SORCE: A phase III randomised double-blind study comparing SOrafenib with placebo in patients with Resected primary renal CEll carcinoma at high or intermediate risk of relapse

TPS682 Background: Glutamine metabolism is upregulated in renal cell carcinoma (RCC) and important for RCC tumor cell proliferation and survival. CB-839 is a first-in-clinic, potent, oral inhibitor of the mitochondrial enzyme glutaminase (GLS), which controls a critical step in tumor cell metabolism of glutamine. CB-839 demonstrated synergistic anti-tumor activity when combined with cabozantinib, a VEGFR2/MET/AXL inhibitor, in preclinical RCC models. In a phase 1 study cohort, CB-839 plus cabozantinib as 2L+ therapy showed encouraging safety and efficacy results, with 50% overall response rate (ORR; RECIST v1.1) and 100% disease control rate in 10 patients with clear cell advanced/metastatic RCC (mRCC). A randomized, double-blind study comparing CB-839 plus cabozantinib vs. cabozantinib plus placebo has been initiated in patients with clear cell mRCC. Methods: In this ongoing international, randomized, double-blind, multi-center study, enrollment is planned for ~300 patients with clear cell mRCC. To be eligible, patients should have received 1-2 prior lines of systemic therapy for mRCC including ≥1 anti-angiogenic therapy or the combination of nivolumab + ipilimumab, have KPS ≥70%, measurable disease (RECIST v1.1), and no prior cabozantinib (or other MET inhibitor). Patients are randomized 1:1 to receive either CB-839 (800 mg twice daily per oral [PO] route) plus cabozantinib (60 mg daily PO) or cabozantinib plus placebo in 28-day cycles until disease progression or unacceptable toxicity. Patients are stratified by prior PD-1/PD-L1 inhibitor therapy and by IMDC prognostic risk group (favorable vs. intermediate vs. poor). The primary endpoint is progression-free survival (PFS) per RECIST v1.1, determined by blinded independent radiology review. Secondary endpoints are investigator-assessed PFS and overall survival. Safety, response per RECIST, and quality of life are also assessed. Findings of this randomized, international clinical trial will inform the efficacy and safety profile of CB-839, a first-in-clinic metabolic inhibitor, in combination with cabozantinib in patients with mRCC. Clinical trial information: NCT03428217.

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Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial

The Lancet ◽

10.1016/s0140-6736(08)61039-9 ◽

2008 ◽

Vol 372 (9637) ◽

pp. 449-456 ◽

Cited By ~ 2162

Author(s):

Robert J Motzer ◽

Bernard Escudier ◽

Stéphane Oudard ◽

Thomas E Hutson ◽

Camillo Porta ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Double Blind ◽

Phase Iii Trial

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Re: Efficacy of Everolimus in Advanced Renal Cell Carcinoma: A Double-Blind, Randomised, Placebo-Controlled Phase III Trial

European Urology ◽

10.1016/j.eururo.2009.03.034 ◽

2009 ◽

Vol 55 (6) ◽

pp. 1482-1484 ◽

Cited By ~ 1

Author(s):

Frédéric Pouliot ◽

Allan J. Pantuck

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Double Blind ◽

Phase Iii Trial

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Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial

Journal of Clinical Oncology ◽

10.1200/jco.20.01800 ◽

2020 ◽

Vol 38 (34) ◽

pp. 4064-4075

Author(s):

Tim Eisen ◽

Eleni Frangou ◽

Bhavna Oza ◽

Alastair W.S. Ritchie ◽

Benjamin Smith ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Disease Free Survival ◽

Phase Iii ◽

Outcome Analysis ◽

Double Blind ◽

Risk Of Recurrence

PURPOSE SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

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