Clinical trial NCT04006405: AURORAX-0087A: GAG Scores for Surveillance of Recurrence in Leibovich Points ≥5 Non-metastatic ccRCC
Official title: AURORAX-0087A: Glycosaminoglycan Scores for Surveillance of Recurrence in Leibovich Points ≥5 Non-metastatic Clear Cell Renal Cell Carcinoma
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Clear Cell Renal Cell Carcinoma
Lead sponsor: Elypta
Sponsor class: INDUSTRY
First posted: 2019-07-05
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population is a representative sample of the North American and European population of ccRCC patients with LP ≥ 5 after curative intent surgery

Brief summary: AUR87A is an observational prospective multicenter diagnostics test cohort study for detection of renal cell carcinoma recurrence as determined by the reference standard, which is imaging using computed tomography (CT) of the chest and abdomen at defined intervals after primary surgery.

Detailed description: Non-metastatic clear cell renal cell carcinoma (ccRCC) recur in \~20% of cases within 5 years after radical surgery. Current postoperative follow-up protocols, being schematic and at best based on risk of recurrence scores, are sub-optimal for early detection of recurrences which could potentially be available for curative management. Blood and urine collected glycosaminoglycans (GAGs) are promising novel class of biomarkers from which a new diagnostic test based on so called GAG scores has been developed. GAG scores have accurately distinguished localized/locally-advanced and advanced RCC from healthy subjects.

AUR87A features an adaptive design. The primary endpoint analysis is conducted when 30 events (i.e. recurrences) are reached - expected at 140 patients with a minimum follow-up of 12 months (cohort 1). An interim analysis at 15 events is conducted to verify whether the sensitivity and specificity estimates are in line with the study assumptions. In case of futility, the GAG scores formulations and/or cut-offs are optimized based on data from cohort 1. The primary endpoints are then validated on a second independent cohort, powered depending on the results from cohort 1. This second cohort is estimated in 140 patients (cohort 2). In case of non-futility, cohort 2 may be used as external validation.

AUR87A will prospectively enroll an estimated 280 non-metastatic ccRCC patients curatively treated with surgery (partial or radical nephrectomy). Patients are followed-up longitudinally using GAG scores in blood and urine every 3 months after surgery, alongside the current standard follow-up protocol, i.e. imaging, as reference standard.

The hypothesis of AUR87A is that postoperative increase of the GAG scores, so called "GAG recurrence ", can predict or detect recurrence at an earlier time-point compared to the reference standard, referred to as "radiological recurrence", and thereby improve the clinical utility of current follow-up protocols.

Eligibility criteria: Inclusion Criteria:

Pre-screening inclusion criteria

* Size of primary tumor \>4cm (\>cT1a) in greatest dimension on pre-operative abdominal CT-scan
* Size of primary tumor ≤4cm is allowed if pre-operative abdominal CT-scan shows suspected RCCs with radiological sign of venous tumor thrombus (renal vein or caval).
* Pre-operative CT-scan of chest and abdomen show no signs of metastatic disease
* Localized and biopsy proven clear cell RCC (ccRCC) under active surveillance which at timepoint of study recruitment, opted for surgery because of growth rate of primary tumor to a size \> 4cm
* Elected for curative intent surgery for RCC

Final screening inclusion criteria

* Any gender being 18 years or older at timepoint of final inclusion
* In postoperative pathology report shown to be ccRCC subtype according to 8th Edition of the American Joint Committee on Cancer (AJCC)
* Leibovich points (LP) ≥5 according to Leibovich score system (2003)
* If pathology report shows multiple subtypes in same tumor, as long as the majority of tumor is ccRCC (\>50%), participant can be included

Exclusion Criteria:

Pre-screening exclusion criteria

* TNM-stage T(any) N(any) M1 according to AJCC, i.e. metastatic disease at diagnosis
* Absence of preoperative chest imaging (chest CT) within 60 days prior to primary surgery
* Previous history of curatively treated for other cancers, still not deemed fully cured and participant still under surveillance for said cancer
* Participants offered active surveillance for RCC instead of curative intent surgery
* Participants offered any type of thermal ablation treatment instead of surgery, i.e. LP cannot be assessed

Final screening exclusion criteria

* Participants with AJCC cN0 status at preoperative imaging in whom a clinically suspicious regional lymph-node metastases (enlarged lymph node(s)) is noted during primary surgery, but who subsequently do not undergo any lymph node dissection. (Note: participants with cN0 status at pre-operative imaging and no clinical signs of regional lymph node metastases during primary surgery can still be included irrespective of lymph node dissection having been performed, i.e. being pN0 or pN1 if it is performed or pNx if it is not performed)
* Participants with AJCC cN1 status at pre-operative imaging in which lymph node dissection is not performed (i.e. pNx).
* Elected for any adjuvant therapy (i.e. systemic therapy) outside or within any clinical study
* Non-clear cell RCC histology or benign tumor (i.e. oncocytoma and angiomyolipoma, which are the most common benign types, but also any other rare types of benign renal tumors) after pathological analysis
* Any hereditary form of RCC (e.g. Von Hippel-Lindau, Birt-Hogg-Dubé, Hereditary Papillary RCC)
* RCC with pure sarcomatoid differentiation, also called sarcoma of the kidney
* Previous history of curatively treated for RCC with a suspected de novo RCC in the remaining kidney tissue
* Prior or current use of instillation therapy with hyaluronic acid and/or chondroitin sulfate (HA-CS).
* Use of heparin, including low molecular weight heparin (e.g. Enoxaparin, Dalteparin, Tinzaparin) for concurrent disease in need of blood dilution (e.g. ongoing deep vein thrombosis or lung emboli). Note: use of of heparin for thrombus prophylaxis in conjunction with primary surgery or postoperatively ≤4 weeks will be allowed.
* Patients who were not radically operated during primary surgery with the exception of histological positive surgical margin in participants who have undergone partial nephrectomy.

Primary outcomes:
measure: Sensitivity and specificity of GAG recurrence
timeFrame: minimum follow-up of 12 months
Secondary outcomes:
measure: Absolute and relative risk increase (ARI/RRI) of radiological recurrence
timeFrame: within 6 months since last GAG score evaluation
measure: Recurrence-free survival (RFS)
timeFrame: minimum follow-up of 12 months
measure: Positive and negative predictive value (PPV/NPV) of GAG recurrence
timeFrame: minimum follow-up of 12 months
measure: Area under the receiver-operating-characteristic curve (AUC) of GAG scores
timeFrame: minimum follow-up of 12 months
measure: RFS, overall survival (OS) and cancer specific survival (CSS)
timeFrame: follow-up time of 2 years and 5 years respectively after primary surgery
measure: Concordance-index (C-index) of preoperative GAG scores
timeFrame: follow-up time of 2 years and 5 years respectively after primary surgery
measure: Lead-time GAG vs. radiological recurrence among true positives
timeFrame: minimum follow-up of 12 months
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Leuven
country: Belgium
facility: UZ Leuven
city: Calgary
country: Canada
facility: Prostate Cancer Centre
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Roskilde
country: Denmark
facility: Zealand University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Bologna
country: Italy
facility: AOU San Orsola Malpighi
city: Florence
country: Italy
facility: Careggi University Hospital
city: Milano
country: Italy
facility: San Raffaele Hospital
city: Orbassano
country: Italy
facility: AOU San Luigi Gonzaga
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena
city: Verona
country: Italy
facility: AOU Integrata Verona
city: Coimbra
country: Portugal
facility: Hospital da Luz Coimbra
city: Gijón
country: Spain
facility: Hospital Universitario Cabueñes
city: Valencia
country: Spain
facility: University Hospital of Valencia
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Umeå
country: Sweden
facility: Norrlands University Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Frimley
country: United Kingdom
facility: Frimley Park Hospital
city: London
country: United Kingdom
facility: Guys & St Thomas Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
affiliation: Lund University, Dept. Clinical Sciences, Skåne University Hospital
name: Saeed Dabestani
role: PRINCIPAL_INVESTIGATOR
References: