First-in-Class Cancer Stemness Inhibitor Shows Promising Results in Advanced Colorectal Cancer


The latest results from an open-label, phase Ib study of the STAT3 inhibitor BBI-608 (napabucasin) with a standard chemotherapy (FOLFIRI with or without bevacizumab) in the treatment of advanced colorectal cancer, have been presented at the ASCO 2016 Gastrointestinal Symposium. Evidence of antitumor activity and a favorable safety profile were seen in phase I studies.

First-in-Class Cancer Stemness Inhibitor Advanced Colorectal Cancer

First-in-Class Cancer Stemness Inhibitor Advanced Colorectal Cancer

Joleen M. Hubbard, MD

The latest results from an open-label, phase Ib study of the STAT3 inhibitor BBI-608 (napabucasin) with a standard chemotherapy (FOLFIRI with or without bevacizumab) in the treatment of advanced colorectal cancer, have been presented at the ASCO 2016 Gastrointestinal Symposium. Evidence of antitumor activity and a favorable safety profile were seen in phase I studies.1-3

"BBI-608 is a cancer stem cell inhibitor targeting the 'stemness' of the cancer cell, meaning it [the drug] aims to target processes that the cancer cell uses to resist cancer treatments. This particular drug targets the STAT3 and beta-catenin pathways, felt to play a critical role in malignant growth and development of metastases," explained Joleen M. Hubbard, MD, assistant professor of oncology at the Mayo Clinic in Minnesota who presented the data.

Cancer stem cells are hypermalignant and consequently highly tumorigenic and metastatic. They have been isolated from many different cancer types and are found to be resistant to conventional chemotherapy and radiation. Stemness genes have been shown to be induced by such treatments and consequently stemness-high cancer cells remain after the completion of therapies and are considered to be responsible for relapse.

Using gene-silencing techniques, STAT3 was found to be important for cancer stemness, and the molecule BBI-608 was found to block transcription of genes driven by STAT3. Subsequent in vitro and in vivo work confirmed BBI-608 can block development of or kill stemness-high cancer cells, making it a promising candidate for clinical development.4Relevant to this study, it demonstrated strong synergy with 5 fluorouracil and irinotecan in experimental mouse models of colon cancer.3

The trial, sponsored by Boston Biomedical Inc, recruited patients with advanced unresectable, metastatic or recurrent colorectal carcinoma for whom a number of standard chemotherapies would be acceptable as determined by the investigator. The study was conducted at multiple sites in the US and one in Canada (NCT02024607).

The primary objective of the study was to evaluate the safety, tolerability, and antitumor activity of BBI-608 in combination with FOLFIRI, with and without bevacizumab, in patients with advanced colorectal cancer. Secondary objectives included the pharmacokinetics and pharmacodynamics of BBI-608 and assess the antitumor activity of BBI-608 and FOLFIRI, with and without bevacizumab.3


The study enrolled 18 patients who were heavily pretreated. Of these, 10 had received and progressed on FOLFIRI and all patients had received an average of more than three previous courses of therapy. The patients had a Karnofsky performance status ≥70% and adequate bone marrow, hepatic, and renal function. Seventeen patients were evaluable for response, 9 of them received BBI-608 in combination with FOLFIRI and bevacizumab and 8 received BBI-608 with FOLFIRI alone. Objective tumor responses were assessed every 8 weeks. The doses are shown inTable 1., and the regimens were administered biweekly until progression of disease, unacceptable toxicity, or other specified discontinuation criterion was met.1,2,3

"It is felt that by targeting the STAT3 and beta-catenin pathway, BBI-608 may help prevent the resistance that develops with FOLFIRI +/- bevacizumab treatment. Synergy has also been seen with other chemotherapy regimens, supporting this theory," said Hubbard. The study was conducted to confirm the recommended phase II dose for BBI-608.

Table 1.Doses and Regimens in BBI-608 Phase 1B Study in Advanced Colorectal Cancer


240 mg BID


5-FU400 mg/m2bolus, irinotecan 180 mg/m2, leucoverin 400 mg/m2infusion


5 mg/kg

Data were available for 17 of the patients. The most common AEs are shown inTable 2.and investigators encountered no new AEs, no dose limiting toxicities, and noted that the safety profile was similar to that experienced when each regimen was used as monotherapy.1-3

Table 2.Most Common Adverse Effects in Phase IB Study of BBI-608 in Advanced Colorectal Cancer

Most Common Adverse Events

Grade 1, grade 2 diarrhea

Abdominal pain




There were several grade 3 AEs related to protocol therapy namely diarrhea (3 patients), fatigue (2 patients) and dehydration (1 patient). Dose reduction and/or antidiarrheal medications ensured resolution of all AEs.1-3


Prolonged disease control for more than 24 weeks was achieved in &ge;50% of patients, (59%, 10/17 evaluable patients) or (56%, 10/18 intent-to-treat patients) Partial response (PR) or stable disease (SD) was achieved by 94% (16/17 of evaluable patients). The PRs (2) were 44% and 33% regression by Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria). The majority (13/14) of patients with SD had tumor regression <25%. For the 17 evaluable patients, the median progression-free survival was 5.56 months. No significant pharmacokinetic interactions were noted.1-3

The study authors conclude that BBI-608 at 240 mg bid combined with FOLFIRI with or without bevacizumab is safe and shows anticancer activity even in patients who previously failed on FOLFIRI therapy. The dose of 240 mg BID is now considered to be the recommended dose of BBI-608 when used with FOLFIRI, with or without bevacizumab, in further studies.1-3

Commenting on future data and development for BBI-608, Hubbard stated, "In other arms of this phase Ib study, BBI-608 is being studied with other combinations of gastrointestinal cancer treatment including FOLFOX, FOLFOX + bevacizumab, CAPOX, and regorafenib. It's also being studied in combination with chemotherapy for pancreatic cancer, as well as chemotherapy for gastric cancer."

Reflecting further on the potential of BBI-608, Axel Grothey, MD, professor of oncology at the Mayo Clinic and coauthor of the abstract and poster, said in a press release, "These clinical studies of napabucasin in advanced gastroenterological cancers, including the presentation of data in refractory colorectal cancer specifically, show encouraging clinical activity by targeting cancer stem cell pathways that contribute to cancer recurrence, metastases, and resistance to therapies. I look forward to the further investigation of this innovative approach to cancer treatment in additional clinical studies."2


  1. Hubbard JM, O&rsquo;Neil BH, Jonker DJ et al. Phase 1b study of cancer stem cell (CSC) pathway inhibitor BBI-608 administered in combination with FOLFIRI with and without bevacizumab (Bev) in patients (pts) with advanced colorectal cancer.J Clin Oncol. 2016;34 (suppl 4S; abstr569)
  2. Accessed January 25, 2016.
  3. Accessed January 25, 2016.
  4. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness.Proc Natl Acad Sci U S A. 2015;112(6):1839-1844.
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