BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).

Abstract

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

“…It is also being trialed in lung, advanced pancreatic, and mismatch repair-deficient colorectal cancers in combination with the anti-PD-L1 checkpoint inhibitor, Durvalumab (NCT02983578); in advanced solid tumors in combination with Durvalumab and chemotherapy (NCT03421353); and, in treatment-refractory non-Hodgkin's lymphoma in combination with acalabrutinib (NCT03527147), with no results reported at this time. Napabucasin, which inhibits STAT3-mediated transcription of target genes that regulate stemness, such as Nanog, is in phase III trial for patients with metastatic colorectal cancer in combination with the trichemotherapeutic, FOLFIRI (NCT03522649), and metastatic pancreatic adenocarcinoma in combination with nab-paclitaxel and gemcitabine (NCT02993731), along with several other phase I studies in other cancers, with positive patient outcomes being associated with safety and tolerance already reported in several solid tumor types [214][215][216]. Napabucasin has been demonstrated to sensitize tumor cells to checkpoint inhibition and it has been linked to high tumor infiltration of CD8 + T cells in mice bearing 4T1 mammary tumors [217], with similar results being reported in mesothelioma [218].…”

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.…”

The Anticancer Effect of Napabucasin (BBI608), a Natural Naphthoquinone

“…Obtained from patients with AML ex vivo, data showed that napabucasin is highly active against diverse AML cell lines in the primary patient sample with ages from 21 to 83, and the younger patients (<60 years old) had a median EC50 of 4.52 ± 4.26 µmol/L compared to older people (≥60 years old) with 6.84 ± 3.66 µmol/L [19]. A phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temo-zolomide (TMZ) at full dose, and the disease control rate was observed in five patients (55.5%), of whom four achieved PR (44.4%), and one achieved SD (11.1%), showing encouraging antitumor activity in patients with recurrent glioblastoma [48]. Not only with TMZ, napabucasin can also be safely combined with weekly paclitaxel (NCT01325441) with acceptable tolerability in patients with heavily pretreated platinum-resistant ovarian cancer (PROC), and in 56 patients, DCR was 48%, ORR was 18%, median progression-free survival was 15 weeks, and median overall survival was 38 weeks [34].…”