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Investigational New Drugs

, Volume 32, Issue 1, pp 188–194 | Cite as

Phase II trial of combination nab-paclitaxel, carboplatin and gemcitabine in first line therapy of advanced urothelial carcinoma

  • Ajjai AlvaEmail author
  • Stephanie Daignault
  • David C. Smith
  • Maha Hussain
PHASE II STUDIES

Summary

Background Paclitaxel has significant single agent activity in urothelial cancer. The 130 nm albumin bound paclitaxel (nab-paclitaxel, ABI-007) delivers more paclitaxel to tumor than conventional paclitaxel without cremophor related toxicities. We assessed the efficacy of nab-paclitaxel in combination with carboplatin and gemcitabine as first line therapy in advanced urothelial cancer. Methods Eligible patients had histologically confirmed metastatic, locally recurrent or advanced pure or mixed urothelial cancer, ECOG performance status of 0–2, no prior chemotherapy for current disease stage and no taxane for ≥ 1 year. Therapy consisted of nab-paclitaxel at 220 mg/m2 intravenously with optional dose escalation to 260 mg/m2 for subsequent cycles, with carboplatin AUC 5 on day 1 and gemcitabine at 800 mg/m2 on days 1 and 8 in 21-day cycles. Dose modifications in all three drugs to −1 and −2 levels were allowed for toxicity. Primary endpoint was overall response rate by RECIST 1.0. Secondary endpoints were safety, progression free and overall survival. Using a two-stage design, 32 patients were planned to be enrolled. Results Due to poor accrual only 16 patients were enrolled. Thirteen patients had metastatic disease, 3 were women, and median age was 73.9 years (range 51.3–83). ECOG PS was 0 in 4 (25.0 %) and 1 in 11 (68.8 %) patients. Creatinine clearance by Cockroft-Gault formula was less than 60 in 43 % of patients and 50 % of patients had visceral disease at baseline. The regimen was associated with severe toxicity, mainly cytopenias. Adverse events required removal of 11 patients (68.8 %) from study. Seven patients (43.7 %) missed ≥ 1 dose due to toxicity and 7 patients were reduced to −2 dose level. Nine (56.4 %) grade ≥ 3 neutropenia and thrombocytopenia each but only 1 episode of febrile neutropenia (6.3 %) was reported. Grade ≥ 3 anemia was noted in 6 patients (37.5 %). Grade 2 neuropathy was seen in 12.5 % but no grade ≥ 3 neuropathy was observed. One patient had confirmed PR (6.7 %; 95 % CI, 0–32 %) and 2 (13.3 %) had unconfirmed PR. Six other patients (40 %) had SD. Due to censoring at study exit due to adverse events before true progression, median PFS was 11.2 months (95 % CI,2.0–11.2 m). Median overall survival was 13.1 months (95 % CI, 9.8–19.6 m). Conclusions The combination of nab-paclitaxel, carboplatin and gemcitabine was poorly tolerated in this high risk patient population at these doses and schedule. Other nab-paclitaxel based combinations should be explored in first line therapy of advanced urothelial cancer.

Keywords

Nano-particle albumin bound paclitaxel Urothelial cancer Chemotherapy 

Notes

Acknowledgments

This study was supported by Celgene Corporation. The authors acknowledge the contributions of Tamara Huebner, R.N. (study coordination), Patricia Harvey (data management), Charles Leister (regulatory management) and Beesea Hsieh (data processing).

Conflict of interest

The authors declare that they have no conflict of interest.

Funding support

The work was supported in part by a grant from Celgene (previously Abraxis Bioscience). AA is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number 2KL2TR000434. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ajjai Alva
    • 1
    • 2
    Email author
  • Stephanie Daignault
    • 1
  • David C. Smith
    • 1
    • 2
  • Maha Hussain
    • 1
    • 2
  1. 1.University of Michigan Comprehensive Cancer CenterAnn ArborUSA
  2. 2.Division of Hematology/Oncology, Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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