Background: Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of Class IIa HDACs. SIK2 is overexpressed in 30% of ovarian cancers and associated with decreased progression-free survival (Ahmed et al., 2010). Treatment with GRN-300, an orally bioavailable small-molecule inhibitor of SIK2, was shown to improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice (Zhou et al., 2017). Methods: Part 1 of the study will evaluate the safety, MTD, RP2D (Recommended Phase 2 Dose), and PK of daily GRN-300 monotherapy. For the dose-escalation enrollment of patients with advanced solid tumors of any histology, four dose levels of GRN-300 are planned: 100, 200, 300, and 400 mg BID. Subsequently, GRN-300 will be administered at the determined RP2D in an ovarian cancer expansion cohort. Part 2 will evaluate the safety, PK, and preliminary clinical activity in an open-label study of the combination of GRN-300 and paclitaxel weekly x3. Paclitaxel will be administered in one of two different dosing levels: 60 mg/m2 initially, then dose escalated to 80 mg/m2. In the combination regimen, GRN-300 will be administered at the RP2D dose as determined in Part 1 of this study. The two dose findings will be conducted independently using the BOIN design (Liu 2015, Yuan 2016). Study drug may be administered per protocol for continuous 28-day cycles until disease progression, adverse events, or other criteria as described in the protocol. Tumor biopsies and blood plasma samples including peripheral blood mononuclear cells (PBMCs) will be collected for exploratory biomarker analysis to predict and to monitor responses to GRN-300 treatment. Major eligibility criteria At least 18 years of age. Recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer (advanced solid tumors of any other histology only for the monotherapy dose escalation enrollment in Part 1) In Part 2, diagnosis of recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer for which treatment with paclitaxel is indicated. Received at least one prior second-line treatment. The first 3 dose groups (100, 200, and 300 mg BID of GRN-300) have been completed without DLT and preliminary PK analysis indicate dose proportionality. Enrollment to dose group 4 (400 mg BID) began in February 2022. Clinical trial information: NCT04711161.