NCT02535351

Brief Summary

Two randomized trials in the cytokine era clearly showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC) increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs) including first-line sunitinib and pazopanib in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy. Therefore it is unknown if similar survival benefit could be achieved without CN with these new targeted agents. At the same time there is a need to better understand mechanisms of primary and secondary resistance to TKIs in mRCC patients and to identify eighter prognostic and predictive biomarkers to better define risk factors and potentially druggable targets.

Trial Health

57
Monitor

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
13

participants targeted

Target at below P25 for phase_3

Timeline
Completed

Started Nov 2015

Typical duration for phase_3

Geographic Reach
1 country

1 active site

Status
terminated

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

August 4, 2015

Completed
24 days until next milestone

First Posted

Study publicly available on registry

August 28, 2015

Completed
2 months until next milestone

Study Start

First participant enrolled

November 1, 2015

Completed
2.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 28, 2018

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

September 28, 2018

Completed
Last Updated

November 14, 2018

Status Verified

November 1, 2018

Enrollment Period

2.9 years

First QC Date

August 4, 2015

Last Update Submit

November 12, 2018

Conditions

Clear-cell Metastatic Renal Cell Carcinoma

Keywords

Clear cell Metastatic renal cell carcinomaCytoreductive nephrectomyFirst line treatment

Outcome Measures

Primary Outcomes (1)

  • Overall Survival benefit of cytoreductive nephrectomy with TKIs vs upfront TKIs in subjects with mRCC

    To compare clinical benefit, as measured by Overall Survival (OS), provided by CN followed by TKIs vs upfront TKIs in subjects with mRCC

    5 years

Secondary Outcomes (2)

  • Progression-free survival (PFS) and response rate (RR) benefit of cytoreductive nephrectomy with TKIs vs upfront TKIs

    Radiological assessment: every 12 weeks (±1 week) until Progressive disease (up to 12 months) or treatment discontinuation (up to 5 years)

  • Safety profile (Adverse events)

    day 1, every cycle (6 weeks for patients treated with Sunitinib and 4 weeks for patients treated with Pazopanib) until treatment discontinuation (up to 5 years).

Other Outcomes (2)

  • CTCs count

    at baseline, pre- and post-operatively (in patients undergoing CN), 24 weeks after randomization and at the time of Progressive Disease up to 5 years

  • CTCs count

    at baseline, pre- and post-operatively (in patients undergoing CN), 24 weeks after randomization and at the time of Progressive Disease up to 5 years

Study Arms (2)

A: TKIs

ACTIVE COMPARATOR

sunitinib 50 mg orally 4 weeks on/ 2 weeks off or pazopanib 800 mg orally continuously

Drug: sunitinib or pazopanib

B: TKIs + Cytoreductive Nephrectomy

EXPERIMENTAL

Cytoreductive nephrectomy + sunitinib 50 mg orally 4 weeks on/ 2 weeks off or pazopanib 800 mg orally continuously

Drug: sunitinib or pazopanibProcedure: Cytoreductive nephrectomy

Interventions

sunitinib or pazopanibDRUG

First-line treatment

Also known as: sutent or votrient
A: TKIsB: TKIs + Cytoreductive Nephrectomy
Cytoreductive nephrectomyPROCEDURE

Cytoreductive nephrectomy and first-line treatment

B: TKIs + Cytoreductive Nephrectomy

Eligibility Criteria

Age18 Years - 75 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Written informed consent
  • ECOG Performance Status 0-1
  • Favorable or intermediate MSKCC or Heng risk score
  • Biopsy (primary tumour or metastases) confirming the diagnosis of predominantly clear cell RCC
  • Resectable asymptomatic in situ primary (asymptomatic primary is defined as the absence of symptoms which can be exclusively assigned to the primary tumor such as flank pain and/or gross hematuria necessitating blood transfusion.)
  • Tumour suitable to nephrectomy in the opinion of the urologist. Patients with Inferior vena cava thrombosis can be included
  • Documented metastatic disease (CT scan or MRI)
  • Life expectancy \> or = 24 weeks
  • Up to three different metastatic sites
  • ≥ 3 metastatic lesions
  • Platelets \> 100,000/ml
  • Haemoglobin \> 9.0 g/dl
  • neutrophils \>1,500/mm3
  • Bilirubin \< or = 2 mg/dl, except for patients affected by Gilbert's syndrome
  • AST and ALT \< or = 2.5 times the UNL
  • +2 more criteria

You may not qualify if:

  • Prior surgery or systemic treatment for mRCC
  • Bilateral RCC
  • Brain and liver metastases
  • Non-clear-cell histology
  • Poor prognosis as defined by MSKCC or Heng criteria
  • Documented widespread disease (\> or =4 metastatic organ sites)
  • Oligometastatic disease suitable of metastasectomy (\<3 lesions confined at one organ site)
  • Symptomatic primary tumour at presentation
  • High surgical risk in the opinion of the urologist
  • Patients with \> 3 of the following surgical risk factors are not eligible:
  • Serum albumin CTCAE v 4.0 grade 2 or worse
  • Serum LDH \> 1.5 times upper limit of normal
  • Symptoms at presentation due to metastases
  • Clinical stage T4 disease
  • History of malabsorption syndrome
  • +7 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Fondazione IRCCS Istituto Nazionale Tumori

Milan, Mi, 20133, Italy

Location

Related Publications (9)

  • Flanigan RC, Yonover PM. The role of radical nephrectomy in metastatic renal cell carcinoma. Semin Urol Oncol. 2001 May;19(2):98-102.

    PMID: 11354539BACKGROUND

  • Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. doi: 10.1056/NEJMoa003013.

    PMID: 11759643BACKGROUND

  • Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. doi: 10.1016/s0140-6736(01)06103-7.

    PMID: 11583750BACKGROUND

  • Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004 Mar;171(3):1071-6. doi: 10.1097/01.ju.0000110610.61545.ae.

    PMID: 14767273BACKGROUND

  • Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. doi: 10.1056/NEJMoa1303989.

    PMID: 23964934BACKGROUND

  • Choueiri TK, Xie W, Kollmannsberger C, North S, Knox JJ, Lampard JG, McDermott DF, Rini BI, Heng DY. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011 Jan;185(1):60-6. doi: 10.1016/j.juro.2010.09.012. Epub 2010 Nov 12.

    PMID: 21074201BACKGROUND

  • Gossage L, Murtaza M, Slatter AF, Lichtenstein CP, Warren A, Haynes B, Marass F, Roberts I, Shanahan SJ, Claas A, Dunham A, May AP, Rosenfeld N, Forshew T, Eisen T. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes Chromosomes Cancer. 2014 Jan;53(1):38-51. doi: 10.1002/gcc.22116. Epub 2013 Oct 29.

    PMID: 24166983BACKGROUND

  • Heng DY, Wells JC, Rini BI, Beuselinck B, Lee JL, Knox JJ, Bjarnason GA, Pal SK, Kollmannsberger CK, Yuasa T, Srinivas S, Donskov F, Bamias A, Wood LA, Ernst DS, Agarwal N, Vaishampayan UN, Rha SY, Kim JJ, Choueiri TK. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014 Oct;66(4):704-10. doi: 10.1016/j.eururo.2014.05.034. Epub 2014 Jun 13.

    PMID: 24931622BACKGROUND

  • Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020 May;17(5):271-291. doi: 10.1038/s41585-020-0297-9. Epub 2020 Mar 17.

    PMID: 32203306DERIVED

MeSH Terms

Conditions

Clear-cell metastatic renal cell carcinoma

Interventions

Sunitinibpazopanib

Intervention Hierarchy (Ancestors)

PyrrolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsIndolesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-Ring

Study Officials

  • Giuseppe Procopio, MD

    Fondazione IRCCS ISTITUTO NAZIONALE TUMORI

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

August 4, 2015

First Posted

August 28, 2015

Study Start

November 1, 2015

Primary Completion

September 28, 2018

Study Completion

September 28, 2018

Last Updated

November 14, 2018

Record last verified: 2018-11

Locations

IT(1)