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

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.

• Authors: Sarina A Piha-Paul, Jennifer J Wheler, Siqing Fu, Charles Levenback, Karen Lu, Gerald S Falchook, Aung Naing, David S Hong, Apostolia M Tsimberidou, Razelle Kurzrock
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 7 Pg. 1846-55 (Apr 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24742900 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Bevacizumab
• temsirolimus
• Aspartate Aminotransferases
• Sirolimus

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Aspartate Aminotransferases (blood)
• Bevacizumab
• Carcinoma (drug therapy, secondary)
• Fatigue (chemically induced)
• Female
• Humans
• Hypercholesterolemia (chemically induced)
• Hypertension (chemically induced)
• Male
• Middle Aged
• Mucositis (chemically induced)
• Neutropenia (chemically induced)
• Ovarian Neoplasms (drug therapy, pathology)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives)
• Thrombocytopenia (chemically induced)
• Uterine Cervical Neoplasms (drug therapy, pathology)