Background: Many cancers are associated with DNA repair and cell cycle mutations that result in G1/S checkpoint deficiencies and high levels of endogenous damage and replication stress. This can lead to dependence on WEE1 kinase, which provides an important G2/M checkpoint, allowing repair of DNA damage prior to mitosis. AZD1775 is a highly selective, small-molecule WEE1 inhibitor being developed for the treatment (tx) of advanced solid tumors. It has previously shown single-agent activity in patients (pts) with BRCA-1/2 mutations (Do, JCO 2015). We described initial safety and efficacy of the dose escalation portion of an open Phase Ib study (NCT02482311) of AZD1775 in pts with refractory solid tumors, and a dose of AZD1775 175 mg PO BID was identified (submitted to AACR 2016). Here we describe the expansion portion of this study in 6 matched cohorts: BRCA-1/2-mutant and wildtype (WT) ovarian cancer (OvC); cyclin-E (CCNE1)-amplified and non-amplified triple-negative breast cancer (TNBC); and any of MYC/MYCL/MYCN-amplified and all non-amplified small-cell lung cancer (SCLC). The objective of this portion of the study is to evaluate the safety, tolerability, and efficacy of AZD1775 monotherapy in these cohorts. Methods: 140 pts will be enrolled in the expansion portion: 20 pts with recurrent BRCA-1/2 WT OvC following > 3 prior therapies, ≥ 20 BRCA-1/2 mutant OvC pts following failure of PARP inhibitor therapy, 50 with recurrent TNBC following > 2 therapies ( ≥ 15 with cyclin E (CCNE1) amplified TNBC); and 50 with SCLC following > 1 therapy ( ≥ 15 with any of MYC/MYCL/MYCN amplified SCLC). All pts must have measurable advanced solid tumors per RECIST, and adequate organ function. Pts will receive AZD1775 175 mg PO BID D1-3, 8-10 of a 21-day cycle. All pts will receive prophylactic antiemetics. Pts will be restaged every 2 cycles the first year, every 4 cycles thereafter, and continue until disease progression or intolerable toxicity. Tumor samples will be collected for correlative biomarker analysis. Clinical trial information: NCT02482311