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A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma
Ravindran Kanesvaran1, Kevin Watt2, James D Turnbull3
1Duke University Medical Center, Durham, NC.
Background:
Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor tyrosine kinase signaling, have both been shown to provide clinical benefit in patients with advanced renal cell carcinoma (RCC). We sought to determine the safety and efficacy of combination therapy with these agents in patients with advanced RCC.
Methods:
We conducted a phase 1b dose escalation trial of sunitinib and everolimus in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary end point was to determine the maximum tolerated dose/recommended phase 2 dose.
Results:
A total of 4 out of a planned 30 subjects were enrolled onto this study (M:F = 2:2; mean age 52 years, 50% with Karnofsky performance status < 80). The first 3 patients were enrolled onto a 4 + 2 dosing schedule of daily sunitinib 50 mg and weekly everolimus 30 mg. Mean time receiving drug was 99 days. One partial response was seen. Toxicities included mucositis, thrombocytopenia, anemia, fatigue, dehydration, and hypoglycemia. Because of multiple grade 3 to 4 toxicities, the protocol was amended to 2 + 1 dosing of sunitinib 37.5 mg and daily everolimus 5 mg. The first patient on this schedule died from multiorgan failure with septic shock after 1 cycle of treatment. Subsequently, the study was closed. Pharmacokinetic results inconclusively suggest that toxicities could be attributed to the drug exposure.
Conclusion:
Combined use of everolimus and sunitinib in the treatment of metastatic RCC was not well tolerated in this small cohort.
Insights
Combination therapy with everolimus and sunitinib showed poor tolerability in advanced renal cell carcinoma patients. The study was closed early due to severe toxicities, indicating this combination is not well-tolerated.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Advanced renal cell carcinoma (RCC) is a significant clinical challenge.
- Everolimus (mTOR inhibitor) and sunitinib (VEGF/PDGFR inhibitor) have shown individual efficacy in advanced RCC.
- Investigating combination therapy for improved outcomes in advanced RCC is crucial.
Purpose of the Study:
- To determine the safety and efficacy of combining everolimus and sunitinib in advanced RCC.
- To establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for this combination therapy.
Main Methods:
- A Phase 1b dose escalation trial was conducted.
- Patients with advanced metastatic RCC were enrolled.
- The primary endpoint was to determine the MTD/RP2D.
Main Results:
- Only 4 patients were enrolled due to early study closure.
- Initial dosing (sunitinib 50 mg + everolimus 30 mg) led to severe toxicities including mucositis, thrombocytopenia, and dehydration.
- A modified dosing schedule (sunitinib 37.5 mg + everolimus 5 mg) resulted in a fatal outcome (multiorgan failure) in one patient.
- One partial response was observed.
Conclusions:
- Combined everolimus and sunitinib therapy was not well-tolerated in this small cohort of advanced RCC patients.
- The observed toxicities suggest this combination may not be a viable treatment strategy.
- Further investigation into this combination is limited by safety concerns.
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