The principal objective of the trial is to investigate whether the sequence of the nephrectomy in patients who receive sunitinib has an effect on patient outcome.
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
- Renal and urinary tract therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The duration of progression free survival: the time interval between the date
of randomization and the first date of progression (local or distant) or death
due to any cause. Progression will be defined according to the RECIST 1.1. In
case the patient is still alive without progression, the date of
progression/death will be censored at the date of last follow up.
In case of early progression within 4 weeks after surgery, the actual date of
progression (if confirmed) will be at week 16 in the immediate arm and week 28
in the deferred arm (see Protocol sections 7.1).
Secondary outcome
* Overall survival
* Morbidity
* Overall response to treatment in the deferred nephrectomy arm including the
proportion of patients who become unresectable
* Effect of nephrectomy on early progression in both arms
Background summary
For patients with RCC and disease confined to the kidney the only effective
therapy with a high probability of cure is surgical removal of the primary
tumor. Unfortunately, up to 30 % of all patients with renal cell carcinoma have
metastatic disease at the time of diagnosis with the primary tumor in situ.
Surgery alone is ineffective for the majority of patients with primary
metastatic renal cell carcinoma and multiple non-resectable metastases, apart
from the few patients who present with solitary metastases in whom surgical
complete resection of the lesion in conjunction with nephrectomy may lead to
prolonged survival and possibly cure in exceptional cases. Randomized
controlled trials (Southwest Oncology Group
(SWOG) S8949 and European Organization for Research and Treatment of Cancer
(EORTC) 30947) have shown a small but statistically significant survival
benefit of 6 monts for cytoreductive nephrectomy (CN) before immunotherapy with
interferon alfa in the treatment of metastatic renal cell carcinoma (mRCC)
versusinterferon alpha alone.
Oral tyrosine kinase inhibitors targeting VEGF and platelet-derived growth
factor (PDGF) receptors have altered the systemic treatment of mRCC. Compared
with cytokine therapy sunitinib at a dose of 50 mg daily for 4 weeks on and 2
weeks off induces a high partial response (PR) rate of up to 40% at metastatic
sites. Sunitinib is standard of treatment for clear cell subtype, which
comprise 70-80 % of all mRCC, but not necessarily standard for other cell
types. Sunitinib was evaluated in a phase III trial of 750 patients with
largely good- or intermediate-prognosis metastatic clear cell RCC who had not
received prior systemic treatment. The objective response rate was
significantly increased with sunitinib (39 versus 8 percent with IFNa). Median
PFS was significantly prolonged (11 versus 5 months, hazard ratio [HR] 0.54).
This benefit included patients at good, intermediate, and poor risk (PFS 14.5
versus 7.9, 10.6 versus 3.8, and 3.7 versus 1.2 months, respectively). Based on
this pivotal trial, sunitinib was registered in the US and Europe in 2007 for
the treatment of metastatic RCC and became the approved first-line therapy for
all patients including patients with primary tumors in situ.
Many centers perform immediate nephrectomy followed by the approved first-line
drug sunitinib as the new standard.
In summary, there is evidence that mRCC patients with a good performance, good
and intermediate MSKCC risk, low risk of surgery and a clear cell subtype
receiving sunitinib as approved systemic treatment may benefit from CN.
However, despite these selection criteria, individual prediction of a CN
benefit remains elusive. Studies should be designed to identify those
individuals in whom CN alters the natural history of mRCC. Identification would
require understanding of new clinical and molecular predictors. Therefore,
there is a rationale for deferred nephrectomy following targeted therapy and
investigation of pretreated primary tumor tissue. In addition, deferred
nephrectomy may improve the clinical outcome.
Recently cases have been described in which the surgical management in advanced
RCC was altered by pretreating the tumor in situ with targeted agents.
Experience from phase II trials investigating deferred surgery after targeted
therapy in renal and other tumors suggest that sunitinib discontinued at least
24 hours prior to surgery is safe. The effect of downsizing the primary tumor
is most prominent in the first two to three months suggesting that two to three
presurgical cycles of sunitinib may be sufficient. In renal and other cancers,
a few days of treatment with tyrosine kinase inhibitors have been shown in
patients and animal models to induce a maximal inhibition of cell proliferation
and induction of apoptosis.
Study objective
The principal objective of the trial is to investigate whether the sequence of
the nephrectomy in patients who receive sunitinib has an effect on patient
outcome.
Study design
This is a randomized multicenter phase III comparison trial. Eligible patients
will be randomized between immediate versus deferred nephrectomy.
Intervention
Arm A will undergo immediate nephrectomy followed by standard medical treatment
for metastatic renal cell carcinoma and compared to arm B in which nephrectomy
is deferred until after 3 courses of standard medical treatment for mRCC.
Study burden and risks
Accepted treatment of mRCC is a combination of surgery and medical treatment.
The sequence is unknown, but treatment with sunitinib and the techniques of
nephrectomy are well established, therefore the trial treatment does not
deviate from standard treatment with the exception of serum collection and an
additional restaging CT scan.
Avenue E. Mounier, 83/11
Brussels 1200
BE
Avenue E. Mounier, 83/11
Brussels 1200
BE
Listed location countries
Age
Inclusion criteria
- Histologically confirmed metastatic Renal Cell Cancer of clear-cell subtype with a resectable asymptomatic in situ primary.
- Metastatic RCC (mRCC): metastases are not completely resectable at the time of
surgery or during an additional intervention. Multiple lesions at one site will make
the patient not eligible for complete resection.
- Histology *clear-cell* subtype: If the diagnosis is not established patients need
to undergo a transcutaneous tru-cut needle biopsy of the primary tumor.
- Resectable tumor: primary tumor must be resectable and resectability should not
be doubtful at entry. Patients with distant metastases and bulky locoregional
lymph node metastases larger than the primary tumor can be included if
resectability of the lymph nodes is surgically feasible.
- 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. As para-neoplastic symptoms cannot
be assigned to the primary tumor alone in metastatic disease, they are not
included in this definition.
- Patients who will receive Sunitinib (Sutent®) as background therapy.
- Measurable disease according to RECIST 1.1 criteria.
- Prior therapies:
- Prior systemic therapy for metastatic RCC is not allowed
- Prior local radiotherapy for bone lesions is allowed
- Concomitant medications:
- Investigational or systemic therapy for metastatic RCC must not be used during
the period of protocol treatment.
- No systemic corticosteroid and/ or other immunosuppressive systemic therapies
- Age * 18 years.
- Life expectancy > 3 months.
- WHO performance status 0 or 1.
- Adequate bone marrow function (Leucocytes > 3.0 x 109/l, platelets >100 x 109/l,
hemoglobin > 6.0 mmol/l or > 10.0 g/dL.)
- Prothrombin time (PT) or international normalized ratio (INR) * 1.2 x upper limit of
normal (ULN).
- Partial thromboplastin time (PTT) * 1.2 x ULN.
- Adequate hepatic function (bilirubin * 1.5 x ULN, SGPT/ALT * 2.5 x ULN or * 5 x
ULN if liver lesions).
- Serum calcium < 10.0 mg/dL.
- Adequate renal function: calculated or measured clearance creatinine >30 ml/min.
- Clinically normal cardiac function based on the institutional lower limit of normal
LVEF assessed by MUGA or ECHO and normal 12 lead ECG.
- Patients with any history of malignancies who are disease-free for more than 5
years are eligible.
- Women must be post-menopausal with a total cessation of menses of >1 year, or
if of childbearing potential must not be pregnant (negative serum pregnancy test
at entry) or lactating; and must agree to use effective contraceptive methods
(with a documented failure rate < 1% e.g.; vasectomized partner sterile prior to
trial entry and sole sexual partner or double-barrier contraception) from 2 weeks
before to enrollment. The duration of the contraception will depend on the
treatment that patient will receive.
- Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be assessed with the patient before registration in the
trial.
- Before patient randomization, written informed consent must be given according
to ICH/GCP, and national/local regulations.
Exclusion criteria
- Patients for whom complete surgical remission can be achieved by
removing metastatic sites at nephrectomy or during an additional
intervention.
- Patients with symptomatic primary necessitating nephrectomy.
- Patients with previous partial or total nephrectomy.
- Patients with unresectable bulky locoregional lymph node metastases larger than the primary tumor.
- Patients with only bone metastases.
- Patients having more than 3 of the following surgical risk factors will not be eligible:
- serum albumin CTCAE v4.0 grade 2 or worse
- serum LDH > 1.5 x UNL
- liver metastases
- symptoms at presentation due to mestastases
- retroperitoneal lymph node involvement
- supra-diaphragmatic lymph node involvement
- clinical stage T3 or T4
- Patients with serious cardiac illness (myocardial infarction and/or (un)treatable angina
pectoris not responding to treatment) within the past 12 months.
- Uncontrolled high blood pressure (BP) defined as BP * 150/100 mm Hg despite
optimal medical therapy.
- Clinical signs of CNS involvement.
- Current pulmonary disease.
- Patients with active or uncontrolled infections or with serious illnesses,
malabsorption syndrome or medical conditions, including patients with a history of
chronic alcohol abuse, hepatitis, HIV and/or cirrhosis.
- History, within the past five years, of malignancies other than renal cell
carcinoma (except: basal or squamous cell carcinoma of the skin, in situ carcinoma
of the cervix, resected incidental prostate cancer staged pT2 with Gleason Score *
6 and postoperative PSA < 0.5 ng/ml).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL29931.031.09 |