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

2 Citations (Scopus)

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

Fingerprint

Renal Cell Carcinoma
Therapeutics
Confidence Intervals
Disease-Free Survival
Safety
sorafenib
Nuclear Family
Antineoplastic Agents
Population
Diarrhea
Skin

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

Cite this

Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study. / Gore, M.E.; Jones, R.J.; Ravaud, A.; Kuczyk, M.; Demkow, T.; Bearz, A.; Shapiro, J.; Strauss, U.P.; Porta, C.

In: BJU International, Vol. 119, No. 6, 2017, p. 846-853.

Research output: Contribution to journalArticle

Gore, M.E. ; Jones, R.J. ; Ravaud, A. ; Kuczyk, M. ; Demkow, T. ; Bearz, A. ; Shapiro, J. ; Strauss, U.P. ; Porta, C. / Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study. In: BJU International. 2017 ; Vol. 119, No. 6. pp. 846-853.
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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-na{\"i}ve 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-na{\"i}ve 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-na{\"i}ve mRCC. Alternative protocols for sorafenib dose escalation could be explored. {\circledC} 2016 The Authors BJU International {\circledC} 2016 BJU International Published by John Wiley & Sons Ltd",
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author = "M.E. Gore and R.J. Jones and A. Ravaud and M. Kuczyk and T. Demkow and A. Bearz and J. Shapiro and U.P. Strauss and C. Porta",
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TY - JOUR

T1 - Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study

AU - Gore, M.E.

AU - Jones, R.J.

AU - Ravaud, A.

AU - Kuczyk, M.

AU - Demkow, T.

AU - Bearz, A.

AU - Shapiro, J.

AU - Strauss, U.P.

AU - Porta, C.

N1 - Export Date: 20 February 2018 CODEN: BJINF Correspondence Address: Gore, M.E.; Royal Marsden HospitalUnited Kingdom; email: martin.gore@rmh.nhs.uk

PY - 2017

Y1 - 2017

N2 - 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

AB - 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

KW - #KidneyCancer

KW - dose escalation

KW - renal cell carcinoma

KW - sorafenib

KW - targeted therapy

KW - tyrosine kinase inhibitor

KW - alanine aminotransferase

KW - hemoglobin

KW - triacylglycerol lipase

KW - antineoplastic agent

KW - carbanilamide derivative

KW - nicotinamide

KW - abdominal pain

KW - adult

KW - aged

KW - alopecia

KW - anorexia

KW - area under the curve

KW - Article

KW - backache

KW - body weight disorder

KW - bone metastasis

KW - constipation

KW - desquamation

KW - diarrhea

KW - dose response

KW - drug dose escalation

KW - drug dose reduction

KW - drug efficacy

KW - drug safety

KW - drug tolerability

KW - drug withdrawal

KW - dry skin

KW - dyspnea

KW - fatigue

KW - female

KW - fever

KW - gastrointestinal disease

KW - hand foot syndrome

KW - human

KW - hypertension

KW - hyponatremia

KW - hypophosphatemia

KW - hypothyroidism

KW - intention to treat analysis

KW - kidney failure

KW - kidney metastasis

KW - liver metastasis

KW - lung metastasis

KW - lymph node metastasis

KW - major clinical study

KW - male

KW - maximum plasma concentration

KW - mucosa inflammation

KW - multicenter study

KW - nausea

KW - open study

KW - phase 2 clinical trial

KW - priority journal

KW - progression free survival

KW - proteinuria

KW - pruritus

KW - rash

KW - sensory neuropathy

KW - side effect

KW - taste disorder

KW - treatment duration

KW - voice disorder

KW - vomiting

KW - weight reduction

KW - analogs and derivatives

KW - Carcinoma, Renal Cell

KW - clinical trial

KW - disease free survival

KW - Kidney Neoplasms

KW - methodology

KW - middle aged

KW - pathology

KW - secondary

KW - treatment outcome

KW - very elderly

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents

KW - Disease-Free Survival

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Niacinamide

KW - Phenylurea Compounds

KW - Research Design

KW - Treatment Outcome

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DO - 10.1111/bju.13740

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JO - BJU International

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