Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study

M.E. Gore, R.J. Jones, A. Ravaud, M. Kuczyk, T. Demkow, A. Bearz, J. Shapiro, U.P. Strauss, C. Porta

Research output: Contribution to journalArticle

Abstract

Objective: To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC). Patients and Methods: Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety. Results: In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5–69.2] and 17.9% (n = 12/67; 95% CI 9.6–29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0–11.7) months (ITT). The most common AEs of any grade were hand–foot skin reaction (66.3%) and diarrhoea (63.9%). Conclusion: Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd
Original languageEnglish
Pages (from-to)846-853
Number of pages8
JournalBJU International
Volume119
Issue number6
DOIs
Publication statusPublished - 2017

Keywords

  • #KidneyCancer
  • dose escalation
  • renal cell carcinoma
  • sorafenib
  • targeted therapy
  • tyrosine kinase inhibitor
  • alanine aminotransferase
  • hemoglobin
  • triacylglycerol lipase
  • antineoplastic agent
  • carbanilamide derivative
  • nicotinamide
  • abdominal pain
  • adult
  • aged
  • alopecia
  • anorexia
  • area under the curve
  • Article
  • backache
  • body weight disorder
  • bone metastasis
  • constipation
  • desquamation
  • diarrhea
  • dose response
  • drug dose escalation
  • drug dose reduction
  • drug efficacy
  • drug safety
  • drug tolerability
  • drug withdrawal
  • dry skin
  • dyspnea
  • fatigue
  • female
  • fever
  • gastrointestinal disease
  • hand foot syndrome
  • human
  • hypertension
  • hyponatremia
  • hypophosphatemia
  • hypothyroidism
  • intention to treat analysis
  • kidney failure
  • kidney metastasis
  • liver metastasis
  • lung metastasis
  • lymph node metastasis
  • major clinical study
  • male
  • maximum plasma concentration
  • mucosa inflammation
  • multicenter study
  • nausea
  • open study
  • phase 2 clinical trial
  • priority journal
  • progression free survival
  • proteinuria
  • pruritus
  • rash
  • sensory neuropathy
  • side effect
  • taste disorder
  • treatment duration
  • voice disorder
  • vomiting
  • weight reduction
  • analogs and derivatives
  • Carcinoma, Renal Cell
  • clinical trial
  • disease free survival
  • Kidney Neoplasms
  • methodology
  • middle aged
  • pathology
  • secondary
  • treatment outcome
  • very elderly
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Disease-Free Survival
  • Female
  • Humans
  • Male
  • Middle Aged
  • Niacinamide
  • Phenylurea Compounds
  • Research Design
  • Treatment Outcome

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    Gore, M. E., Jones, R. J., Ravaud, A., Kuczyk, M., Demkow, T., Bearz, A., Shapiro, J., Strauss, U. P., & Porta, C. (2017). Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study. BJU International, 119(6), 846-853. https://doi.org/10.1111/bju.13740