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First‐in‐human, phase I/IIa study of CRLX301, a nanoparticle drug conjugate containing docetaxel, in patients with advanced or metastatic solid malignancies

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Summary

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38–76); median number of prior systemic therapies was 5(range 0–10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.

Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Not applicable.

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Acknowledgements

We thank the patients who participated in this study and their families for supporting them.

Funding

Cerulean Pharma Inc.

Author information

Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Sarina A. Piha-Paul & Kyaw Z. Thein

  2. Division of Hematology and Medical Oncology, Oregon Health and Science University/ Knight Cancer Institute, Portland, OR, USA

    Kyaw Z. Thein

  3. Department of Medical Oncology, Liverpool Hospital, Sydney, Australia

    Paul De Souza

  4. Department of Medicine and Health Sciences, Macquarie University, Sydney, Australia

    Richard Kefford

  5. Department of Hematology and Medical Oncology, University of Pennsylvania, Philadelphia, PA, USA

    Tara Gangadhar

  6. NewLink Genetics Corporation, Ames, IA, USA

    Christopher Smith & Shelly Schuster

  7. UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Institute of Nanomedicine, Chapel Hill, NC, USA

    William C. Zamboni

  8. Division of Medical Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Claire E. Dees

  9. Department of Medical Oncology, Monash Health/Monash University, Melbourne, Australia

    Ben Markman

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  1. Sarina A. Piha-Paul
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Contributions

All the authors have contributed to the preparation of this manuscript and approved the final version.

Corresponding author

Correspondence to Sarina A. Piha-Paul.

Ethics declarations

The study protocol was approved by the Institutional Review Board or Independent Ethics Committee at each participating site and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and all local and federal regulatory guidelines. All patients signed informed consent prior to enrolling onto the study.

Conflicts of Interest/Competing Interests

None of the authors have any conflict of interest relevant to the subject of this manuscript.

Sarina A. Piha-Paul receives Research/Grant Funding through the institution from the following sources: AbbVie, Inc.; ABM Therapeutics, Inc.; Acepodia, Inc; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma, Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Daiichi Sankyo; Eli Lilly; ENB Therapeutics; Five Prime Therapeutics; Gene Quantum; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Silverback Therapeutics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; NCI/NIH; P30CA016672 – Core Grant (CCSG Shared Resources).

Paul De Souza receives funding through his institution as a consultant for BioSceptre.

Tara Gangadhar receives honoraria for scientific advisory board participation from Merck, and BMS.

Christopher Smith and Shelly Schuster were employees of and held stock in NewLink Genetics Corporation.

William C. Zamboni receives research funding from: Apollomics (formally CBT Pharma); Meryx Pharma; OBI Pharma; ChemoGLO, LLC; Glolytics, LLC; Nemucore, Inc; NexImmune; ZY Therapeutics; Merrimack Pharma; Genentech. Has worked or is working as a consultant: Cerulean Pharma; BlueLink Pharmaceuticals; Ellipses Pharma; Syros Pharmaceuticals; OBI Pharmaceuticals; Akagera Medicines; Merrimack Pharmaceuticals. Additional positions held: CEO, MediGLO - Medical and Pharmaceutical Consulting, LLC; CSO, ChemoGLO, LLC; CSO, Glolytics, LLC.

All remaining authors have declared no conflicts of interest.

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Statement of Translational Relevance

To mitigate the increased toxicities of commercially available docetaxel, cyclodextrin-containing polymer (CDPs)-based nanoparticles (CRLX301) was designed to produce docetaxel-containing nanoparticles. In this first-in-human, phase I/IIa study, dose-escalation was explored in two different dosing schedules (IV weekly (QW) or every 3 weeks (Q3W)). Forty-two patients were recruited onto the study with n = 37 patients in dose escalation (n = 17 on QW and n = 20 on Q3W) and n = 5 patients were treated during the expansion at 75 mg/m2 Q3W. Four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) had a partial response (PR) [total = 6/31 patients (19.4 %)]. The responses were seen primarily in prostate and breast adenocarcinoma. Clinical benefit rate (CBR; percentage of SD ≥ 4 months + PR) was 19.4 %. Interestingly, a higher number of instances of SD ≥ 4 months were achieved at lower doses of CRLX301. This may be explained by PK results which showed prolonged exposures of total and released docetaxel in plasma after administration of CRLX301 (7 days) when compared with docetaxel (24 h).

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Piha-Paul, S.A., Thein, K.Z., De Souza, P. et al. First‐in‐human, phase I/IIa study of CRLX301, a nanoparticle drug conjugate containing docetaxel, in patients with advanced or metastatic solid malignancies. Invest New Drugs 39, 1047–1056 (2021). https://doi.org/10.1007/s10637-021-01081-x

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