Ashwin Gollerkeri

A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.

OBJECTIVE PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib. METHODS The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort. RESULTS In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population. CONCLUSIONS Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.

Abstract 1646: In vivo target validation in orthotopic hepatocellular carcinoma model using formulated siRNA

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence continues to increase. Although there are approved therapies for HCC, the prognosis remains poor. The 5-year survival rate is Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1646. doi:10.1158/1538-7445.AM2011-1646