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A phase I trial of intraperitoneal nab-paclitaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity

Abstract

Purpose

To evaluate intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies that are primarily confined to the peritoneal cavity in a phase I trial.

Methods

Using a 3 + 3 dose escalation of IP nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle, we evaluated six dose levels (35–175 mg/m2/dose). Maximum tolerated dose (MTD) and pharmacokinetics (PK) of IP nab-paclitaxel were determined.

Results

There were no dose-limiting toxicities (DLTs) in cohorts 1–3. There was a DLT in one of six patients in cohort 4 (112.5 mg/m2) (grade 3 neutropenia causing treatment delay > 15 days) and a DLT in one of three patients in cohort 6 (175 mg/m2) (grade 4 neutropenia and grade 3 abdominal pain). A second patient in cohort 6 experienced a serious adverse event (cycle 1, grade 4 ANC ≤ 7 days, cycle 4, grade 2 left ventricular dysfunction). This dose level was determined to be above the MTD. No DLTs were seen in seven patients treated in cohort 5 (140 mg/m2). The MTD of IP nab-paclitaxel was established at 140 mg/m2 on days 1, 8, and 15 of a 28-day cycle. There was a PK advantage for IP nab-paclitaxel, with an IP plasma area under the concentration–time curve (AUC) ratio of 147-fold (range 50–403) and therapeutic range systemic drug levels. Eight of 27 enrolled patients had progression-free survival ≥ 6 months. One patient experienced complete response, and one patient experienced partial response. Six patients had stable disease.

Conclusions

Weekly IP nab-paclitaxel has a favorable toxicity profile, a significant pharmacologic advantage, and promising clinical activity.

Clinical trial registration

NCT00825201.

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Fig. 1

References

  1. Levin L, Hryniuk WM (1987) Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5(5):756–767. https://doi.org/10.1200/jco.1987.5.5.756

    Article  CAS  PubMed  Google Scholar 

  2. Alberts DS, Liu PY, Hannigan EV, O’Toole R, Williams SD, Young JA, Franklin EW, Clarke-Pearson DL, Malviya VK, DuBeshter B (1996) Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335(26):1950–1955. https://doi.org/10.1056/nejm199612263352603

    Article  CAS  PubMed  Google Scholar 

  3. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, Wadler S, Sickel J (2001) Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19(4):1001–1007. https://doi.org/10.1200/jco.2001.19.4.1001

    Article  CAS  PubMed  Google Scholar 

  4. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA (2006) Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354(1):34–43. https://doi.org/10.1056/NEJMoa052985

    Article  CAS  PubMed  Google Scholar 

  5. National Cancer Institute Division of Cancer Treatment & Diagnosis (2006) NCI Clinical Announcement: Intraperitoneal chemotherapy for ovarian cancer. http://ctep.cancer.gov/highlights/docs/clin_annc_010506.pdf. Accessed 25 Jun 2018

  6. Morgan RJ Jr, Newman EM, Doroshow JH, McGonigle K, Margolin K, Raschko J, Chow W, Somlo G, Leong L, Tetef M, Shibata S, Hamasaki V, Carroll M, Vasilev S, Akman S, Coluzzi P, Wagman L, Longmate J, Paz B, Yen Y, Klevecz R (1998) Phase I trial of intraperitoneal iododeoxyuridine with and without intravenous high-dose folinic acid in the treatment of advanced malignancies primarily confined to the peritoneal cavity: flow cytometric and pharmacokinetic analysis. Cancer Res 58(13):2793–2800

    CAS  PubMed  Google Scholar 

  7. Morgan RJ Jr, Doroshow JH, Synold T, Lim D, Shibata S, Margolin K, Schwarz R, Leong L, Somlo G, Twardowski P, Yen Y, Chow W, Lin P, Paz B, Chu D, Frankel P, Stalter S (2003) Phase I trial of intraperitoneal docetaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity: dose-limiting toxicity and pharmacokinetics. Clin Cancer Res 9(16 Pt 1):5896–5901

    CAS  PubMed  Google Scholar 

  8. Morgan RJ Jr, Synold TW, Xi B, Lim D, Shibata S, Margolin K, Schwarz RE, Leong L, Somlo G, Twardowski P, Yen Y, Chow W, Tetef M, Lin P, Paz B, Koczywas M, Wagman L, Chu D, Frankel P, Stalter S, Doroshow JH (2007) Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity. Clin Cancer Res 13(4):1232–1237. https://doi.org/10.1158/1078-0432.ccr-06-1735

    Article  CAS  PubMed  Google Scholar 

  9. Blum JL, Savin MA, Edelman G, Pippen JE, Robert NJ, Geister BV, Kirby RL, Clawson A, O’Shaughnessy JA (2007) Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 7(11):850–856. https://doi.org/10.3816/CBC.2007.n.049

    Article  CAS  PubMed  Google Scholar 

  10. Teneriello MG, Tseng PC, Crozier M, Encarnacion C, Hancock K, Messing MJ, Boehm KA, Williams A, Asmar L (2009) Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer. J Clin Oncol 27(9):1426–1431. https://doi.org/10.1200/jco.2008.18.9548

    Article  CAS  PubMed  Google Scholar 

  11. Gardner ER, Dahut W, Figg WD (2008) Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment. J Chromatogr B Anal Technol Biomed Life Sci 862(1–2):213–218. https://doi.org/10.1016/j.jchromb.2007.12.013

    Article  CAS  Google Scholar 

  12. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 12(4):1317–1324. https://doi.org/10.1158/1078-0432.ccr-05-1634

    Article  CAS  PubMed  Google Scholar 

  13. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P, Zhang H, Iglesias JL, Renschler MF (2012) Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 30(17):2055–2062. https://doi.org/10.1200/jco.2011.39.5848

    Article  CAS  PubMed  Google Scholar 

  14. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. https://doi.org/10.1056/NEJMoa1304369

    Article  CAS  Google Scholar 

  15. Coleman RL, Brady WE, McMeekin DS, Rose PG, Soper JT, Lentz SS, Hoffman JS, Shahin MS (2011) A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 122(1):111–115. https://doi.org/10.1016/j.ygyno.2011.03.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Egawa T, Kemmochi T, Nishiya S, Mihara K, Ito Y, Nagashima A (2014) Nanoparticle albumin-bound Paclitaxel for unresectable or recurrent gastric cancer. (Gan to kagaku ryoho) Cancer Chemother 41(12):2251–2253

    Google Scholar 

  17. Markman M, Rowinsky E, Hakes T, Reichman B, Jones W, Lewis JL Jr, Rubin S, Curtin J, Barakat R, Phillips M et al (1992) Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study. J Clin Oncol 10(9):1485–1491. https://doi.org/10.1200/jco.1992.10.9.1485

    Article  CAS  PubMed  Google Scholar 

  18. Francis P, Rowinsky E, Schneider J, Hakes T, Hoskins W, Markman M (1995) Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: a Gynecologic Oncology Group pilot Study. J Clin Oncol 13(12):2961–2967

    Article  CAS  PubMed  Google Scholar 

  19. Hofstra LS, Bos AM, de Vries EG, van der Zee AG, Willemsen AT, Rosing H, Beijnen JH, Mulder NH, Aalders JG, Willemse PH (2002) Kinetic modeling and efficacy of intraperitoneal paclitaxel combined with intravenous cyclophosphamide and carboplatin as first-line treatment in ovarian cancer. Gynecol Oncol 85(3):517–523

    Article  CAS  PubMed  Google Scholar 

  20. Fushida S, Furui N, Kinami S, Ninomiya I, Fujimura T, Nishimura G, Ohta T, Yokogawa K, Miyamoto K, Miwa K (2002) Pharmacologic study of intraperitoneal paclitaxel in gastric cancer patients with peritoneal dissemination. (Gan to kagaku ryoho) Cancer Chemother 29(12):2164–2167

    Google Scholar 

  21. Mohamed F, Marchettini P, Stuart OA, Yoo D, Sugarbaker PH (2003) A comparison of hetastarch and peritoneal dialysis solution for intraperitoneal chemotherapy delivery. Eur J Surg Oncol 29(3):261–265

    Article  CAS  PubMed  Google Scholar 

  22. Markman M (1996) Intraperitoneal taxol. Cancer Treat Res 81:1–5

    Article  CAS  PubMed  Google Scholar 

  23. Kinoshita J, Fushida S, Tsukada T, Oyama K, Watanabe T, Shoji M, Okamoto K, Nakanuma S, Sakai S, Makino I, Furukawa H, Hayashi H, Nakamura K, Inokuchi M, Nakagawara H, Miyashita T, Tajima H, Takamura H, Ninomiya I, Fujimura T, Masakazu Y, Hirakawa K, Ohta T (2014) Comparative study of the antitumor activity of Nab-paclitaxel and intraperitoneal solvent-based paclitaxel regarding peritoneal metastasis in gastric cancer. Oncol Rep 32(1):89–96. https://doi.org/10.3892/or.2014.3210

    Article  CAS  PubMed  Google Scholar 

  24. de Bree E, Tsiftsis DD (2007) Experimental and pharmacokinetic studies in intraperitoneal chemotherapy: from laboratory bench to bedside. Recent Results Cancer Res (Fortschritte der Krebsforschung Progres dans les recherches sur le cancer) 169:53–73

    Google Scholar 

  25. Cristea MC, Synold TW, Frankel PH, Rivkin SE, Lim D, Chung VM, Chao J, Wakabayashi MT, Paz IB, Han ES, Lin P, Leong LA, Hakim A, Carroll MI, Openshaw H, Prakash N, Dellinger TH, Park MS, Morgan R (2015) Pharmacologic advantage (PA) of intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies primarily confined to the peritoneal cavity. (Abstract 2553). In: Paper presented at the 2015 ASCO annual meeting, Chicago, IL

  26. Wright AA, Cronin A, Milne DE, Bookman MA, Burger RA, Cohn DE, Cristea MC, Griggs JJ, Keating NL, Levenback CF, Mantia-Smaldone G, Matulonis UA, Meyer LA, Niland JC, Weeks JC, O’Malley DM (2015) Use and effectiveness of intraperitoneal chemotherapy for treatment of ovarian cancer. J Clin Oncol 33(26):2841–2847. https://doi.org/10.1200/jco.2015.61.4776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Walker J, Brady M, DiSilvestro P, Fujiwara K, Alberts D, Zheng W, Tewari K, Cohn D, Powell M, Van Le L (2016) A phase III trial of bevacizumab with IV versus IP chemotherapy for ovarian, fallopian tube, and peritoneal carcinoma: an NRG Oncology Study. Gynecol Oncol 141(Supplement 1):208. https://doi.org/10.1016/j.ygyno.2016.04.535

    Article  Google Scholar 

  28. Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, Aoki D, Jobo T, Kodama S, Terauchi F, Sugiyama T, Ochiai K, Japanese Gynecologic Oncology G (2013) Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 14(10):1020–1026. https://doi.org/10.1016/S1470-2045(13)70363-2

    Article  CAS  PubMed  Google Scholar 

  29. Grass F, Vuagniaux A, Teixeira-Farinha H, Lehmann K, Demartines N, Hubner M (2017) Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg 104(6):669–678. https://doi.org/10.1002/bjs.10521

    Article  CAS  PubMed  Google Scholar 

  30. Tempfer C, Giger-Pabst U, Hilal Z, Dogan A, Rezniczek GA (2018) Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal carcinomatosis: systematic review of clinical and experimental evidence with special emphasis on ovarian cancer. Arch Gynecol Obstet 298(2):243–257. https://doi.org/10.1007/s00404-018-4784-7

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program (ORP) from general research support from Celgene Corporation. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Chris Gandhi, Ph.D. and Nicola M. Solomon, Ph.D., for editorial assistance and critical review of the manuscript.

Funding

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program (NCCNMIRV0016) and general research support from Celgene Corporation. Additional support for the study was provided by Cancer Center Support Grant P30CA033572.

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Correspondence to Mihaela C. Cristea.

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Conflict of interest

MC receives personal fees from Astra Zeneca and VC is a member of the Celgene Speaker’s Bureau.

Ethical approval

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Cristea, M.C., Frankel, P., Synold, T. et al. A phase I trial of intraperitoneal nab-paclitaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity. Cancer Chemother Pharmacol 83, 589–598 (2019). https://doi.org/10.1007/s00280-019-03767-9

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  • DOI: https://doi.org/10.1007/s00280-019-03767-9

Keywords

  • Intraperitoneal chemotherapy
  • Nab-paclitaxel
  • Pharmacologic advantage
  • Peritoneal carcinomatosis; ovarian cancer