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Patient self-reporting of tolerability using PRO-CTCAE in a randomized double-blind, placebo-controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in patients with platinum resistant or refractory epithelial ovarian carcinoma

  • Ainhoa Madariaga
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    University of Toronto, Toronto, Ontario, Canada

    Autonomous University of Barcelona, Barcelona, Spain
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  • Sandra A. Mitchell
    Affiliations
    National Cancer Institute at the National Institutes of Health, Rockville, USA
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  • Tyler Pittman
    Affiliations
    Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Lisa Wang
    Affiliations
    University of Toronto, Toronto, Ontario, Canada

    Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Valerie Bowering
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Nisan Kavak
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Judy Quintos
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Karen Chang
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Janelle Ramsahai
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Katherine Karakasis
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • Stephen A. Welch
    Affiliations
    Division of Medical Oncology & Hematology, London Health Science, London, Ontario, Canada
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  • Neesha C. Dhani
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    University of Toronto, Toronto, Ontario, Canada
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  • Stephanie Lheureux
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    University of Toronto, Toronto, Ontario, Canada
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  • Amit M. Oza
    Correspondence
    Corresponding author at: Daniel Bergsagel Chair in Medical Oncology, Professor of Medicine, University of Toronto, Head, Division of Medical Oncology and Hematology, Director, Clinical Cancer Research and Bras Drug Development Program, Princess Margaret Cancer Centre, UHN and Mt. Sinai Health System, 610 University Avenue, Toronto M5G 2M9, Canada.
    Affiliations
    Division of Medical Oncology & Hematology, Bras Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    University of Toronto, Toronto, Ontario, Canada
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Published:August 30, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.08.006

      Highlights

      • Cell cycle modulation with Wee1 inhibition has promising activity in platinum resistant and refractory ovarian cancer.
      • A phase II trial showed improved PFS and OS with adavosertib and gemcitabine, compared to placebo and gemcitabine.
      • PRO-CTCAEs provide objective assessment of symptomatic adverse events (syAEs) and patient reported tolerability.
      • High scores of syAEs showed more frequent diarrhea in the adavosertib arm (25%) vs placebo arm (0%).
      • Longitudinal syAE assessment showed higher fatigue and difficulty swallowing severity in the adavosertib arm.

      Abstract

      Background

      A double-blind, randomized, placebo-controlled, phase 2 trial assessed gemcitabine in combination with the wee1 inhibitor adavosertib or placebo in platinum resistant or refractory high grade serous ovarian cancer (HGSOC), demonstrating improved progression free and overall survival favouring the adavosertib/gemcitabine arm. An exploratory objective of the study included the PRO-CTCAE assessment, to capture self-reporting of frequency, severity and/or interference of symptomatic adverse events (syAEs).

      Methods

      PRO-CTCAE items at baseline, days 1 and 15 of each cycle and off treatment, were completed in two centres, with the objective of characterizing syAEs in the first three months of therapy. The maximum post-baseline score proportion for each syAE was tabulated per patient. The 12-week area under the curve (AUC12w) as a measure of syAE over-time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs.

      Results

      Sixty-one patients were approached for PRO-CTCAE surveys and 55 were evaluable. Among patients with HGSOC, 28 received gemcitabine/adavosertib (arm A) and 19 gemcitabine/placebo (arm B). Survey completion rates were high. The proportion of participants with positive (≥1) PRO-CTCAE scores was higher for difficulty swallowing with gemcitabine/adavosertib (arm A 35.7% vs arm B 5.3%, p = 0.02). The high score (≥3) syAEs showed more frequent diarrhea with gemcitabine/adavosertib (arm A 25% vs arm B 0%, p = 0.03). The proportions of worsening syAEs over time were higher in patients receiving gemcitabine/adavosertib for difficulty swallowing (arm A 35.7% vs arm B 5.3%; p = 0.03) and fatigue severity (arm A 71.43% vs arm B 42.1%; p = 0.04).

      Conclusions

      The longitudinal assessment of patient self-reported tolerability showed greater difficulty swallowing and fatigue severity in patients receiving gemcitabine/adavosertib, compared to gemcitabine/placebo. PRO-CTCAE provides complementary and objective assessment of drug tolerability from a patient's perspective.

      Keywords

      Abbreviations:

      HGSOC (High grade serous ovarian cancer), syAEs (Symptomatic adverse events), PRO-CTCAE (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events), F (Frequency), S (Severity), I (Interference)
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