Greg Kennelty & Kelly Johnson

Napabucasin, a novel oral agent that targets the STAT3 pathway, is the most advanced new drug in clinical development designed specifically to attack cancer stem cells (CSCs), a subset of the total cancer cell population that is believed to drive tumor recurrence and metastasis even after cytotoxic therapy.

The investigational small molecule, also known as BBI608, is being evaluated in the phase III BRIGHTER trial as a second-line treatment for patients with gastric and gastroesophageal junction cancer who already have undergone platinum and fluoropyrimidine-based chemotherapy.

The study, which was launched in June 2014, is seeking to enroll 700 patients who experience clinical or radiologic disease progression during first-line treatment for unresectable or metastatic disease or &ge;6 months after finishing therapy.

Patients are randomized to receive either napabucasin at 480 mg twice daily plus paclitaxel or placebo plus paclitaxel. The primary endpoint is to assess overall survival during a 36-month time frame, while secondary endpoints include progression-free survival, objective response rate, disease control rate, and adverse events profile.

The rationale for pursuing napabucasin as an anticancer therapy has been established in preclinical and early-phase studies in which the drug demonstrated encouraging activity in refractory patients.

In a phase Ib/II study, a subset of patients who had received only one prior line of therapy and who had not received prior therapy with a taxane in the metastatic setting, the overall response rate (ORR) was 50% (3 of 6 patients) and the disease control rate (DCR) was 83% (4 of 6 patients).

In patients who had failed average >2 prior lines of  therapy and who had not previously received a taxane in the metastatic setting (n = 16), the ORR was 31% and DCR was 75%; median progression-free survival was 20.6 weeks and median overall survival was 39.3 weeks. The most common adverse events were grade 1/2 diarrhea, nausea, and abdominal pain.

By targeting STAT3, a transcription factor, napabucasin is believed to suppress stemness pathways including STAT3 and &beta;-catenin.

CSCs are important targets for anticancer therapy because of four key characteristics, according to a research summary by Boston Biomedical, the Cambridge, Massachusetts, biotechnology company that is developing the drug.

These characteristics include stemness, the capacity to self-renew and differentiate into cancer cells; aberrant signaling pathways; resistance to standard therapies; and the ability to promote tumor recurrence and metastasis.

Manish A. Shah, MD, a prominent researcher in the gastrointestinal cancer field who is helping to lead the BRIGHTER trial, discussed the ongoing research in an interview with

Manish, a medical oncologist, is the Bartlett Associate Professor of GI Oncology at Weill Cornell Medical Center at NewYork-Presbyterian Hospital.

Please provide an overview of the BRIGHTER trial and how it has developed since last year?

This is an important second-line study of chemotherapy with or without a novel STAT3 inhibitor, which works as a stem cell or a stemness inhibitor. Cancer stem cells are likely responsible for the development or recurrence and disease progression in patients with solid tumor malignancies, and for the first time we are now able to test agents that are really targeting the stemness phenotype. So the BRIGHTER study is a multicenter, multinational study and we are ahead of accrual with regard to meeting our endpoint. The total study is about 700 patients, and we are nearly half way there already.

What is the efficacy of BBI608 in gastric cancer?

There has been a phase I/II study that has been reported, at least in an abstract form.

What we see is that in the second- and third-line setting, we are seeing response rates that are quite favorable compared with Taxol alone on the order of 30% to 50%. There is hope that this is a new option that could be a positive.

Has there been any research as far as how this drug would fit in with current treatment options?

With more options that will be available, we need to think carefully about how best to line the treatments up in a way that patients get the most benefit. The other thing is to manage toxicities and things like that. One of the emerging ideas is that not all gastric cancers are the same. There are subtypes of gastric cancer that may benefit more from by certain treatment. The main aspect is to identify which cancers would be best treated by a PD-1 inhibitor, which cancers would be best treated by a stem cell inhibitor and how to sequence accordingly.

Have any concerning toxicities surfaced in the BRIGHTER trial?

The trial is ongoing and it&rsquo;s being monitored by a data safety monitoring board. No signals have been raised according to that. We do know that there are side effects from the pills itself and I know that the company is working on a new formulation of the pill.

What&rsquo;s next for the drug after the BRIGHTER trial?

Boston Biomedical is a very progressive company and they are looking at other ways to improve on BBI608. One option is to combine that stemness inhibitor with another stem cell inhibitor that they have in their pipeline to see if we can have dual blockade, and another one is to actually combine BBI608 with some of the PD-1 and PD-L1 inhibitors as well.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02178956.

Becerra C, Stephenson J, Jonker DJ, et al. Phase Ib/II study of cancer stem cell (CSC) inhibitor BBI608 combined with paclitaxel in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma

Shah MA, Muro K, Shitara K, et al.  The BRIGHTER trial: a phase III randomized double-blind study of BBI608 + weekly paclitaxel versus placebo (PBO) + weekly paclitaxel in patients (pts) with pretreated advanced gastric and gastro-esophageal junction (GEJ) adenocarcinoma.

Boston Biomedical. Cancer stem cells. http://bostonbiomedical.com/cancer-stem-cells/. Accessed January 29, 2016.

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Manish A. Shah, MD, a prominent researcher in the gastrointestinal cancer field who is helping to lead the BRIGHTER trial, discussed the ongoing research in an interview with Targeted Oncology.

Greg Kennelty & Kelly Johnson | Authors

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Targeting Cancer Stem Cells in the BRIGHTER Trial: A Q&A With Manish A. Shah, MD