Advanced gynecologic malignancies treated with a combination of the VEGF inhibitor bevacizumab and the mTOR inhibitor temsirolimus

// Sarina A. Piha-Paul 1 , Jennifer J. Wheler 1 , Siqing Fu 1 , Charles Levenback 2 , Karen Lu 2 , Gerald S. Falchook 1 , Aung Naing 1 , David S. Hong 1 , Apostolia M. Tsimberidou 1 , Razelle Kurzrock 3 1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX 2 Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 3 Moores Cancer Center, The University of California San Diego, La Jolla, CA, U.S.A Correspondence: Sarina A. Piha-Paul, email: // Keywords : Gynecologic Malignancy, Bevacizumab, Temsirolimus Received : January 31, 2014 Accepted : March 19, 2014 Published : March 20, 2014 Abstract Background: Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors Patients and Methods: We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus. Results: Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) ≥ 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD ≥ 6 months/PR. Conclusion: Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD ≥ 6 months/PR, suggesting that this combination warrants further study.