A phase 1b study of napabucasin plus weekly paclitaxel in patients with advanced thymoma and thymic carcinoma.
e20001 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity of napabucasin plus paclitaxel was observed in pre-clinical and early clinical testing. The STAT3 pathway is considered important in thymic carcinoma and thymoma, rare cancers with few treatment options. In 1st line, the objective response rate (ORR, partial response [PR] + complete response [CR] per RECIST) with carboplatin-paclitaxel was 22% in thymic carcinoma and 43% in thymoma (Gemma, 2011). A phase 1b cohort was established to evaluate safety and preliminary signs of activity of napabucasin plus paclitaxel in these patients (pts). Methods: Pts with previously-treated advanced thymoma or thymic carcinoma were enrolled with napabucasin (240 - 480 mg orally twice daily) plus paclitaxel (80 mg/m2 IV weekly for 3 of every 4 weeks). Adverse events were evaluated using CTCAE v4.03 and tumor assessments were obtained every 8 wks per RECIST 1.1. Results: A total of 9 pts (thymic carcinoma = 5, thymoma = 4) with a median 3 prior lines of systemic therapy were enrolled. In thymic carcinoma, the starting napabucasin dose was 480 mg BID (n = 2), and 240 mg BID (n = 3). Treatment was well tolerated and 1 pt required dose-reduction. There were no grade 3 AEs reported. As of data cut-off, 3 pts are off-study with progression and 2 remain on treatment. PRs were observed in 4 of 5 pts (ORR = 80%) and the median time on treatment is > 7.0 mo. In thymoma, 4 pts received napabucasin 240 mg BID. AEs included grade 3 diarrhea and dehydration in 1 pt. As of data cut-off, 1 pt was off-study with progression, 2 died (perforated bowel; autoimmune myocarditis secondary to Issac’s syndrome), and 1 pt remains on treatment. PR was observed in 1 pt (ORR 25%). Conclusions: Napabucasin plus weekly paclitaxel has demonstrated clinical safety and encouraging signs of anti-tumor activity in patients with advanced thymic carcinoma and thymoma. Further clinical evaluation of the combination regimen is warranted in this population. Clinical trial information: NCT01325441.