Abstract CT012: Open-label, multicenter, Phase Ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: Expansion cohorts
Authors: Bauer Todd M. , Moore Kathleen , Rader Janet S. , Simpkins Fiona , Mita Alain , Beck J Thaddeus , Hart Lowell , Chu Quincy , Oza Amit , Tinker Anna V. , So Karen , Imedio Esteban Rodrigo , Kumar Sanjeev , Mugundu Ganesh M. , Jenkins Suzanne , Chmielecki Juliann , Jones Suzanne , Spigel David R. , Fu Siqing 
Published: August 2019

Abstract
Background
Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. Previously we reported safety and efficacy of adavosertib monotherapy in patients (pts) with advanced solid tumors (NCT02482311; Bauer et al Cancer Res 2016;76[14 Suppl]); here we report safety and efficacy data from expansion cohorts based on tumor type.
Methods
A total of 80 pts grouped into 6 biomarker-matched cohorts (Table) received adavosertib (175 mg PO bid; days 1–3 and 8–10 per 21-day cycle). Eligible pts had: confirmed diagnosis of ovarian cancer (OC), small-cell lung cancer (SCLC) or triple-negative breast cancer (TNBC); prior treatment (Tx) for metastatic/recurrent disease (≥3 prior Tx for pts with BRCAwt OC; progression following PARPi Tx for BRCA1/2m OC pts; ≤1 chemotherapy-based Tx for SCLC and ≥1 chemotherapy-based Tx for TNBC); measurable disease. Primary objective assessments: ORR; DCR; PFS (RECIST v1.1); safety. Tumor assessments were performed every 6 weeks in year 1 and every 12 weeks thereafter until disease progression or intolerable toxicity. Blood and tumor samples were collected for correlative biomarker and pharmacokinetic (PK) analyses.
Results
Median total Tx duration was 2.4 months. Most frequently reported adverse events (AEs) were diarrhea (61%), nausea (50%) and fatigue (43%). Most commonly reported grade ≥3 AEs were diarrhea (7.5%), nausea, fatigue and small intestine obstruction (6%). AEs leading to dose interruptions (22.5%), reductions (11.3%) or discontinuations (16.3%) were reported. The study showed preliminary antitumor activity, particularly in BRCAwt as well as PARPi-failure BRCAm OC pts (Table). PK and biomarker analyses will be presented.
Conclusions
Adavosertib was generally well tolerated and showed preliminary antitumor activity. DCR was modest across all patient cohorts.
Patient cohortParameterOC, BRCAwtOC, BRCAm, PARPi failureTNBC, CCNE1/MYC/MYCL1/ MYCN non-amplifiedTNBC, CCNE1/MYC/MYCL1/ MYCN amplifiedSCLC, CCNE1/MYC/MYCL1/ MYCN non-amplifiedSCLC, CCNE1/MYC/MYCL1/MYCN amplifiedTotalPatients who received treatment, n163013612380Median age, years (range)62.5 (47–83)59.5 (44–73)58.0 (35–81)54.0 (43–78)64.5 (54–74)63.0 (56–69)60.0(35–83)Prior regimens, n (%) 1 2 3 4 5 6 &gt;6 Median0 0 1 (6) 3 (19) 2 (13) 1 (6) 9 (56) 70 0 2 (7) 3 (10) 7 (23) 8 (27) 10 (33) 60 3 (23) 2 (15) 1 (8) 2 (15) 3 (23) 2 (15) 50 0 1 (17) 2 (33) 2 (33) 1 (17) 0 4.53 (25) 5 (42) 3 (25) 0 1 (8) 0 0 20 1 (33) 2 (67) 0 0 0 0 33 (4) 9 (11) 11 (14) 9 (11) 14 (18) 13 (16) 21 (26) 5ECOG PS, n (%) 0 18 (50) 8 (50)10 (33) 20 (67)4 (31) 9 (69)1 (17) 5 (83)2 (17) 10 (83)1 (33) 2 (67)26 (33)54 (68)ORR, n (%) CR* PR* SD ≥5 weeks PD NE1 (6) 0 1 (6) 10 (63) 4 (25) 1 (6)1 (3) 0 1 (3) 22 (73) 5 (17) 2 (7)0 0 0 9 (69) 3 (23) 1 (8)0 0 0 3 (50) 3 (50) 01 (8) 0 1 (8) 3 (25) 7 (58) 1 (8)0 0 0 1 (33) 2 (67) 03 (4) 0 3 (4) 48 (60) 24 (30) 5 (6)DCR, n (%)†11 (69)23 (77)9 (69)3 (50)4 (33)1 (33)51 (64)Median PFS, months4.53.93.12.01.31.23.0*Confirmed CR/PR; †DCR determined by CR + PR + SD. BRCA1/2m, BRCA1 or BRCA2 mutated; BRCAwt, BRCA1 and BRCA2 wild type; CR, complete response; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; NE, not evaluable; ORR, objective response rate; PARPi, PARP inhibitor; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease
Citation Format: Todd M. Bauer, Kathleen Moore, Janet S. Rader, Fiona Simpkins, Alain Mita, J Thaddeus Beck, Lowell Hart, Quincy Chu, Amit Oza, Anna V. Tinker, Karen So, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Suzanne Jenkins, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Siqing Fu. Open-label, multicenter, Phase Ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: Expansion cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT012.