3554 Background: Sirolimus, a commercially available oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases (RTKs), by vertical disruption of VEGFr signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients, and also by directly inhibiting tumor cell proliferation. Methods: Sunitinib was given at 50 mg daily (d) x 28 q6w. The dose of sirolimus was escalated in cohorts of 3–6 beginning at 4 mg weekly until the MTD was determined. The first cohort received sunitinib alone 50mg d x 14 followed by 14 days off in cycle #1. After the 4mg sirolimus dose cohorts, sunitinib dose was reduced in subsequent cohorts to 37.5mg, and dose escalation of sirolimus was re-initiated at 4mg. Results: 18 patients (pts) with ECOG PS <2 were enrolled, median age 57yo (r:24–76), M:F: 11:7. Median # of prior treatments (Rx): 2(r:0–5), 6 had no prior systemic Rx. Disease primary sites: GI-5 (28%), renal cell- 4 (22%), melanoma-2, soft tissue sarcoma (STS)-2, adenoca unknown 10-2, breast-1, H&N-1, NSCLC-1. At the 50/4 dose level, 4 of 8 required dose reduction (DR) or early discontinuation (ED) of Rx in cycle #1. At the 37.5/4 and 37.5/8 dose levels, 3/9 required DR or ED in cycle #1 or starting cycle #2. Several pts able to complete 1–2 cycles at full dose had significant toxicities including fatigue and hand-foot syndrome. 1 pt developed interstitial pneumonitis, 1 pt died on day 8 due to progressive disease. Four pts received >4 cycles (5-STS, 5-renal papillary, 13-neuroendocrine pancreas, 17-renal clear cell). Among 16 pts undergoing restaging, there was no CR or PR. 5 other pts demonstrated transient central necrosis or size reduction in some tumors. There was no apparent PK interaction at the 4mg sirolimus dose level, and no clear effect on sunitinib-induced increase in circulating VEGF levels. Conclusions: Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature. [Table: see text]
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