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Piha-Paul SA, Thein KZ, 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. 2021;39(4):1047-1056doi: 10.1007/s10637-021-01081-x.
Piha-Paul, S. A., Thein, K. Z., De Souza, P., Kefford, R., Gangadhar, T., Smith, C., Schuster, S., Zamboni, W. C., Dees, C. E., & Markman, B. (2021). First-in-human, phase I/IIa study of CRLX301, a nanoparticle drug conjugate containing docetaxel, in patients with advanced or metastatic solid malignancies. Investigational new drugs, 39(4), 1047-1056. https://doi.org/10.1007/s10637-021-01081-x
Piha-Paul, Sarina A, 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." Investigational new drugs vol. 39,4 (2021): 1047-1056. doi: https://doi.org/10.1007/s10637-021-01081-x
Piha-Paul SA, Thein KZ, De Souza P, Kefford R, Gangadhar T, Smith C, Schuster S, Zamboni WC, Dees CE, Markman B. 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. 2021 Aug;39(4):1047-1056. doi: 10.1007/s10637-021-01081-x. Epub 2021 Feb 16. PMID: 33594602.
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Invest New Drugs. 2021 Aug;39(4):1047-1056. doi: 10.1007/s10637-021-01081-x. Epub 2021 Feb 16.

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

Investigational new drugs

Sarina A Piha-Paul, Kyaw Z Thein, Paul De Souza, Richard Kefford, Tara Gangadhar, Christopher Smith, Shelly Schuster, William C Zamboni, Claire E Dees, Ben Markman

Affiliations

  1. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. [email protected].
  2. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
  3. Division of Hematology and Medical Oncology, Oregon Health and Science University/ Knight Cancer Institute, Portland, OR, USA.
  4. Department of Medical Oncology, Liverpool Hospital, Sydney, Australia.
  5. Department of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
  6. Department of Hematology and Medical Oncology, University of Pennsylvania, Philadelphia, PA, USA.
  7. NewLink Genetics Corporation, Ames, IA, USA.
  8. UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Carolina Institute of Nanomedicine, Chapel Hill, NC, USA.
  9. Division of Medical Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
  10. Department of Medical Oncology, Monash Health/Monash University, Melbourne, Australia.

PMID: 33594602 DOI: 10.1007/s10637-021-01081-x

Abstract

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).

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Keywords: CRLX301; Docetaxel; First‐in‐human study; Nanoparticle; Phase I/IIa study

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