Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma

Abstract

Purpose-Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC.Patients and Methods-Eligibility included advanced RCC and ≤ 2 previous systemic regimens. At the starting dose, temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period.Results-In the first cohort, dose-limiting toxicities (grade 3 treatment-related toxicities that lasted ≥ 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/μL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/μL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents.Conclusion-Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.

Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence

“…In a phase I trial in patients with previously treated advanced RCC, VEGFR tyrosine kinase inhibition with sunitinib plus downstream mTOR inhibition with temsirolimus resulted in substantial toxicity at low starting doses of both agents (sunitinib, 25 mg daily; temsirolimus, 15 mg once weekly), causing trial termination [38].…”

Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop

“…Sometimes drug combinations will be abandoned if the combined toxicity requires such extensive dose reductions that the actual administered doses may be ineffective (e.g., sunitinib and temsirolimus; ref. 25). When combinations of drugs must be administered at a substantially lower dose than planned because of toxicity, it is often unclear whether the lower dose would truly be too low to show efficacy, as such dose reductions typically result in the abandonment of further efficacy analyses.…”

Optimizing recent advances in metastatic renal cell carcinoma

“…Feldman et al [29], Sosman et al [30], Fischer et al [31] Combination therapy Excess toxicity observed with combinations of sunitinib + bevacizumab or sunitinib + temsirolimus Sorafenib + bevacizumab combination seems promising…”

“…Similarly, the combination of sorafenib and bevacizumab produced an impressive response rate of 52% in a phase 1 trial; however, bevacizumab appeared to increase known sorafenib-associated toxicities (hand-foot syndrome, anorexia, hypertension, fatigue), and the maximal tolerated dose was 200 mg by mouth daily (one fourth of the full dose) for sorafenib and 5 mg/kg intravenously every 2 weeks (half the full dose) for bevacizumab [30]. Furthermore, a phase 1 trial of the combination of sunitinib and temsirolimus was terminated after only three patients were accrued because of substantial toxicity observed at low starting doses of both agents [31].…”