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A phase Ib study of Oraxol (oral paclitaxel and encequidar) in patients with advanced malignancies

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Abstract

Purpose

Oraxol is an oral formulation of paclitaxel administered with a novel, minimally absorbed P-glycoprotein inhibitor encequidar (HM30181A). This phase Ib study was conducted to determine the maximum-tolerated dose (MTD) of Oraxol administered at a fixed dose for up to 5 consecutive days in patients with advanced malignancies.

Methods

Part 1 of this study utilized a 3 + 3 dose-escalation design to determine the MTD of oral paclitaxel 270 mg plus oral encequidar 15 mg administered daily. Dose escalation was achieved by increasing the number of consecutive dosing days per week (from 2 to 5 days per week). Dosing occurred for 3 consecutive weeks out of a 4-week cycle. Part 2 treated additional patients at the MTD to determine tolerability and recommended phase II dose (RP2D). Adverse events, tumor responses, and pharmacokinetic profiles were assessed.

Results

A total of 34 patients (n = 24 in Part 1, n = 10 in Part 2) received treatment. The MTD of Oraxol was determined to be 270 mg daily × 5 days per week per protocol definition and this was declared the RP2D. The most common treatment-related adverse events were fatigue, neutropenia, and nausea/vomiting. Hypersensitivity-type reactions were not observed. Of the 28 patients evaluable for response, 2 (7.1%) achieved partial response and 18 (64.3%) achieved stable disease. Pharmacokinetic analysis showed rapid absorption of paclitaxel when administered orally following encequidar. Paclitaxel daily exposure was comparable following 2–5 days dose levels.

Conclusion

The oral administration of encequidar with paclitaxel was safe, achieved clinically relevant paclitaxel levels, and showed evidence of anti-tumor activity.

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Data availability

The data that support the findings of this study are available on request from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank the patients, their families, and all the investigators who participated in this clinical trial.

Funding

Athenex, Inc provided the funding and drug for the clinical trial.

Author information

Authors and Affiliations

  1. Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Wen Wee Ma, Jenny J. Li & Alex A. Adjei

  2. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA

    Nilofer S. Azad

  3. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Elaine T. Lam, Jennifer R. Diamond & Antonio Jimeno

  4. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Grace K. Dy

  5. Indiana University, Indianapolis, IN, USA

    Mateusz Opyrchal

  6. Athenex Pharmaceuticals, Buffalo, NY, USA

    Jay Zhi, Douglas Kramer, Wing-Kai Chan, David Cutler & Rudolf Kwan

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  1. Wen Wee Ma
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Corresponding author

Correspondence to Wen Wee Ma.

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Conflict of interest

NSA is a paid consultant for Mirati and QED; she receives institutional funding from Agios, Inc., Array, Atlas, Bayer HealthCare, BMS, Celgene, Debio, Eli Lilly and Company, EMD Serono, Incyte Corporation, Intensity, Merck & Co., Inc. and Taiho Pharmaceuticals Co., Ltd.; she participates on advisory boards for Incyte, QED, and Glaxo Smith Kline. JRD receives institutional research funding from Adlai Norte, Takeda, Gilead, Merck, AstraZeneca, Astellas, Abbvie, BMS, OnKure, Deciphera, Bayer, Hutchison, and Genentech; she is a consultant for Gilead and OnKure; she owns stock options in OnKure Therapeutics. MO receives research funding from Eli Lilly and Pfizer; he is a consultant for AstraZeneca and Novartis. AJ receives institutional research funding from Pfizer, Merck, SQZ Biotech, Moderna, Iovance, Khar, DebioPharm, Cantargia, and Sanofi; he owns stock options in Champions Oncology and Suvica. JZ, DK, WKC, DC, and RW are employees of Athenex, Inc. DC owns stock in Athenex, Inc. and Merck & Co., Inc. No conflicts of interests were disclosed by the other authors.

Ethical approval

This study was approved by the institutional review boards at each institution and was performed in accordance with the principles of the Declaration of Helsinki.

Consent to participate

Written informed consent to participate in the study was obtained from all participants included in the study.

Consent to publish

Written informed consent for publication of clinical data was obtained from all participants included in the study.

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Ma, W.W., Li, J.J., Azad, N.S. et al. A phase Ib study of Oraxol (oral paclitaxel and encequidar) in patients with advanced malignancies. Cancer Chemother Pharmacol 90, 7–17 (2022). https://doi.org/10.1007/s00280-022-04443-1

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  • DOI: https://doi.org/10.1007/s00280-022-04443-1

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