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A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors

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Abstract

Purpose

LY3022859 is an anti-TGFβRII IgG1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK).

Methods

LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W.

Results

Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2 (4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration.

Conclusions

The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines).

Trial registration

clinicaltrials.gov Identifier: NCT01646203.

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Acknowledgements

We thank David Schaer (Eli Lilly and Company) for useful discussions during the development of this manuscript.

Author information

Author notes

  1. Jan Cosaert

    Present address: Merck KGaA, Darmstadt, Germany

Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics LLC, San Antonio, TX, 78229, USA

    Anthony W. Tolcher & Alex Amaya

  2. Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232, USA

    Jordan D. Berlin & Emily Chan

  3. Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Jan Cosaert, John Kauh, Shande Tang, Kyla Driscoll, Richard Kimbung, S. R. Prasad Kambhampati & Ivelina Gueorguieva

  4. UT M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Sarina A. Piha-Paul & David S. Hong

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  1. Anthony W. Tolcher
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Corresponding author

Correspondence to Anthony W. Tolcher.

Ethics declarations

Funding support

The study was sponsored by Eli Lilly and Company. Jude Richard (INC Research, Austin, TX) provided medical writing services on behalf of the authors, funded by the study sponsor. These included assisting with initial drafting of the manuscript and subsequent revision according to guidance from the authors.

Conflict of interest

JC was an employee of Lilly during the conduct of the study but is now an employee of Merck KGaA. EC has served on advisory boards for Lilly, Taiho, Bayer, EMD Serono, Amgen, Advaxis, Merrimack, Castle Biosciences, and Genentech. JK, ST, KD, RK, SRPK, and IG are employees of Lilly. The remaining authors declare no conflict of interest.

Ethical approval

This study was conducted in accordance with principles of the Declaration of Helsinki and Good Clinical Practice guidelines and with local ethics committee approval and was registered (NCT01646203).

Informed consent

Written informed consent was obtained from all patients.

Electronic supplementary material

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Supplementary material 1 (DOCX 127 KB)

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Tolcher, A.W., Berlin, J.D., Cosaert, J. et al. A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors. Cancer Chemother Pharmacol 79, 673–680 (2017). https://doi.org/10.1007/s00280-017-3245-5

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