A randomized double-blind placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with adavosertib in women with recurrent, platinum resistant epithelial ovarian cancer: A trial of the Princess Margaret, California, Chicago and Mayo Phase II Consortia.

Abstract

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

“…A recent randomised phase II study assessed the combination of AZD1775 and gemcitabine, versus gemcitabine monotherapy, in platinum resistant HGSOC [105]. Impressively, a survival benefit was observed, with median Overall Survival 11.5 months with combination treatment, compared to 7.2 months in the gemcitabine arm (Hazard Ratio 0.56, 95% Confidence Interval 0.34-0.92; p = 0.022).…”

Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors

“…Preliminary results from an open-label, four-arm, Phase II study of adavosertib plus four different types of chemotherapy regimens in patients with platinum-resistant ovarian cancer also suggested that adavosertib plus carboplatin shows promise in terms of efficacy [16]. Furthermore, a randomized Phase II study, also in women with platinumresistant ovarian cancer, has demonstrated that adavosertib and gemcitabine combination therapy improves treatment efficacy compared with gemcitabine alone [17].…”

WEE1 Inhibitor: Clinical Development

“…In addition, there was also a statistically significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95% CI 0.34-0.92, P=0.022) and increased number of patients with PR from 3 to 21% (p=0.02). Again, there was increased grade 3/4 AEs especially hematological toxicity including anemia (31 vs 18%), thrombocytopenia (31 vs 6%), and neutropenia (62 vs 30%) in adavosertib arm compared to placebo arm, respectively [13]. Most of the preclinical and clinical studies have been performed using WEE1 inhibitor from AstraZeneca, namely AZD1775 (MK1775 or adavosertib).…”

“…A double-blind randomized phase 2 trial showed that addition of adavosertib (175mg od on D1–2, D8–9, and D15–16) to gemcitabine (1000mg/m 2 IV D1, D8, and D15 in a 28-day cycle) (Table 1 ) improved PFS from 3.0 to 4.6 months (HR 0.56 (95% CI 0.35–0.90, p=0.015 Log rank) compared to placebo arm in patients with recurrent platinum-resistant/refractory high-grade serous ovarian cancer (HGSOC) [ 13 ](NCT02151292). In addition, there was also a statistically significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95% CI 0.34–0.92, P=0.022) and increased number of patients with PR from 3 to 21% (p=0.02).…”