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Sutent and Avastin
In a poster session, Darren Feldman reported on a current Phase 1 trial of the combined therapies, Avastin and Sutent, at a single institution, Memorial Sloan-Kettering (MSKCC). The theory behind combining these two therapies is that while Sutent is an inhibitor of the vascular endothelial growth factor receptor (VEGFR), a promoter of angiogenesis, it also increases VEGF itself. Avastin blocks VEGF so the combination would theoretically have a longer lasting effect. This trial is similar to the one presented at last year's ASCO conference by Jeffrey Sosman of Vanbderbilt University in which the combination of Nexavar and Avastin was used. In that trial, dose limiting toxicities prevented investigators from reaching the standard dosage for Nexavar of 800 mg per day, which impacted the response rate.
The Phase 1 trial was divided into three cohorts, each receiving the fixed dose of Avastin of 10 mg/kg but each cohort receiving escalating doses of Sutent: 25 mg, 37.5 mg, and 50 mg daily, 4 weeks on, 2 weeks off. This was a small trial with cohorts of 3-6 patients. The third cohort received the standard dose of Sutent of 50 mg daily.
19 patients in total entered the study with six having entered the 2nd dose level and six the 3rd level. Six patients were at 50 mg of Sutent for only one cycle. Grade 3/4 toxicities included hypertension (8 pts), elevated lipase (7 pts), and hand-foot syndrome (3 pts). In addition, there were two grade 4 dose-limiting toxicities of hemorrhaging.
Sutent and Avastin Response
| |
Patients (%) |
|
Partial Response |
7(37%) |
|---|---|
|
Stable Disease |
10(53%) |
|
Progressive Disease |
2(11%) |
Feldman concluded that 10 mg/kg of Avastin and 50 mg of Sutent is "tolerable and safe" in RCC patients, but 42% grade 3/4 hypertension is significant especially compared to the 8% figure for Sutent alone as presented at ASCO 2007 by Motzer in his updated results of Sutent versus Interferon. On the other hand, these are still preliminary data as the trial has not yet matured. MSKCC is planning a randomized placebo-controlled Phase 2 trial of Avastin at 10 mg/kg and Sutent at 50 mg daily.