 928.4 (622.1-1000) mg/m2.

Safety and Adverse Events

The most frequently reported treatment-related AEs of grade 3 or higher were thrombocytopenia (17 patients [68%]), anemia (8 patients [32%]), and neutropenia (6 patients [24%]) as detailed in Table 2 and in eTable 2 in Supplement 2. A total of 16 serious AEs were reported in 12 patients (48%), of which 12 were considered treatment-related. One patient with an ongoing PR during cycle 6 experienced an increase in creatinine levels from a baseline of 1.06 to 1.68 mg/dL (normal reference range, 0.7-1.2 mg/dL; to convert creatinine levels to 16 micromoles per liter, multiply by 88.4). The patient’s renal function improved after stopping frequent ibuprofen use, and the patient was able to complete 8 cycles prior to PD. The incidence of grade 3 or higher chemotherapy-induced peripheral neuropathy in this study was 4%.

Fatal events were reported in 3 patients (12%), including hemorrhagic stroke, cryptosporidiosis infection, and cardiac arrest. One of those patients, age 62, with a long-standing history of multiple embolic cerebral vascular events (CVAs) who was on long-term anticoagulation experienced another embolic CVA with visual changes during cycle 2. He continued on full dose enoxaparin and study treatment. During cycle 3, he experienced a hemorrhagic CVA, with a platelet count of 145 × 103/μL (to convert platelet count to ×109 per liter, multiply by 1), which was within the reference range. Enoxaparin was discontinued. His condition stabilized and because his tumor was responding to therapy, he continued study treatment. On cycle 4, day 13, he experienced a fatal hemorrhagic CVA, with a platelet count of 21 × 103/μL. A second treatment-related death occurred in a patient, age 75, who died of cryptosporidiosis gastroenteritis. On cycle 1, day 11, despite a dose reduction (trial protocol in Supplement 1), and treatment with pegfilgrastim, he was hospitalized with neutropenia and diarrhea. He chose to stop treatment of the infection and of cancer, entered hospice care, and died 23 days after his last dose of chemotherapy. A third death, considered unrelated to study treatment, was of a patient, age 65, who at the end of cycle 7 on full-dose treatment was doing well with an ongoing partial response (PR) and minimal AEs. He was found deceased in his bed by his family, and no autopsy was performed. The cause of death was called a cardiac arrest.

Regarding tolerability, of the 22 patients treated with the recommended phase 2 cisplatin dose schedule of 25 mg/m2, 14 patients (64%), completed 3 or more cycles of treatment without dose interruption or modification. Eight of 22 patients (36%) completed 6 or more cycles, and 4 of 22 patients (18%) completed 9 or more cycles without dose interruption or modification. Grade 4 thrombocytopenia (36% of patients), occurred most often after cycle 1 on day 15 of the 21-day cycle. Outside of the aforementioned hemorrhagic CVAs, no serious bleeding events were observed.

Efficacy

The result for the primary end point—CR by RECIST 1.1 criteria with normalization of tumor marker and PET scan—was negative, and the null hypothesis could not be rejected. Of the 24 patients evaluable for response by RECIST 1.1, the objective response rate was 71%, with CR in 2 patients (8%) and PR in 15 patients (62%). Stable disease was observed in 4 patients (17%), and progressive disease in 3 patients (12%). The rate of disease control (CR + PR + stable disease) at 9 weeks was 88%.

The percentage change in tumor size (sum) from baseline over time and the maximal percentage change in tumor size are shown in Figure 2. In addition to the 2 patients (identification Nos. 10140201 and 10140206) who achieved a CR, a third patient (identification No. 10390) had a 100% reduction in tumor size but had a residual subcentimeter, nontarget liver lesion and persistent elevation of CA19-9 levels (nadir 429 U/mL, baseline 2743 U/mL; to convert CA19-9 levels to kilo units per liter, multiply by 1) and therefore did not meet the definition of CR.

The first patient (10140201) experienced a CR after 12 cycles of treatment (eFigure A in Supplement 2). This patient discontinued study treatment after maximum benefit was achieved and maintained a response for 18.5 months without additional chemotherapy, until recurrence of metastatic disease in the lung. The patient is receiving investigational therapy with an OS of 59 plus months and is still being followed up for survival status.

The second patient (10140206) achieved a CR after 6 cycles of treatment, and continued on study treatment for a total of 8 cycles with a response duration of 6 months. At the time of disease reoccurrence in the pancreas, the patient resumed this regimen off study. A PET scan showed no evidence of metastatic disease, and the primary pancreas tumor appeared resectable on imaging studies. The patient chose to proceed with a Whipple procedure, and tumor tissue was obtained for genomic analysis. Nine months following the surgical resection the patient experienced disease recurrence in the liver, yet lived for another 23 months on additional antitumor therapies, with an OS of 43.7 months.

One patient (10140202) who achieved a PR had a resolution of peritoneal metastases by CT and PET scans after 3 cycles (9 weeks) of treatment (eFigure B in Supplement 2), with an OS of 12.2 months. This patient eventually discontinued treatment after 9 cycles because of thrombocytopenia, which caused multiple treatment cycle delays and resulted in disease progression. Genomic analysis was performed, and the results are discussed in eAppendix 2 in Supplement 2. The results of germline testing performed as routine care are included in eTable 3 in Supplement 2.

Survival

The median OS was 16.4 months (95% CI, 10.2-25.3 months), with 16 patients (64%) alive at 1 year, 10 patients (40%) alive at 2 years, 4 patients (16%) alive at 3 years, and 2 patients (8%) alive at 4 or more years (Figure 3A). Three patients remained alive (36-59 or more months OS) at study conclusion. Median progression-free survival was 10.1 months (95% CI, 6.0-12.5 months) (Figure 3B).

Tumor Markers

Twenty-five patients had tumor markers collected at baseline. Nineteen of 25 patients (76%) had elevated CA19-9 levels measured at baseline, and 18 patients were followed up with subsequent CA19-9 measurements. Of the remaining 6 patients with CA19-9 levels within the reference range at baseline, 2 had elevated CEA or CA-125. The percentage change in CA19-9 from baseline over time and the maximal percent change are shown in Figure 2. Of 18 patients, 5 patients (28%) showed normalization of CA19-9 levels, 8 patients (44%) showed a decrease of at least 90%, and 16 patients (89%) had a decrease in CA19-9 levels of at least 50%. The majority of patients (19) in this study with a baseline elevation in the CA19-9 levels experienced a rapid decrease in the levels of this tumor marker, consistent with radiologic findings of a decrease in tumor size as assessed by RECIST 1.1

Discussion

This phase 1b/2, open-label, multi-institution, prospective clinical trial showed an objective response rate of 71%, with 8% CR and 62% PR. There was an 88% disease control rate, a progression-free survival of 10.1 months, and a 16.4-month median OS, with 64% of patients alive at 1 year, 40% alive at 2 years, 16% alive at 3 years, and 4% alive at 4 years. Although the primary end point of a 25% CR rate was not met, the high objective response rate reported is among the highest observed in phase 1b/2 study results. Direct comparisons cannot be made at this time to previously reported phase 3 clinical trials for PDA, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine.

In the present 25-patient study, the MTD of cisplatin tested in the phase 1b portion was 25 mg/m2. The phase 2 dosing administered to 22 of 25 patients was nab paclitaxel, 125 mg/m2, cisplatin 25 mg/m2, and gemcitabine 1000 mg/m2 given on days 1 and 8 of a 21-day cycle. Tolerance of therapy was acceptable, with nearly two-thirds of patients completing full-dose therapy for 3 or more cycles. Dose reduction was not required unless the platelet count had not recovered to 100 × 103/μL or higher or absolute neutrophil count to at least 1500/μL (to convert neutrophil count to ×109 per liter, multiply by 0.0001) prior to the start of the next cycle. The most common grade 3 or higher AE was thrombocytopenia, most often noted on day 15 of the 21-day cycle. Although hematological toxicity was frequently observed, most adverse events did not require clinical intervention. There were 3 deaths on study, 2 that were attributable to the drug regimen. Because most patients on study were able to tolerate therapy for 6 cycles or more, initiating the 3-drug regimen at lower doses, similar to what was done in a published study for treatment of biliary malignant neoplasms, was not considered.14

With the addition of cisplatin, significant renal dysfunction was not observed, likely because of the low dose of cisplatin and aggressive hydration. In this study, the chemotherapy-induced peripheral neuropathy observed in 4% of patients was less than the 17% reported in the pivotal MPACT trial combination arm of gemcitabine/nab-paclitaxel.5

Patients were visited by a nurse practitioner or a physician at least weekly, with attention given to symptom management and supportive care. Aggressive hydration with IV fluids provided on days 2 and 9 after chemotherapy and pegfilgrastim support provided on day 9 of the 21-day cycle likely minimized toxicities.

Most patients in the present study with a baseline elevation in the CA19-9 levels had a rapid decrease in the levels of this tumor marker, consistent with radiologic findings of a decrease in tumor size. In a retrospective review of the MPACT trial, the CA19-9 level decrease was more predictive of survival benefit vs radiologic response at week 8 in both treatment arms.15 In the present trial, some patients had a substantial rise in CA19-9 levels in the first few weeks of treatment, followed by a marked decrease in the marker (Figure 2). This finding may be important to keep in mind in the early treatment of patients with pancreatic cancer.

Limitations

The results of this small phase 1b/2 study, with a high response rate and evolving OS, are very encouraging. However as with any nonrandomized study, patient selection could have influenced the outcomes; thus, the results may not be generalizable.

Conclusions

This triplet regimen is being studied in patients with PDA in the neoadjuvant setting16 and has been studied and published in advanced biliary cancer17 although with some differences in dosing.14 Considering the rapid disease response, acceptable safety profile, and encouraging antitumor activity of the NABPLAGEM triplet, further study of the regimen in the metastatic setting is planned. In addition, further tumor molecular analysis is needed to correlate molecular findings with patient response to treatment.

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Article Information

Accepted for Publication: June 20, 2019.

Published Online: October 3, 2019. doi:10.1001/jamaoncol.2019.3394

Correction: This article was corrected on November 14, 2019, to add eTable 3 to Supplment 2 and cite it in the Results.

Corresponding Author: Gayle S. Jameson, MSN, ACNP-BC, AOCN, HonorHealth Research Institute, 10510 N 92nd St, Scottsdale, AZ 85258 (gayle.jameson@honorhealth.com).

Author Contributions: Ms Jameson and Dr Borazanci contributed equally to this work and are considered co–first authors. Dr Shemanski and Mr Rosenthal had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Jameson, Borazanci, Poplin, Crowley, Korn, Ansaldo, Von Hoff.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jameson, Borazanci, Babiker, Gordon, Rosenthal, Shemanski, Lebron, Ramanathan, Von Hoff.

Critical revision of the manuscript for important intellectual content: Jameson, Borazanci, Babiker, Poplin, Niewiarowska, Gordon, Barrett, Rosenthal, Stoll-D'Astice, Crowley, Korn, Ansaldo, Von Hoff.

Statistical analysis: Borazanci, Rosenthal, Crowley, Shemanski.

Obtained funding: Jameson, Borazanci, Von Hoff.

Administrative, technical, or material support: Borazanci, Gordon, Barrett, Stoll-D’Astice, Korn, Ansaldo, Lebron, Von Hoff.

Supervision: Jameson, Borazanci, Gordon, Von Hoff.

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.

Funding/Support: Study funding was provided by the Seena Magowitz Foundation, Stand Up to Cancer, Mattress Firm, Lustgarten Foundation, TGen Foundation, and HonorHealth Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Additional Contributions: We offer our heartfelt thanks to the patients and their families for contributing to this study. Nina Aronson Cantafio, BS, Triligent International, provided medical writing assistance. She was financially compensated for this contribution.

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