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Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors

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Summary

Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.

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Acknowledgments

We thank the cancer patients who willingly agreed to participate in the study. We also acknowledge the excellent contribution of Mariangela Mariani (Study director), Luisella Bonomini (Clinical project Manager), Benedetta Reinach (Clinical Data Manager), Manuela Pesenti, Marina Ripamonti and Patrizia Crivori of CLIOSS S.r.l for their professional support in providing information and documentation and Sonia Colombini (Programmer) of CLIOSS S.r.l for her support in programming. Alessia Casolaro and Roberta Ceruti of NMS for assistance with biopsy analyses, Cinzia Pellizzoni for PK analysis support. Professional medical writing assistance during the preparation of this manuscript was provided by Prasad Kulkarni, Ph.D., CMPP of Asclepius Medical Communications LLC, Ridgewood, New Jersey, USA and was funded by the Cancer Treatment Centers of America.

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Authors and Affiliations

  1. Western Regional Medical Center, Cancer Treatment Centers of America, 14200 W Celebrate Life Way, Goodyear, AZ, 85338, USA

    Glen J. Weiss

  2. Virginia G. Piper Cancer Centers at Scottsdale Healthcare, Scottsdale, AZ, USA

    Glen J. Weiss, Gayle Jameson, Daniel D. Von Hoff & Ramesh K. Ramanathan

  3. CLInical Organization for Strategies and Solutions (CLIOSS) S.r.l, Mayo Scottsdale, Nerviano, Italy

    Cristina Davite, Claudia Di Giulio & Alessandro Di Sanzo

  4. Nerviano Medical Sciences S.r.l., Nerviano, Italy

    Barbara Valsasina, Rachele Alzani, Patrizia Carpinelli, Arturo Galvani & Antonella Isacchi

  5. Accelera S.r.l, Nerviano, Italy

    Francesco Fiorentini

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  1. Glen J. Weiss
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  2. Gayle Jameson
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  3. Daniel D. Von Hoff
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Contributions

Conception and design: C Davite and D. Von Hoff.

Acquisition of data: G. Weiss, G. Jameson, F. Fiorentini, C. Di Giulio, and R. Ramanathan.

Analysis and interpretation of data: G. Weiss, B. Valsasina, R. Alzani, P Carpinelli, and F. Fiorentini.

Writing, review, and/or revision of the manuscript: G. Weiss, A. Isacchi, A. Galvani, B. Valsasina, C. Di Giulio, C. Davite, G. Jameson, R. Ramanathan, and D. Von Hoff.

Administrative, technical, or material support (eg, reporting or organizing data, constructing databases): C. Di Giulio and A. Di Sanzo.

Study supervision: G. Weiss.

Corresponding author

Correspondence to Glen J. Weiss.

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Conflict of interest

Glen Weiss has no direct conflicts of interest related to this work, but has the following unrelated disclosures: consulting or advisory roles with Pharmatech, Paradigm, Blend Therapeutics, and Viomics; service on speakers’ bureaus with Medscape, Novartis, and Merck; and receipt of travel and accommodation expenses from Nantworks. Rachele Alzani, Patrizia Carpinelli, Arturo Galvani, Antonella Isacchi, and Barbara Valsasina are employees of Nerviano Sciences s.r.l. Francesco Fiorentini is an employee of Accelera s.r.l. Cristina Davite, Claudia Di Giulio, and Alessandro Di Salvo are employees of Clioss s.r.l. Gayle Jameson, Daniel Von Hoff, and Ramesh Ramanathan have no conflicts to disclose.

Ethical approval

The study protocol, amendments to the protocol, and the sample informed consent file were reviewed and approved by the Institutional Review Board (IRB) at the study site. The study conformed to Good Clinical Practice guidelines published by the International Council for Harmonization (ICH), ethical principles as set forth in the Declaration of Helsinki (1996 version), and all applicable local regulatory requirements and laws.

Informed consent

Signed written informed consent was obtained from each patient prior to undertaking any trial-related procedure.

Funding

This study was funded by Nerviano Medical Sciences S.r.l, Nerviano, Italy.

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Weiss, G.J., Jameson, G., Von Hoff, D.D. et al. Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors. Invest New Drugs 36, 85–95 (2018). https://doi.org/10.1007/s10637-017-0491-7

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