A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer.

Abstract

196 Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.

STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma

“…In combination with chemotherapeutic drugs, full-dose napabucasin (500 mg, twice daily) and paclitaxel has passed safety and tolerability tests and shown encouraging clinical responses in patients with different advanced solid tumors, including gastric and gastroesophageal junction (GEJ) adenocarcinoma [91], platinum-resistant ovarian cancer (PROC) [92], pancreatic ductal adenocarcinoma (PDAC) [93], triple-negative breast cancer (TNBC) [94] and other cancer types [90] in individual cohorts of a phase Ib/II trial (NCT01325441). Particularly, in the gastric and GEJ adenocarcinoma cohort, this combination has shown promising results in both taxane-naïve ( n = 16) and taxane-exposed patients ( n = 19), with DCR being 75% versus 68% [91].…”

“…So far, napabucasin is the only STAT3-targeted drug that has been clinically studied in combination with other therapies. As discussed before, early-phase trials have revealed promising antitumor efficacy when combining napabucasin with standard chemodrugs including paclitaxel [90,91,92,93,94], gemcitabine plus nab-paclitaxel [99] and FOLFIRI with or without bevacizumab [97,98], as well as another targeted drug panitumumab [95,96] in several solid malignancies. Preclinical results have also suggested that napabucasin may synergize with paclitaxel to overcome drug resistance [86] and sensitize CRC to immune checkpoint inhibitors in syngeneic tumor models [124].…”

Novel STAT 3 inhibitors for treating gastric cancer

“…A second pancreatic study enrolling 41 patients, all of whom had received two prior lines of chemotherapy (including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin combination chemotherapy and gemcitabine/nab-paclitaxel), combined napabucasin with weekly paclitaxel. Here, of 31 evaluable patients, the disease control rate was 48% [43]. In colorectal cancer, a phase Ib study of napabucasin in combination with 5-fluorouracil, leucovorin and irinotecan combination chemotherapy (FOLFIRI) with and without bevacizumab showed that in 18 heavily pretreated patients (10 of whom had previously progressed on FOLFIRI), disease control was observed in 94% of the 16 evaluable patients [44].…”

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

“…Napabucasin (BBI608) is a small molecule inhibitor of STAT3 evaluated for the treatment of several cancers including platinum-resistant ovarian cancer, gastric adenocarcinoma, and pancreatic cancer [99]. A phase Ib/II study tested napabucasin in combination with nab-paclitaxel for pre-treated metastatic PDAC [100]. Results were promising with a response rate of 7%, and a disease control rate of 52% in evaluable patients (n = 31).…”