First-in-class "Stemness" Inhibitor Napabucasin Shows Promise in Advanced Ovarian Cancer

Agustin A. Garcia, MD

Napabucasin (BBI-608, BB608) is a first-in-class cancer “stemness” inhibitor that targets the STAT3 pathway, has acceptable toxicity, and shows some antitumor activity in combination with paclitaxel in platinum-resistant ovarian cancer. Results of an early phase trial were presented at a poster session at the 2016 ASCO Annual Meeting.

The objectives of this trial (NCT01325441) were to evaluate the preliminary antitumor activity of napabucasin in combination with weekly paclitaxel in patients with advanced epithelial ovarian, fallopian, or peritoneal cancer that progressed on a prior taxane-based regimen and that was platinum resistant or refractory. Napabucasin previously showed reduction of p-STAT3 and the cancer stem cell marker CD44 as monotherapy and reduction of tumor volume in combination with paclitaxel in a human ovarian cancer xenograft model.

The recommended phase II dose for this combination was determined in an open-label phase Ib dose-escalation study; following that, phase II enrolled patients to disease-specific cohorts. Napabucasin was administered at 500 mg twice a day (in 125 mg capsules) or at 480 mg twice a day (in 80 mg capsules). Paclitaxel was administered intravenously once weekly at a dose of 80 mg/m²on 3 of every 4 weeks. The objective tumor response was assessed per RECIST v1.1.

There were 56 women enrolled who had received a median of 4 prior lines of therapy, including paclitaxel only (92%), docetaxel only (4%), or both (4%). Treatment was tolerated without dose-limiting toxicity or unexpected adverse events (AE). Grade 3 AEs included rapidly-reversible diarrhea (17.9%), abdominal pain (7%.1), vomiting (5.4%), nausea (3.6%), dehydration, hyponatremia, ascites, anemia, and fatigue (<4% each); 80% of patients with grade 3 AEs continued on treatment at a reduced dose.

The disease control rate (stable disease or at least 8 weeks of partial or complete response) was 48% in all patients, 71% in 38 patients evaluated per protocol, and 64% in the 11 patients who had received only 1 or 2 prior treatments.

In all patients, the response rate was 20%, median progression-free survival (PFS) was 3.7 months, and median overall survival (OS) was 9.9 months. Median time to response in patients with objective responses (n = 15) was 2.1 months; the duration of response was 3.9 months.

CA-125 levels were measured at baseline and at least once during the study in 48 patients. In the 15 patients with objective responses, all of them had reduced levels of CA-125; the average maximum reduction (86%) was reached by cycle 4.6. Of the 12 patients with stable disease, 7 had reductions in CA-125 levels; the average maximum reduction (56%) was reached by cycle 3.3. Of the 21 patients with progressive disease, 6 had CA-125 reduction; the average maximum reduction (38%) was reached by cycle 2.2.

The study authors concluded that napabucasin can be safely combined with weekly paclitaxel at a dose of 80 mg/m²in heavily pretreated patients with platinum-resistant ovarian cancer. Complete and partial response, durable disease control, prolonged PFS and OS, and significant decreases in CA-125 tumor marker levels were observed in this population, warranting further clinical study.

Lead author of the study, Agustin A. Garcia, MD, Los Angeles County Hospital/University of Southern California, Los Angeles, CA, said, &ldquo;Napabucasin, or BBI, has a fairly unique mechanism of action as a stem cell inhibitor. The target is the stem pathway in ovarian cancer. It has some activity in preclinical models as a single agent, but particularly enhanced activity when you combine it with chemotherapy such as paclitaxel.&rdquo;

He noted that in this trial, the 20% response rate was encouraging in these very heavily pretreated patients, with a &ldquo;pretty prolonged and impressive clinical benefit. The vast majority of patients had some clinical benefit. I think it is a drug worth further exploring in ovarian cancer.&rdquo; He was not sure in what line of therapy and in combination with what other agents napabucasin might ultimately be used.

Concerning the future development of napabucasin, Matthew Hitron, MD, Boston Biomedical, Inc., Cambridge, MA, a coauthor of the study, commented, &ldquo;BBI608, or napabucasin, is at the point where we are considering several pivotal trial indications, including ovarian cancer. The design of the study is under discussion with several investigators and will likely involve BBI608 combined with weekly paclitaxel and in the platinum resistant setting, but the specific endpoints and the setting are still to be determined.&rdquo;

Garcia AA, Hays JL, Cote MC, et al. A phase Ib/II study of cancer stemness inhibitor napabucasin (BB608) combined with weekly paclitaxel in platinum-resistant ovarian cancer.J Clin Oncol34, 2016 (suppl; abstr 5578).