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A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

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Abstract

Purpose

A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy.

Experimental design

Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4–19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D).

Results

The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease.

Conclusions

The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

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Notes

  1. Not for reasons of tolerability or toxicity.

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Acknowledgments

The authors wish to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operation staff. This study was sponsored by Bristol-Myers Squibb (BMS) Inc.

Conflict of interest

L.Q.M. Chow, D.I. Jonker, G.K. Dy, G. Nicholas, C. Fortin, A.A. Adjei, C.P. Belani, and S.A. Laurie have no conflicts of interest to declare. D. Patricia, A. Gupta, J.-S. Park, S. Zhang, and E.I. Sbar are employees of the Bristol-Myers Squibb (BMS) Company and hold stock in BMS, the manufacturer of BMS-690514.

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Author notes

  1. Laura Q. M. Chow

    Present address: Division of Medical Oncology, Department of Medicine, Seattle Cancer Care Alliance, University of Washington, 825 Eastlake Avenue E, Box 358081 MS: G4-940, Seattle, WA, 98109-1023, USA

Authors and Affiliations

  1. Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada

    Laura Q. M. Chow, Derek I. Jonker, Garth Nicholas, Catherine Fortin & Scott A. Laurie

  2. Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Grace K. Dy & Alex A. Adjei

  3. Bristol-Myers Squibb Company, 100 Nassau Park Blvd., Princeton, NJ, 08540, USA

    Daniel Patricia, Ashok Gupta, Jong-Soon Park, Steven Zhang & Eric I. Sbar

  4. Penn State Hershey Cancer Institute, 500 University Dr., Hershey, PA, 17033, USA

    Chandra P. Belani

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  1. Laura Q. M. Chow
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Corresponding author

Correspondence to Laura Q. M. Chow.

Additional information

ClinicalTrials.gov Identifier: NCT00420186.

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Chow, L.Q.M., Jonker, D.I., Dy, G.K. et al. A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies. Cancer Chemother Pharmacol 71, 1273–1285 (2013). https://doi.org/10.1007/s00280-013-2126-9

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