Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma.

BACKGROUND: Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC. METHODS: Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained. RESULTS: Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed. CONCLUSIONS: The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.

Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design.

BACKGROUND: Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents. METHODS: The characteristics and outcome of refractory GCT patients enrolled in 7 single-agent phase 2 trials conducted at Memorial Sloan-Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all-transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression-free survival (PFS), and overall survival (OS). RESULTS: Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty-six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8-1.3) and 4.7 months (95% CI, 3.5-6.4), respectively. Eighty-six of the 90 patients have died. The 12- and 16-week PFS rates were 9% (95% CI, 3-15%) and 6% (95% CI, 1%-11%), respectively. CONCLUSIONS: Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve-week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials.

Sarcomatoid-variant renal cell carcinoma: treatment outcome and survival in advanced disease.

OBJECTIVES: Sarcomatoid variant is a spindle cell phenotype of renal cell carcinoma (RCC), which is associated with a poor prognosis. We reviewed outcomes of systemic therapy for metastatic, sarcomatoid-variant RCC. METHODS: Clinical features, treatment outcome, and survival were evaluated in 63 patients with sarcomatoid-variant metastatic RCC (47 clear cell, 16 nonclear cell). Initial systemic treatment included antiangiogenesis-targeted therapy (n=34), cytokines (n=20), and chemotherapy (n=9). RESULTS: Five of 63 patients (8%) achieved an objective response to the first systemic treatment: 1 (5%) to cytokine and 4 (12%) to sunitinib-targeted therapy. Median progression-free survival for 63 patients was 3 months (95% confidence interval), and median overall survival was 10 months (95% confidence interval). The median progression-free survival for patients treated with sunitinib versus all others was 4.4 months versus 2 months (P=0.03), and 3 months for patients with clear-cell histology versus 1.6 months for nonclear-cell histology (P=0.004). CONCLUSIONS: Metastatic sarcomatoid-variant RCC was associated with a poor response to systemic therapy. Sunitinib treatment resulted in a modest response rate, but studies to characterize the underlying tumor biology of sarcomatoid-variant RCC, to assess outcome to targeted agents, and to develop novel treatment strategies are warranted.