Targeting mTOR and VEGF in CRPC: Preliminary results of a phase I/II trial of temsirolimus (T) and bevacizumab (B) in docetaxel-refractory metastatic CRPC.

Abstract

e15208 Background: Despite the availability of novel agents in the docetaxel-refractory setting, their activity is often short lived as all pts eventually progress. Activation of the PI3K/AKT/mTOR/VEGF/CXCR6 pathway regulates proliferation, differentiation, and malignant transformation in PCa progression. mTOR inhibition inhibits CXCL16, IL8/VEGF levels and other CXCR6 targets including CD44 and matrix metalloproteinase 3. Combination strategies capable of blocking the CXCR6/VEGF/AKT/mTOR signaling pathway could become a more effective therapeutic strategy for CRPC. Methods: Eligible docetaxel-refractory CRPC pts had serologic or objective PD after 1 or 2 prior chemotherapies. Pts with CNS metastases or active spinal cord compression were excluded. A staged-cohort design to study primarily safety of the combination was undertaken. Once the MTD was established a two-stage phase 2 trial was implemented. An underlying ORR >20% was deemed sufficient to warrant further study, whereas an ORR rate <5% would not. Starting doses of T and B were 15mg wk and 5mg/kg e/2 wk. Exploratory endpoints included CTCs, VEGF levels and Th1 cytokine production. Results: To date 22 of a total planned 28 pts are enrolled, median age was 64 and half of the pts were ECOG 1. Most pts had bone disease and the median PSA was 205 ng/mL. Pts have received a median of 4 cycles of treatment (range: 1-12). All pts have discontinued therapy; 48% PD, 38% AEs and 5% consent withdrawal. PSA reductions were observed in 30% of pts. No RECIST defined PR was seen. The most common AEs included anorexia (67%), mucositis (53%), fatigue (57%) and myelosuppression in over 60% of pts. CTC analysis and VEGF/TOR and cytokine levels are currently underway. Conclusions: The combination of T and B demonstrated significant toxicity in a heavily pretreated CRPC pt population. Minimal antitumor activity was observed. Exploratory studies and their correlation with clinical outcome are underway.