BBI608-503-103HCC: A phase Ib/II clinical study of napabucasin (BBI608) in combination with sorafenib or amcasertib (BBI503) in combination with sorafenib (Sor) in adult patients with hepatocellular carcinoma (HCC).

Abstract

4077 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Amcasertib targets multiple serine threonine stemness kinases and inhibits Nanog and other cancer stemness pathways. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with sorafenib. Methods: A phase Ib/II open-label, multi-center study in adult patients with advanced HCC who have not received prior systemic chemotherapy was performed to determine the safety, tolerability, and recommended Phase II dose (RP2D) ,according to the criteria for DLT and for dose-escalation of Napabucasin (Arm 1), administered at 160 mg BID (dose level I) and at 240 mg BID (dose level II) in combination with sorafenib and of Amcasertib (Arm 2), administered at 100 mg QD (dose level I) and at 200 mg QD (dose level II) in combination with sorafenib. Results: 20 pts were enrolled, 10 in Arm 1 and 10 in Arm 2. 12 patients were evaluable for DLT determination; 2 pts d/c prior to starting protocol treatment; 11 pts received evaluation by RECIST, 6 pts in Arm 1 and 5 pts in Arm 2. The safety profile was consistent with that of each agent as monotherapy and most common AEs were attributed to (Sor) and included rash, PPE, grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. No signs of drug-drug interactions were observed in pharmacokinetics. Among all patients who received RECIST evaluation, Disease Control Rate (DCR=CR+PR+SD) for Arm 1 was 100% (6/6pts) and 100% (5/5pts) for Arm 2. DCR in ITT Arm 1 population was 67% and 50% in Arm 2. Median OS is not yet reached. Conclusions: In this phase Ib study, RP2D were determined for napabucasin and amcasertib to be safely combined with sorafenib at full dose, showing encouraging anti-tumor activity in patients with HCC who have not received prior systemic chemotherapy. A randomized phase II is schedule to start. Clinical trial information: NCD02279719. [Table: see text]

Napabucasin Drug‐Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers

“… 1 , 3 In vitro assays have shown that NQO1‐expressing cancer cells are more sensitive to napabucasin. 1 , 3 Several clinical trials have investigated napabucasin as a single agent or in combination with several anticancer treatments (data reported in congress abstracts 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 or articles 16 , 17 , 18 , 19 ). A phase 3 study of napabucasin in combination with 5‐fluorouracil, leucovorin, and irinotecan vs 5‐fluorouracil, leucovorin, and irinotecan alone in patients with previously treated metastatic colorectal cancer (NCT02753127) is ongoing.…”

Study of sex-biased differences in genomic profiles in East Asian hepatocellular carcinoma

“…One notable example is Napabucasin (BBI608), a first-in-class cancer stemness inhibitor that suppresses cancer stemness by targeting STAT3-driven gene transcription [ 60 ]. A phase Ib/II clinical trial study in patients with HCC demonstrated encouraging anti-tumor activity and acceptable safety profile of napabucasin when combined with sorafenib [ 61 ].…”

Therapeutic Targeting Strategies of Cancer Stem Cells in Gastrointestinal Malignancies

“…In Arm 1, the DCR was observed in all of the evaluable patients (6/6) (DCR was 67% in the ITT population). Median PFS was 24.9 weeks in the ITT population and 32.6 weeks in the evaluable patients [26].…”