A randomized placebo-controlled trial of saracatinib (AZD0530) plus weekly paclitaxel in platinum-resistant ovarian, fallopian-tube, or primary peritoneal cancer (SaPPrOC).

Abstract

5514 Background: Weekly paclitaxel (wPxl) has activity in platinum-resistant ovarian cancer (PROC). Upregulated Src kinase activity is seen in Pxl-resistant ovarian cancer models. This trial investigated the combination of wPxl and the oral Src inhibitor saracatinib (AZD0530) in PROC. Methods: Patients with PROC (defined as relapse within 6 months of prior platinum chemotherapy, confirmed either by CT scan or symptomatic CA125 rise) were randomised 2:1 to receive four 8 week cycles of wPxl (80mg/m2/week x6 with 2 week break) plus saracatinib (S; 175mg od) or placebo (P) continuously, starting 1 week prior to wPxl, until disease progression. Patients were stratified as <6 months or ≥6 months taxane interval/no prior taxane. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate (RR), duration of response (DoR), time to progression (TTP) and toxicity. Results: 107 patients were randomised during 2011-12, 71 (66.4%) to wPxL+S and 36 (33.6%) to wPxL+P. Taxane interval was <6 months in 23 (22.1%), ≥6 months in 76 (72.4%). 43 (41.0%) had received >2 lines of prior chemotherapy; 78% (wPxL+S) vs 72% (wPxL+P) of patients received ≥1 cycle of wPxl; relative dose intensity was 96% vs 98% for wPxL+S and wPxL+P respectively. The 6-month PFS rate was 29% (wPxL+S) vs 35% (wPxL+P). Median PFS was 3.9 vs 5.3 months (HR 1.04; 95% CI 0.68, 1.59; p=0.86); median OS was 12.7 vs 12.8 months (HR 1.50, 95% CI 0.63, 3.56; p=0.36); RR were 0.0% vs 2.9% (CR) and 29% vs 38.9% (PR) for wPxL+S vs wPxL+P respectively. Median DoR was 5.6 vs 3.6 months; TTP was 3.9 vs 5.5 months (HR 1.10; 95% CI 0.71, 1.72;p=0.67). Grade 3+ Serious Adverse Events were 36.2% vs 30.6%; the most frequent toxicities (any grade) were abdominal pain (4.3%) and febrile neutropenia (4.3%) for wPxL+S, and vomiting (5.6%) for wPxL+P. Conclusions: In this randomised phase II trial, the addition of saracatinib to wPxl did not improve 6-month PFS in patients with PROC. Clinical trial information: NCT01196741.

Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells

“…Despite the frequent activation of Src, the Src family kinase inhibitor, dasatinib has shown limited activity as a single agent for recurrent HGSOC, with only 21% of patients progression-free after 6 months (42). Another Src family kinase inhibitor, saracatinib, evaluated in combination with chemotherapy for recurrent platinum-resistant ovarian cancer, showed no added clinical benefit (43). Interestingly, saracatinib monotherapy rapidly gives rise to MEK/MAPK bypass pathway activation and drug resistance in breast cancer xenografts (24;25).…”

Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines

“…Pharmacokinetic analysis showed that concurrent administration of dasatinib with paclitaxel did not significantly alter either dasatinib or paclitaxel drug concentrations [ 14 ]. Two randomized studies of another SRC inhibitor, saracatinib, with chemotherapy in ovarian cancer demonstrated no improvement in response rate or survival, but higher toxicity [ 22 , 23 ]. Therefore, the addition of dasatinib to chemotherapy is unlikely to be beneficial in an unselected patient population and there is a need to identify biomarkers that can be used to direct therapy.…”