A phase I study of sunitinib in combination with sirolimus in adults with advanced refractory malignancies

Abstract

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]

A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer

“…In one of them, PPE and fatigue were common AEs. The other study was terminated because of substantial toxicity ( Li et al , 2009 ; Patel et al , 2009 ).…”