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A phase I study of AZD2171 and Temsirolimus in patients with advanced gynecological malignancies
Susana M Campos1, Suzanne Berlin2, Carolyn N Krasner3
1Division of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA. scampos@partners.org.
Purpose:
Temsirolimus, a mTOR inhibitor, and AZD2171, a VEGFR inhibitor, have independently shown activity in patients with gynecological malignancies. Understanding the pivotal role of the PI3K/PTEN/AKT/mTOR pathway in regulating angiogenesis, a phase I study utilizing Temsirolimus and AZD2171 was initiated to study the safety of targeting the mTOR and VEGF pathway in patients with recurrent or refractory gynecological malignancies.
Methods:
Patients with advanced gynecological cancers were enrolled in this phase 1 study with Temsirolimus and AZD2171. A traditional 3 + 3 design was followed. The primary objective was to determine the MTD of the combination. Secondary objectives included efficacy, progression free survival (PFS) and toxicity profile. An expansion phase was planned after the MTD was determined.
Results:
The study enrolled 11 patients over 16 months. All patients were enrolled in dose level 1. Due to toxicity, the trial was halted at dose level 1. No MTD was determined. The most common grade 3/4 toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Five patients were evaluable for best overall clinical response. The best overall clinical response was stable disease. Two patients died without documented progression of disease. The median PFS was 7.2 months.
Conclusions:
Despite a conservative dose escalation, the toxicity data demonstrated that the combination of AZD2171 and Temsirolimus was not tolerable. Increased awareness of novel toxicities, pharmacological interactions, coupled with strict patient selection and early mitigation of side effects may enhance phase I clinical trial development.
Insights
The combination of Temsirolimus (mTOR inhibitor) and AZD2171 (VEGF inhibitor) showed unacceptable toxicity in gynecological cancer patients. Further phase I clinical trials require strict patient selection and early toxicity management.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Temsirolimus (mTOR inhibitor) and AZD2171 (VEGF inhibitor) show independent activity in gynecological malignancies.
- The PI3K/PTEN/AKT/mTOR pathway is crucial for angiogenesis.
- Targeting both mTOR and VEGF pathways may offer therapeutic benefits.
Purpose of the Study:
- To evaluate the safety and determine the maximum tolerated dose (MTD) of combined Temsirolimus and AZD2171.
- To assess the efficacy, progression-free survival (PFS), and toxicity profile of the combination therapy.
- To explore the potential of dual mTOR and VEGF pathway inhibition in gynecological cancers.
Main Methods:
- Phase 1 clinical trial with a 3+3 dose escalation design.
- Enrollment of patients with recurrent or refractory gynecological malignancies.
- Primary endpoint: MTD; Secondary endpoints: efficacy, PFS, toxicity.
Main Results:
- The study enrolled 11 patients; all treated at dose level 1.
- The trial was halted due to toxicity, and no MTD was determined.
- Common toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Median PFS was 7.2 months.
Conclusions:
- The combination of AZD2171 and Temsirolimus was not tolerable at the tested dose.
- Future phase I trials necessitate enhanced patient selection and proactive side effect management.
- Further research into dual pathway inhibition requires careful consideration of toxicity profiles.
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