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4 4 4 i i DD . 4 4 4 ij D8 D8 D8 D8 & & & $ J & & & J & & & Napabucasin (BBI-608) Cancer Stemness Inhibitor
Everyone For metastatic patients there is a helpful development. The cancer stemness inhibitor Napabucasin (BBI-608) performed favorably in a Phase 1b/2 clinical trial when combined with gemcitabine (gem) and nab-paclitaxel (nabPTX) Among 66 (Intent To Treat) patients, the Disease Control Rate was 77% (51 patients), with 2 Complete Responses (3%) and 28 Partial Responses (42%). Maturing median progression free survival and overall survival (OS) in ITT pts was >7.1 and >10.7 months, respectively. A Complete Response (absence of disease) is a very usual and welcome event. The following documents give details: HYPERLINK "http://jaxelection.altervista.org/pancreatic/NapabucasinBBI-608.doc" http://jaxelection.altervista.org/pancreatic/NapabucasinBBI-608.doc HYPERLINK "http://jaxelection.altervista.org/pancreatic/NapabucasinBBI-608ASCO2017_4106.pdf" http://jaxelection.altervista.org/pancreatic/NapabucasinBBI-608ASCO2017_4106.pdf The study included both therapy nave patient and those having 1-2 prior therapies. We dont know which of the two fared better. To be eligible for the Phase 1b trial (link below), the patient may have had two prior systemic therapies. For the Phase 3 trial, the patient must not have previously received chemotherapy or any investigational agent. There are more limitations, so study the eligibility criteria carefully. The Phase 1b/2 trial is still open at 12 sites. It is non-randomized, so everyone receives the therapy. Enrollment was initially 250, but currently available berths are probably less than 100. See HYPERLINK "https://clinicaltrials.gov/show/NCT02231723" https://clinicaltrials.gov/show/NCT02231723 Also starting is a Phase 3 trial at 24 sites including Australia, with enrollment of 1,132. It is randomized, so only about half of patients receive the experimental agent. See HYPERLINK "https://clinicaltrials.gov/show/NCT02993731" https://clinicaltrials.gov/show/NCT02993731 Both trials meet the definition of prudent choices, since, at minimum, everyone receives standard therapy, either Nab-Paclitaxel + Gemcitabine or FOLFIRI or a MM-398 (a form of Irinotecan) combination. Of course, there is no cure with the exception of resection (surgery), and surgery does not guarantee cure. The objective is to get the patient resectable, or, if not that, to buy time until the next helpful therapy comes along. PhilipJax
A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts)
HYPERLINK "http://ascopubs.org/author/Bekaii-Saab%2C+Tanios+S" Tanios S. Bekaii-Saab HYPERLINK "javascript:popRef('A685445')" , HYPERLINK "http://ascopubs.org/author/Starodub%2C+Alexander" Alexander Starodub HYPERLINK "javascript:popRef('A685448')" , HYPERLINK "http://ascopubs.org/author/El-Rayes%2C+Bassel+F" Bassel F. El-Rayes HYPERLINK "javascript:popRef('A685453')" , HYPERLINK "http://ascopubs.org/author/O%27Neil%2C+Bert+H" Bert H. O'Neil HYPERLINK "javascript:popRef('A685456')" , HYPERLINK "http://ascopubs.org/author/Shahda%2C+Safi" Safi Shahda HYPERLINK "javascript:popRef('A685459')" , HYPERLINK "http://ascopubs.org/author/Ciombor%2C+Kristen+Keon" Kristen Keon Ciombor HYPERLINK "javascript:popRef('A685463')" , ... HYPERLINK "http://ascopubs.org/author/Noonan%2C+Anne+M" Anne M. Noonan HYPERLINK "javascript:popRef('A685469')" , HYPERLINK "http://ascopubs.org/author/Hanna%2C+Wahid+Tewfik" Wahid Tewfik Hanna HYPERLINK "javascript:popRef('A685471')" , HYPERLINK "http://ascopubs.org/author/Sehdev%2C+Amikar" Amikar Sehdev HYPERLINK "javascript:popRef('A685478')" , HYPERLINK "http://ascopubs.org/author/Shaib%2C+Walid+Labib" Walid Labib Shaib HYPERLINK "javascript:popRef('A685481')" , HYPERLINK "http://ascopubs.org/author/Mikhail%2C+Sameh" Sameh Mikhail HYPERLINK "javascript:popRef('A685503')" , HYPERLINK "http://ascopubs.org/author/Neki%2C+Anterpreet+S" Anterpreet S. Neki HYPERLINK "javascript:popRef('A685506')" , HYPERLINK "http://ascopubs.org/author/Oh%2C+Cindy" Cindy Oh HYPERLINK "javascript:popRef('A685509')" , HYPERLINK "http://ascopubs.org/author/Li%2C+Youzhi" Youzhi Li HYPERLINK "javascript:popRef('A685516')" , HYPERLINK "http://ascopubs.org/author/Li%2C+Wei" Wei Li HYPERLINK "javascript:popRef('A685524')" , HYPERLINK "http://ascopubs.org/author/Borodyansky%2C+Laura" Laura Borodyansky HYPERLINK "javascript:popRef('A685535')" , HYPERLINK "http://ascopubs.org/author/Li%2C+Chiang" Chiang Li HYPERLINK "javascript:popRef('A685542')"
DOI: 10.1200/JCO.2017.35.15_suppl.4106 Journal of Clinical Oncology 35, no.15_suppl (May 2017) 4106-4106 HYPERLINK "http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106" http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106
HYPERLINK "http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106" Abstract 4106
Background: Cancer stem cells are fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents.
Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m2 and gem 1000 mg/m2for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion.
Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-nave and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). [The CR was later revised to 2.] Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is >7.1 and >10.4 m, respectively.
Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. HYPERLINK "http://clinicaltrials.gov/show/NCT02231723" \t "_blank" Clinical trial information: NCT02231723.
SubsetDCR %
ORR %
OS-1 %EvaluableITTEvaluableITTAll92 (55/60)77 (55/71)45 (27/60)38 (27/71)N/AEnrolled > 1 yr ago93 (28/30)76 (28/37)53 (16/30)43 (16/37)48Enrolled >1 yr & Rxed >8 wks (27)93 (25)59 (16)56 HYPERLINK "http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106" \o "Facebook" HYPERLINK "http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106" \o "Twitter" HYPERLINK "http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106" \o "Email" \t "_blank" HYPERLINK "http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106"
ARTICLE CITATION
DOI: 10.1200/JCO.2017.35.15_suppl.4106 Journal of Clinical Oncology 35, no.15_suppl (May 2017) 4106-4106.
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Napabucasin Combination Shows Early Signs of Activity in Pancreatic Cancer
Angelica Welch Published Online: Tuesday, Jul 18, 2017 HYPERLINK "http://www.onclive.com/web-exclusives/napabucasin-combination-shows-early-signs-of-activity-in-pancreatic-cancer" http://www.onclive.com/web-exclusives/napabucasin-combination-shows-early-signs-of-activity-in-pancreatic-cancer
INCLUDEPICTURE "http://www.onclive.com/_media/_upload_image/Tanios-Bekaii-Saab.jpg" \* MERGEFORMATINET
Tanios Bekaii-Saab, MD
The first-in-class stemness inhibitor napabucasin (BBI-608) is being studied in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma. In results from the phase Ib/II study presented at the 19th World Congress on Gastrointestinal (GI) Cancer, this combination was shown to be safe and demonstrated encouraging signs of efficacy. The combination is currently being evaluated in a phase III study (NCT02993731). In an interview with OncLive at the GI Congress, lead author Tanios Bekaii-Saab, MD, professor of Medicine, Mayo Clinic, discussed the promise of napabucasin in a disease that lacks treatment options.
OncLive: Please provide an overview of your study.
Bekaii-Saab: At this years World Congress on Gastrointestinal Cancer, we presented the results of one of our studies that is looking at an agent called napabucasin. It is a first-in-class agent in terms of its targetswhich are thought to be very important in cancer stemness. So, the whole concept of cancer stem cells and stemnesswe know it is one of the major bad drivers in cancer because it makes it tough for chemotherapy to work effectively by creating these mechanisms of resistance. These are super resistant cells. The stemness factor is equally interesting because it is under pressure and a lot of the cancer cells can revert back to that stemness effect and even back to cancer stem cells, which essentially makes it very difficult to kill. The agent essentially targets pathways that are very relevant to stem cells and stemness. And preclinically, it seemed very promising when combined with various chemotherapies including taxanes and gemcitabine. So, with that rationale, we moved into this phase I/II study in pancreas cancer, combining napabucasin with gemcitabine and nab-paclitaxel. It enrolled about 66 patients total on the study. When we looked at the efficacy of combining napabucasin with gemcitabine and nab-paclitaxel, one of the most interesting findings was to see a response rate close to 55%. In a disease where you rarely see responses, the only example would be FOLFIRINOX in a highly-selected patient population, the response rate was 30% to 31%. So, this was a very promising signaland we had 2 complete responders, which you rarely see in this disease. There was a lot of interesting activity, particularly when we look at the maturing progression-free survival and overall survivalthey again look higher than what would be expected for this combination. Then, we looked at the safetywhich was one of the primary endpoints of the studyand it appears that napabucasin does not add to the toxicities of the chemotherapy regimen itself. There are additional GI toxicities, primarily diarrhea, but these tend to resolve within 24 hours after stopping the drug and readjusting, or can be managed with supportive care. It is a learning curve, like with all of these new first-in-class agents, you tend to learn with the first patient or two. We learned in our experience that it is actually easy to manage and most of these patients actually do extremely well on this treatment.
What are the next steps?
The cumulative knowledge from this study essentially led to the development of the phase III study that is ongoing, CanStem 111P, which is essentially a standard-of-care arm of gemcitabine plus nab-paclitaxel plus napabucasin versus gemcitabine and nab-paclitaxel. Very straightforwardstandard-of-care plus the experimental agent versus standard-of-care. It is 1132 patients, so a very large study, probably one of the largest in pancreas cancer, but it includes 2 interim analyses at the 50% and 80% marks, where we are going to check for fatality or for significant activity. And, of course, we continue to monitor safety. We have about 10% of the sites accruing, and will have more to follow.
Will napabucasin be used strictly in combination with chemotherapy?
It is very interesting. As a single agent, most of these agents in this group are very challenging. The whole concept of cancer stem cells and stemness is not just an isolated event, it is an event that happens even more so under pressureunder the pressure of chemotherapy. In most diseases, we expect this agent to work best when combined with chemotherapy, not as a single agent. When given alone in a study in colorectal cancer, it was interesting to see that when they actually enriched for the biomarker, which was prespecified, that hazard ratio was 0.21. So, as a single agent, it seems to have activity in a subgroup of patients.
When you look at it combined with chemo, you would expect that phosphorylated STAT pool would expand quite significantly under pressure from the chemo. I think that, certainly, there may be a biomarker analysis, and this is being done as an exploratory endpoint. But, I think it is a completely different story when you combine this agent with very active chemotherapy.
What do you hope community oncologists take away from these findings?
Two things. Onewe have a very promising signal, and it also a very safe regimen to use. Twothis is an opportunity to actually improve upon the activity of an established regimen. Also, it would be important to consider being part of the study, if you have the capacitywe are still looking for more sites. Or, look to see where the study is available and refer patients to this study. I strongly believe that this combination has a good shot to change the standard of care if it turns out to be positive. We will not know until the phase III is completedbut it is certainly promising enough to keep moving forward.
Bekaii-Saab, et al. A phase Ib/II study of cancer stemness inhibitor napabucasin in combination with gemcitabine (gem) & nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). Ann Oncol. 2017;28(suppl 3); LBA-002.
Expert Discusses Promising Early Signals of Napabucasin Combination in Pancreatic Cancer
Angelica Welch Published Online:5:31 PM, Wed July 19, 2017 HYPERLINK "http://www.targetedonc.com/news/expert-discusses-promising-early-signals-of-napabucasin-combination-in-pancreatic-cancer" http://www.targetedonc.com/news/expert-discusses-promising-early-signals-of-napabucasin-combination-in-pancreatic-cancer
Napabucasin (BBI-608), a first-in-class stemness inhibitor, is being studied in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma. In results from the phase Ib/II study presented at the 19th World Congress on Gastrointestinal (GI) Cancer, this combination was shown to be safe and demonstrated encouraging signs of efficacy. The combination is currently being evaluated in a phase III study (NCT02993731). In an interview with Targeted Oncology at the GI Congress, lead author Tanios Bekaii-Saab, MD, professor of Medicine, Mayo Clinic, discussed the promise of napabucasin in a disease that lacks treatment options. TARGETED ONCOLOGY: Please provide an overview of your study. Bekaii-Saab: At this years World Congress on Gastrointestinal Cancer, we presented the results of one of our studies that is looking at an agent called napabucasin. It is a first-in-class agent in terms of its targetswhich are thought to be very important in cancer stemness. So, the whole concept of cancer stem cells and stemnesswe know it is one of the major bad drivers in cancer because it makes it tough for chemotherapy to work effectively by creating these mechanisms of resistance. These are super resistant cells. The stemness factor is equally interesting because it is under pressure and a lot of the cancer cells can revert back to that stemness effect and even back to cancer stem cells, which essentially makes it very difficult to kill. The agent essentially targets pathways that are very relevant to stem cells and stemness. And preclinically, it seemed very promising when combined with various chemotherapies including taxanes and gemcitabine. So, with that rationale, we moved into this phase I/II study in pancreas cancer, combining napabucasin with gemcitabine and nab-paclitaxel. It enrolled about 66 patients total on the study. When we looked at the efficacy of combining napabucasin with gemcitabine and nab-paclitaxel, one of the most interesting findings was to see a response rate close to 55%. In a disease where you rarely see responses, the only example would be FOLFIRINOX in a highly-selected patient population, the response rate was 30% to 31%. So, this was a very promising signaland we had 2 complete responders, which you rarely see in this disease. There was a lot of interesting activity, particularly when we look at the maturing progression-free survival and overall survivalthey again look higher than what would be expected for this combination. Then, we looked at the safetywhich was one of the primary endpoints of the studyand it appears that napabucasin does not add to the toxicities of the chemotherapy regimen itself. There are additional GI toxicities, primarily diarrhea, but these tend to resolve within 24 hours after stopping the drug and readjusting, or can be managed with supportive care. It is a learning curve, like with all of these new first-in-class agents, you tend to learn with the first patient or two. We learned in our experience that it is actually easy to manage and most of these patients actually do extremely well on this treatment. TARGETED ONCOLOGY: What are the next steps? Bekaii-Saab: The cumulative knowledge from this study essentially led to the development of the phase III study that is ongoing, CanStem 111P, which is essentially a standard-of-care arm of gemcitabine plus nab-paclitaxel plus napabucasin versus gemcitabine and nab-paclitaxel. Very straightforwardstandard-of-care plus the experimental agent versus standard-of-care. It is 1132 patients, so a very large study, probably one of the largest in pancreas cancer, but it includes 2 interim analyses at the 50% and 80% marks, where we are going to check for fatality or for significant activity. And, of course, we continue to monitor safety. We have about 10% of the sites accruing, and will have more to follow. TARGETED ONCOLOGY: Will napabucasin be used strictly incombination with chemotherapy? Bekaii-Saab: It is very interesting. As a single agent, most of these agents in this group are very challenging. The whole concept of cancer stem cells and stemness is not just an isolated event, it is an event that happens even more so under pressure under the pressure of chemotherapy. In most diseases, we expect this agent to work best when combined with chemotherapy, not as a single agent. When given alone in a study in colorectal cancer, it was interesting to see that when they actually enriched for the biomarker, which was prespecified, that hazard ratio was 0.21. So, as a single agent, it seems to have activity in a subgroup of patients. When you look at it combined with chemo, you would expect that phosphorylated STAT pool would expand quite significantly under pressure from the chemo. I think that, certainly, there may be a biomarker analysis, and this is being done as an exploratory endpoint. But, I think it is a completely different story when you combine this agent with very active chemotherapy. TARGETED ONCOLOGY: What do you hope community oncologists take away from these findings? Bekaii-Saab: Two things. One we have a very promising signal, and it also a very safe regimen to use. Two this is an opportunity to actually improve upon the activity of an established regimen. Also, it would be important to consider being part of the study, if you have the capacitywe are still looking for more sites. Or, look to see where the study is available and refer patients to this study. I strongly believe that this combination has a good shot to change the standard of care if it turns out to be positive. We will not know until the phase III is completedbut it is certainly promising enough to keep moving forward.
Bekaii-Saab, et al. A phase Ib/II study of cancer stemness inhibitor napabucasin in combination with gemcitabine (gem) & nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). Ann Oncol. 2017;28(suppl 3); LBA-002.
First-in-Class Cancer Stemness Inhibitor Shows Promising Results in Advanced Colorectal Cancer
Colin G. Evans, PhD Published Online: 5:58 PM, Tue January 26, 2016 HYPERLINK "http://www.targetedonc.com/conference/2016-asco-gi/first-in-class-cancer-stemness-inhibitor-promising-results-advanced-colorectal-cancer" http://www.targetedonc.com/conference/2016-asco-gi/first-in-class-cancer-stemness-inhibitor-promising-results-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.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.4 Relevant 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 w e r e h e a v i l y p r e t r e a t e d . O f t h e s e , 1 0 h a d r e c e i v e d a n d p r o g r e s s e d o n F O L F I R I a n d a l l p a t i e n t s h a d r e c e i v e d a n a v e r a g e o f m o r e t h a n t h r e e p r e v i o u s c o u r s e s o f t h e r a p y . T h e p a t i e n t s h a d a K a r n o f s k y p e r f o r m a n c e s t a t u s e"7 0 % a n d a d e q u a t e b o n e m a r r o w , h e p a t i c , a nd 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 in Table 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
BBI-608240 mg BIDFOLFIRI5-FU400 mg/m2 bolus, irinotecan 180 mg/m2, leucoverin 400 mg/m2 infusionbevacizumab5 mg/kg Data were available for 17 of the patients. The most common AEs are shown in Table 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 EventsGrade 1, grade 2 diarrheaAbdominal painNauseaVomitingAnorexia There were several grade 3 AEs related to protocol therapy namely diarrhea (3 patients), fatigu e ( 2 p a t i e n t s ) a n d d e h y d r a t i o n ( 1 p a t i e n t ) . D o s e r e d u c t i o n a n d / o r a n t i d i a r r h e a l m e d i c a t i o n s e n s u r e d r e s o l u t i o n o f a l l A E s . 1 - 3
E f f i c a c y
P r o l o n g e d d i s e a s e c o n t r o l f o r m o r e t h a n 2 4 w e e k s w a s a c h i e v e d i n e"5 0 % o f p a t i e n t s , ( 5 9 % , 1 0 / 1 7 e v a l u a b l e p a t i e n t s ) o r ( 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
References
Hubbard JM, ONeil 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)
http://bostonbiomedical.com/boston-biomedicals-investigational-cancer-stem-cell-pathway-inhibitor-napabucasin-bbi608-featured-at-the-asco-2016-gastrointestinal-cancers-symposium/ Accessed January 25, 2016.
http://bostonbiomedical.com/wp-content/uploads/Abst569-BBI608-246-ASCOGI2016.pdf Accessed January 25, 2016.
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.
New Cancer Stem Cell Pathway Drug May Change Standard of Care
5 September, 2017 | HYPERLINK "http://letswinpc.org/promising-science/2017/09/05/new-cancer-stem-cell-pathway-drug-may-change-standard-of-care/?utm_source=Let%27s+Win!&utm_campaign=43b3d1a923-EMAIL_CAMPAIGN_2017_09_06&utm_medium=email&utm_term=0_02715713fc-43b3d1a923-121532657" http://letswinpc.org/promising-science/2017/09/05/new-cancer-stem-cell-pathway-drug-may-change-standard-of-care/?utm_source=Let%27s+Win!&utm_campaign=43b3d1a923-EMAIL_CAMPAIGN_2017_09_06&utm_medium=email&utm_term=0_02715713fc-43b3d1a923-121532657
Pancreatic cancer remains a very tough-to-treat disease, but new therapeutic front-line and second-line combinations are, nonetheless, improving patient overall survival times.
However, more effective regimens are needed, and different novel agent combinations are continually being tested in clinical trials. One new avenue of research is focused on targeting the cancer stem cell pathway.
The thought behind this approach is that we hope we may be able to reverse or control cancer, in this case pancreatic cancer, from resisting chemotherapy, which we know is one of the biggest issues doctors and their patients face, explains HYPERLINK "https://www.healthcare4ppl.com/physician/arizona/scottsdale/tanios-s-bekaii-saab-1598770331.html" \t "_blank" Dr. Tanios Bekii-Saab, co-leader of the HYPERLINK "http://www.mayo.edu/research/centers-programs/cancer-research/research-programs/gastrointestinal-cancer-program/overview?_ga=2.36564384.1632461390.1504622946-1168609669.1504622946" \t "_blank" Gastrointestinal Cancer Program at the Mayo Clinic in Phoenix, Arizona, and lead researcher of a stem cell pathway inhibitor called napabucasin (BBI-608).
This drug is being investigated in several trials including those for colorectal cancer as well as pancreatic cancer. In 2016, the U.S. Food and Drug Administration granted Orphan Drug Designation for napabucasin in gastric, gastroesophageal, and pancreatic cancer. So far the early results are promising, and it is exciting because we are looking at the problem in a brand new way, says Bekaii-Saab.
Stemness Versus Stem Cell
Many people are familiar with the term stem cell. These cells are basically divided into two types: embryonic stem cells, which exist only at the earliest stages of development, and various types of tissue-specific or adult stem cells that appear during fetal development and remain in our bodies throughout life. Stem cells are also unique because these cells can regenerate, or self-renew. When it comes to cancer, stem cells also seem to play a role. And the hypothesis is rather complicated.
Simply, not all tumor cells are equal, explains Bekaii-Saab. The biggest portion of a tumor is made up of cells that are proliferative or differentiated, with both types being short-lived, he says.
But some tumor cells seem to have the same characteristics of tissue stem cells. And unlike normal stem cells that help maintain organ health by continually producing new healthy cells, these cancer stem cells boost tumor growth, metastasis, and resistance to therapy. Researchers have recently understood that even cancer cells that are not stem cells or have stem-like features can even revert back to a stem-like state, making them tough to treat, he adds.
These cells generally represent just one to three percent of all cells in a tumor, but they are the only cells with the ability to regenerate malignant cells and fuel the growth of the cancer, he says. As cancer grows and spreads, these cells will become the predominant component. And even if a patient is a surgical candidate, some cells that remain after surgery and lead to a recurrence are cancer stem cells.
Previously, there was no way to target those cells. But due to research advances it is possible today. And the thought is that targeting these cancer stem cells or inhibiting the molecular pathways they need to thrive could boost the benefits of chemotherapy for pancreatic cancer patients and other patients with various types of cancer.
Stemness is a tough concept, but basically many people describe it as trying to think of cancer as a weed that youre trying to get rid of in your lawn, saw Bekaii-Saab. The stem cells are the roots. So if you get rid of the leaves of the weed, but not the root, the weed is going to return with a vengeance.
A Strong Signal
Napabucasin (BBI 608) blocks cancer stem cell self-renewal and induces cell death in cancer stem cells and non-stem cancer cells by inhibiting the STAT3 and beta-catenin pathways, both of which play a role in the malignant growth and spread of cancer, says Bekaii-Saab.
So far, early studies are promising and those results have led to a much larger on-going HYPERLINK "http://letswinpc.org/clinical-trials/2017/06/15/adding-a-new-drug-to-standard-treatment-for-metastatic-pancreatic-cancer/" \t "_blank" phase III study that will assess the efficacy of napabucasin plus weekly nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine alone in patients with pancreatic cancer who have not received prior systemic anti-cancer treatment.
What we have with early results is a very promising signal, a reason to move forward with a larger trial, says Bekaii-Saab, adding the regimen is also very safe. We have an opportunity to actually improve an established regimen, and thats always a reason to move forward, also. I do think this combination might be able to change the standard of care, if the study results are as promising as earlier work.
Dr. Tanios Bekii-Saab
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HYPERLINK "http://www.mayo.edu/research/centers-programs/cancer-research/research-programs/gastrointestinal-cancer-program/overview?_ga=2.36564384.1632461390.1504622946-1168609669.1504622946" http://www.mayo.edu/research/centers-programs/cancer-research/research-programs/gastrointestinal-cancer-program/overview?_ga=2.36564384.1632461390.1504622946-1168609669.1504622946
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' J ' _ First-in-Class Cancer Stemness Inhibitor Shows Promising Results in Advanced Colorectal Cancer Title - 8 @ _PID_HLINKS A - z c h t t p : / / w w w . m a y o . e d u / r e s e a r c h / c e n t e r s - p r o g r a m s / c a n c e r - r e s e a r c h / r e s e a r c h - p r o g r a m s / g a s t r o i n t e s t i n a l - c a n c e r - p r o g r a m / o v e r v i e w ? _ g a = 2 . 3 6 5 6 4 3 8 4 . 1 6 3 2 4 6 1 3 9 0 . 1 5 0 4 6 2 2 9 4 6 - 1 1 6 8 6 0 9 6 6 9 . 1 5 0 4 6 2 2 9 4 6 L C z h t t p : / / l e t s w i n p c . o r g / c l i n i c a l - t r i a l s / 2 0 1 7 / 0 6 / 1 5 / a d d i n g - a - n e w - d r u g - t o - s t a n d a r d - t r e a t m e n t - f o r - m e t a s t a t i c - p a n c r e a t i c - c a n c e r / c h t t p : / / w w w . m a y o . e d u / r e s e a r c h / c e n t e r s - p r o g r a m s / c a n c e r - r e s e a r c h / r e s e a r c h - p r o g r a m s / g a s t r o i n t e s t i n a l - c a n c e r - p r o g r a m / o v e r v i e w ? _ g a = 2 . 3 6 5 6 4 3 8 4 . 1 6 3 2 4 6 1 3 9 0 . 1 5 0 4 6 2 2 9 4 6 - 1 1 6 8 6 0 9 6 6 9 . 1 5 0 4 6 2 2 9 4 6 ] a h t t p s : / / w w w . h e a l t h c a r e 4 p p l . c o m / p h y s i c i a n / a r i z o n a / s c o t t s d a l e / t a n i o s - s - b e k a i i - s a a b - 1 5 9 8 7 7 0 3 3 1 . h t m l < J h t t p : / / l e t s w i n p c . o r g / p r o m i s i n g - s c i e n c e / 2 0 1 7 / 0 9 / 0 5 / n e w - c a n c e r - s t e m - c e l l - p a t h w a y - d r u g - m a y - c h a n g e - s t a n d a r d - o f - c a r e / ? u t m _ s o u r c e = L e t % 2 7 s + W i n ! & u t m _ c a m p a i g n = 4 3 b 3 d 1 a 9 2 3 - E M A I L _ C A M P A I G N _ 2 0 1 7 _ 0 9 _ 0 6 & u t m _ m e d i u m = e m a i l & u t m _ t e r m = 0 _ 0 2 7 1 5 7 1 3 f c - 4 3 b 3 d 1 a 9 2 3 - 1 2 1 5 3 2 6 5 7 h t t p : / / w w w . t a r g e t e d o n c . c o m / c o n f e r e n c e / 2 0 1 6 - a s c o - g i / f i r s t - i n - c l a s s - c a n c e r - s t e m n e s s - i n h i b i t o r - p r o m i s i n g - r e s u l t s - a d v a n c e d - c o l o r e c t a l - c a n c e r [ y h t t p : / / w w w . t a r g e t e d o n c . c o m / n e w s / e x p e r t - d i s c u s s e s - p r o m i s i n g - e a r l y - s i g n a l s - o f - n a p a b u c a s i n - c o m b i n a t i o n - i n - p a n c r e a t i c - c a n c e r V q h t t p : / / w w w . o n c l i v e . c o m / w e b - e x c l u s i v e s / n a p a b u c a s i n - c o m b i n a t i o n - s h o w s - e a r l y - s i g n s - o f - a c t i v i t y - i n - p a n c r e a t i c - c a n c e r ? ; _ h t t p : / / w w w . m e d p a g e t o d a y . c o m / h e m a t o l o g y o n c o l o g y / l y m p h o m a / 5 3 0 0 7 ? p o p = 0 & b a = 1 & x i d = t m d - m d & h r = t r e n d M D , C = h t t p : / / w w w . m e d s c a p e . c o m / v i e w a r t i c l e / 8 6 5 0 5 5 ? s r c = t r e n d m d _ p i l o t ' A = h t t p : / / w w w . m e d s c a p e . c o m / v i e w a r t i c l e / 4 3 3 1 4 3 ? s r c = t r e n d m d _ p i l o t R Y a h t t p : / / w w w . m e d p a g e t o d a y . c o m / h e m a t o l o g y o n c o l o g y / l u n g c a n c e r / 5 8 8 7 7 ? p o p = 0 & b a = 1 & x i d = t m d - m d & h r = t r e n d M D g / T h t t p : / / w w w . m e d p a g e t o d a y . c o m / a s c o / l u n g - c a n c e r / 6 0 0 1 1 ? p o p = 0 & b a = 1 & x i d = t m d - m d & h r = t r e n d M D K ? h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / j c o . 2 0 0 4 . 2 2 . 9 0 1 4 0 . 3 5 7 7 ? u t m _ m e d i u m = c p c & u t m _ c a m p a i g n = J _ C l i n _ O n c o l _ T r e n d M D _ 0 & u t m _ s o u r c e = T r e n d M D J < h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / j c o . 2 0 0 4 . 2 2 . 9 0 1 4 0 . 4 1 1 0 ? u t m _ m e d i u m = c p c & u t m _ c a m p a i g n = J _ C l i n _ O n c o l _ T r e n d M D _ 0 & u t m _ s o u r c e = T r e n d M D 6 h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / j c o . 2 0 0 9 . 2 7 . 1 5 s . 3 5 5 6 ? u t m _ m e d i u m = c p c & u t m _ c a m p a i g n = J _ C l i n _ O n c o l _ T r e n d M D _ 0 & u t m _ s o u r c e = T r e n d M D 5 h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / j c o . 2 0 0 9 . 2 7 . 1 5 s . 2 5 7 6 ? u t m _ m e d i u m = c p c & u t m _ c a m p a i g n = J _ C l i n _ O n c o l _ T r e n d M D _ 0 & u t m _ s o u r c e = T r e n d M D 2 h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / j c o . 2 0 0 9 . 2 7 . 1 5 s . 3 5 1 5 ? u t m _ m e d i u m = c p c & u t m _ c a m p a i g n = J _ C l i n _ O n c o l _ T r e n d M D _ 0 & u t m _ s o u r c e = T r e n d M D p R > h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / J C O . 2 0 1 7 . 3 5 . 1 5 _ s u p p l . 4 1 0 6 p R > h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / J C O . 2 0 1 7 . 3 5 . 1 5 _ s u p p l . 4 1 0 6 p R ~ > h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / J C O . 2 0 1 7 . 3 5 . 1 5 _ s u p p l . 4 1 0 6 p R { > h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / J C O . 2 0 1 7 . 3 5 . 1 5 _ s u p p l . 4 1 0 6 $ 6 x + h t t p : / / c l i n i c a l t r i a l s . g o v / s h o w / N C T 0 2 2 3 1 7 2 3 p R u > h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / J C O . 2 0 1 7 . 3 5 . 1 5 _ s u p p l . 4 1 0 6 p R r > h t t p : / / a s c o p u b s . o r g / d o i / a b s / 1 0 . 1 2 0 0 / J C O . 2 0 1 7 . 3 5 . 1 5 _ s u p p l . 4 1 0 6 D o j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 4 2 ' ) 7 i l ( h t t p : / / a s c o p u b s . o r g / a u t h o r / L i % 2 C + C h i a n g C i j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 3 5 ' ) m 2 f 0 h t t p : / / a s c o p u b s . o r g / a u t h o r / B o r o d y a n s k y % 2 C + L a u r a B c j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 2 4 ' ) [ ` % h t t p : / / a s c o p u b s . o r g / a u t h o r / L i % 2 C + W e i @ ] j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 1 6 ' ) + i Z ( h t t p : / / a s c o p u b s . o r g / a u t h o r / L i % 2 C + Y o u z h i O W j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 0 9 ' ) 2 z T ' h t t p : / / a s c o p u b s . o r g / a u t h o r / O h % 2 C + C i n d y @ Q j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 0 6 ' ) 1 ? N 0 h t t p : / / a s c o p u b s . o r g / a u t h o r / N e k i % 2 C + A n t e r p r e e t + S E K j a v a s c r i p t : p o p R e f ( ' A 6 8 5 5 0 3 ' ) ~ 1 H , h t t p : / / a s c o p u b s . o r g / a u t h o r / M i k h a i l % 2 C + S a m e h F E j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 8 1 ' ) x e B 0 h t t p : / / a s c o p u b s . o r g / a u t h o r / S h a i b % 2 C + W a l i d + L a b i b O ? j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 7 8 ' ) & v < , h t t p : / / a s c o p u b s . o r g / a u t h o r / S e h d e v % 2 C + A m i k a r F 9 j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 7 1 ' ) 6 1 h t t p : / / a s c o p u b s . o r g / a u t h o r / H a n n a % 2 C + W a h i d + T e w f i k N 3 j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 6 9 ' ) 3 % 0 , h t t p : / / a s c o p u b s . o r g / a u t h o r / N o o n a n % 2 C + A n n e + M D - j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 6 3 ' ) f * 3 h t t p : / / a s c o p u b s . o r g / a u t h o r / C i o m b o r % 2 C + K r i s t e n + K e o n N ' j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 5 9 ' ) W $ * h t t p : / / a s c o p u b s . o r g / a u t h o r / S h a h d a % 2 C + S a f i A ! j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 5 6 ' ) ] . h t t p : / / a s c o p u b s . o r g / a u t h o r / O % 2 7 N e i l % 2 C + B e r t + H D j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 5 3 ' ) = r 0 h t t p : / / a s c o p u b s . o r g / a u t h o r / E l - R a y e s % 2 C + B a s s e l + F O j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 4 8 ' ) H 1 h t t p : / / a s c o p u b s . o r g / a u t h o r / S t a r o d u b % 2 C + A l e x a n d e r B j a v a s c r i p t : p o p R e f ( ' A 6 8 5 4 4 5 ' ) ) x 3 h t t p : / / a s c o p u b s . o r g / a u t h o r / B e k a i i - S a a b % 2 C + T a n i o s + S d 4 , h t t p s : / / c l i n i c a l t r i a l s . g o v / s h o w / N C T 0 2 9 9 3 7 3 1 n < , h t t p s : / / c l i n i c a l t r i a l s . g o v / s h o w / N C T 0 2 2 3 1 7 2 3 ^ z Q h t t p : / / j a x e l e c t i o n . a l t e r v i s t a . o r g / p a n c r e a t i c / N a p a b u c a s i n B B I - 6 0 8 A S C O 2 0 1 7 _ 4 1 0 6 . p d f o t D h t t p : / / j a x e l e c t i o n . a l t e r v i s t a . o r g / p a n c r e a t i c / N a p a b u c a s i n B B I - 6 0 8 . d o c
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