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

  • Mihaela C. Cristea
  • Paul Frankel
  • Timothy Synold
  • Saul Rivkin
  • Dean Lim
  • Vincent Chung
  • Joseph Chao
  • Mark Wakabayashi
  • Benjamin Paz
  • Ernest Han
  • Paul Lin
  • Lucille Leong
  • Amy Hakim
  • Mary Carroll
  • Neal Prakash
  • Thanh Dellinger
  • Min Park
  • Robert J. Morgan
Original Article
  • 18 Downloads

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.

Keywords

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

Notes

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.

Compliance with ethical standards

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mihaela C. Cristea
    • 1
  • Paul Frankel
    • 2
  • Timothy Synold
    • 3
  • Saul Rivkin
    • 4
  • Dean Lim
    • 1
  • Vincent Chung
    • 1
  • Joseph Chao
    • 1
  • Mark Wakabayashi
    • 5
  • Benjamin Paz
    • 6
  • Ernest Han
    • 5
  • Paul Lin
    • 5
  • Lucille Leong
    • 1
  • Amy Hakim
    • 5
  • Mary Carroll
    • 1
  • Neal Prakash
    • 7
  • Thanh Dellinger
    • 5
  • Min Park
    • 4
  • Robert J. Morgan
    • 1
  1. 1.Department of Medical Oncology and Therapeutics ResearchCity of Hope National Medical CenterDuarteUSA
  2. 2.Division of Biostatistics, Department of Information SciencesCity of Hope National Medical CenterDuarteUSA
  3. 3.Department of Cancer BiologyCity of Hope National Medical CenterDuarteUSA
  4. 4.Swedish Cancer InstituteSeattleUSA
  5. 5.Division of Gynecologic Oncology, Department of SurgeryCity of Hope National Medical CenterDuarteUSA
  6. 6.Division of Surgical Oncology, Department of SurgeryCity of Hope National Medical CenterDuarteUSA
  7. 7.Division of Neurology, Department of Medical SpecialtiesCity of Hope National Medical CenterDuarteUSA

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