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A phase I study of gemcitabine + dasatinib (gd) or gemcitabine + dasatinib + cetuximab (GDC) in refractory solid tumors

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Abstract

Purpose

This study was conducted to define the maximum tolerated dose (MTD), recommended phase two dose (RPTD), and toxicities of gemcitabine + dasatinib (GD) and gemcitabine + dasatinib + cetuximab (GDC) in advanced solid tumor patients.

Methods

This study was a standard phase I 3 + 3 dose escalation study evaluating two combination regimens, GD and GDC. Patients with advanced solid tumors were enrolled in cohorts of 3–6 to either GD or GDC. Gemcitabine was dosed at 1000 mg/m2 weekly for 3 of 4 weeks, dasatinib was dosed in mg PO BID, and cetuximab was dosed at 250 mg/m2 weekly after a loading dose of cetuximab of 400 mg/m2. There were two dose levels for dasatinib: (1) gemcitabine + dasatinib 50 mg ± cetuximab, and (2) gemcitabine + dasatinib 70 mg ± cetuximab. Cycle length was 28 days. Standard cycle 1 dose-limiting toxicity (DLT) definitions were used. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase the risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on-treatment.

Results

Twenty-five patients were enrolled, including 21 with pancreatic adenocarcinoma. Three patients received prior gemcitabine. Twenty-one patients were evaluable for toxicity and 16 for response. Four DLTs were observed: Grade (Gr) 3 neutropenia (GDC1, n = 1), Gr 3 ALT (GD2, n = 2), and Gr 5 pneumonitis (GDC2, n = 1). Possible treatment-emergent adverse events (TEAEs) in later cycles included: Gr 3–4 neutropenia (n = 7), Gr 4 colitis (n = 1), Gr 3 bilirubin (n = 2), Gr 3 anemia (n = 2), Gr 3 thrombocytopenia (n = 2), Gr 3 edema/fluid retention (n = 1), and Gr 3 vomiting (n = 3). Six of 16 patients (3 of whom were gemcitabine-refractory) had stable disease (SD) as best response, median duration = 5 months (range 1–7). One gemcitabine-refractory patient had a partial response (PR). Median PFS was 2.9 months (95% CI 2.1, 5.8). Median OS was 5.8 months (95% CI 4.1, 11.8). Dermal wound biopsies demonstrated that dasatinib resulted in a decrease of total and phospho-Src levels, and cetuximab resulted in a decrease of EGFR and ERBB2 levels.

Conclusions

The MTD/RPTD of GD is gemcitabine 1000 mg/m2 weekly for 3 of 4 weeks and dasatinib 50 mg PO BID. The clinical activity of GD seen in this study was modest, and does not support its further investigation in pancreatic cancer.

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Acknowledgements

We gratefully acknowledge the participation of the patients and their caregivers in this study. We would like to acknowledge the Duke University GI Oncology Clinical Trials Team.

Funding

This was an investigator-initiated study supported by Bristol Myers Squib, Inc. The study was independently managed and analyzed. The final responsibility for the manuscript and the decision to submit for publication was made by the investigators. This work was also supported by National Institute of Health Grant 5K24-CA113755-05 (HH).

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Authors and Affiliations

  1. Duke University Medical Center, Seeley G. Mudd Bldg 10 Bryan Searle Drive, Box 3505, Durham, NC, 27710, USA

    Niharika B. Mettu, Donna Niedzwiecki, Christel Rushing, Andrew B. Nixon, Jingquan Jia, Sherri Haley, Wanda Honeycutt & Hope Uronis

  2. Genentech-Roche, San Francisco, CA, USA

    Herbert Hurwitz

  3. Sarah Cannon Research Institute, Nashville, TN, USA

    Johanna C. Bendell

Authors
  1. Niharika B. Mettu
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  2. Donna Niedzwiecki
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  3. Christel Rushing
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  4. Andrew B. Nixon
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  5. Jingquan Jia
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  10. Hope Uronis
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Corresponding author

Correspondence to Niharika B. Mettu.

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Conflict of interest

NBM is a clinical investigator on clinical trials supported by Incyte, ARMO, OncoMed, and Genentech/Roche. HU is a clinical investigator on clinical trials supported by Macrogenics, Merck, Genentech/Roche. ABN reports honoraria for consulting and advisory boards for Eli Lilly, Pfizer, and Kanghong Pharma. He has received grant support from Acceleron Pharma, Amgen, AstraZeneca/MedImmune, Eureka Therapeutics, Genentech, Leadiant Biosciences, MedPacto Inc, Novartis, Seattle Genetics, and Tracon Pharma. HH is employed by Genentech/Roche. The remaining authors have no conflicts of interest.

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Mettu, N.B., Niedzwiecki, D., Rushing, C. et al. A phase I study of gemcitabine + dasatinib (gd) or gemcitabine + dasatinib + cetuximab (GDC) in refractory solid tumors. Cancer Chemother Pharmacol 83, 1025–1035 (2019). https://doi.org/10.1007/s00280-019-03805-6

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