A phase 1 study of the SYK inhibitor fostamatinib and weekly paclitaxel for recurrent platinum-resistant ovarian cancer.
Authors: Gaillard Stephanie , Wilkinson Mary , Martin Lainie P. , Deery Amy , Langsdale Amanda , Bayable Asnakech , Zahurak Marianna , Huang Peng , Armstrong Deborah Kay , Shih Ie-Ming , Wang Tian-Li 
Published: June 2023

5574 Background: Response to chemotherapy in patients (pts) with recurrent platinum-resistant ovarian cancer (PROC) is generally < 15%. Spleen tyrosine kinase (SYK) is overexpressed in PROC and is a key mediator of paclitaxel resistance in ovarian cancer cells. Fostamatinib (Fos), an orally available inhibitor of SYK, is currently FDA approved for the treatment of idiopathic thrombocytopenic purpura. The active form of Fos (R406) was shown to synergistically enhance taxane-mediated cytotoxicity in preclinical ovarian cancer models. This phase 1 study aimed to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Fos when combined with standard weekly paclitaxel (wPac) for pts with PROC. Methods: Pts with PROC, defined as progression ≤6 months of last platinum, were eligible. A modified toxicity probability interval (mTPI) dose escalation design was used to determine the MTD/RP2D and response was assessed using RECISTv1.1 criteria. All pts received paclitaxel (wPac) 80mg/m2 intravenously on Days 1, 8, and 15, of a 28-day cycle. Fos was administered orally twice a day (BID) on a continuous schedule. Three dose levels (DL) were planned: DL1 - 100mg, DL2 - 150mg, and DL3 - 200mg. MTD was determined based on cycle 1 dose-limiting toxicities (DLTs) and responses were assessed every 2 cycles. A dose expansion cohort to further assess adverse events (AEs) and tolerability was performed. Results: 27 eligible pts, median age 62 years (range 35-79 years) with high-grade serous (n = 18), clear cell (n = 4), carcinosarcoma (n = 3), or other (n = 2) histology were treated at 3 centers. Twelve pts were treated in the dose escalation cohort (DL1 = 6, DL2 = 3, DL3 = 3). Common AEs at least possibly attributed to Fos, wPac, or both included diarrhea (70%), fatigue (52%), anemia (44%), neutropenia (33%), nausea (33%), hypertension (30%), and dysgeusia (30%). Treatment-emergent grade 3-4 AEs were neutropenia (37%), anemia (26%), and thromboembolic event (22%). During DL1, updated toxicity management guidelines not consistent with the original protocol were released and 2 of the 3 pts treated prior to the amendment were not considered evaluable for DLT. Thus 3 more pts were enrolled to DL1 after the amendment. Of the 10 pts evaluable for DLT in dose escalation, no DLTs were reported on any of the 3 DLs (DL1 = 4, DL2 = 3, DL3 = 3). DL3 was selected for dose expansion. One of 15 pts in the dose expansion cohort had a DLT (neutropenia) and one patient had a grade 5 infection. Of 18 pts treated at DL3, 7 (39%) had partial or complete response (95% CI: 17.3, 64.3%). Overall, 27 patients received a median of 3 cycles (range 0-10). Analysis of pharmacokinetic and correlative molecular studies of target expression are ongoing. Conclusions: The RP2D of Fos will be 200 mg orally BID when combined with wPac. AE profile of the combination was as expected and the combination demonstrated promising efficacy in pts with recurrent PROC. Clinical trial information: NCT03246074 .