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Phase II Trial of Angiotensin-(1-7) for the Treatment of Patients with Metastatic Sarcoma
Paul D Savage1, James Lovato2, K Bridget Brosnihan3
1Department of Medicine, Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center of Wake Forest University, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Abstract:
Background. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous antiangiogenic hormone with anticancer activity. In a phase I study of Ang-(1-7), two of three patients with metastatic sarcoma experienced disease stabilization. This phase II study examined clinical and biomarker outcomes for patients with metastatic sarcoma. Methods. Ang-(1-7) was administered by subcutaneous injection at a dose of 20 mg daily. If excessive toxicities occurred in the first cohort, a dose deescalation cohort was allowed. Blood samples were obtained to measure changes in biomarkers. Results. Treatment was well-tolerated and the dose deescalation cohort was not required. Plasma PlGF concentrations following treatment were not statistically significantly changed. A significant increase in plasma Ang-(1-7) was observed at 4 hours after injection. The median progression-free survival was 2.7 months (95% CI; 1.4 to 4.1 months), and the median overall survival was 10.2 months (95% CI; 5.3 to 18.3 months). Two patients with vascular sarcomas demonstrated prolonged disease stabilization of 10 months (hemangiopericytoma) and 19 months (epithelioid hemangioendothelioma). Conclusions. Ang-(1-7) at a dose of 20 mg daily was well-tolerated. This prospective phase II study failed to confirm the PlGF biomarker effect identified in the prior phase I study. Prolonged disease stabilization in hemangiopericytoma and epithelioid hemangioendothelioma may warrant further investigation.
Insights
Angiotensin-(1-7) [Ang-(1-7)] showed good tolerance in a phase II trial for metastatic sarcoma. While not confirming previous biomarker findings, it offered prolonged disease stabilization in specific vascular sarcomas.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with established antiangiogenic and anticancer properties.
- Previous phase I studies indicated potential disease stabilization in metastatic sarcoma patients treated with Ang-(1-7).
Purpose of the Study:
- To evaluate the clinical efficacy and biomarker changes of Angiotensin-(1-7) in patients with metastatic sarcoma.
- To assess the safety and tolerability of daily subcutaneous Ang-(1-7) administration.
Main Methods:
- A phase II clinical trial administered Angiotensin-(1-7) at 20 mg daily via subcutaneous injection.
- Biomarker analysis, including plasma PlGF and Ang-(1-7) levels, was performed.
- Progression-free survival and overall survival were primary endpoints.
Main Results:
- The treatment was well-tolerated, negating the need for dose deescalation.
- No statistically significant changes in plasma PlGF were observed, but plasma Ang-(1-7) levels increased post-injection.
- Median progression-free survival was 2.7 months and median overall survival was 10.2 months.
- Two patients with vascular sarcomas (hemangiopericytoma, epithelioid hemangioendothelioma) achieved prolonged disease stabilization (10 and 19 months, respectively).
Conclusions:
- Daily subcutaneous Angiotensin-(1-7) at 20 mg is a safe and tolerable treatment for metastatic sarcoma.
- The study did not replicate the PlGF biomarker effect seen in phase I, suggesting complex biomarker interactions.
- The observed prolonged disease stabilization in specific vascular sarcomas warrants further investigation into Ang-(1-7) as a targeted therapy.
