Clinical Trial: IPI-926-03
For metastatic pancreatic ductal adenocarcinoma patients who have not been treated with other chemotherapy
Update in IPI-926-03 trial
On January 27th. 2012, Infinity Pharmaceuticals stopped the IPI-926-03 trial after an interim analysis found that patients on the gemcitabine + placebo arm were living longer than 6 months, while patients on the gemcitabine + IPI-926 arm were living shorter than 6 months. No additional toxicities were noted in the gemcitabine + IPI-926 arm. The full text of the announcement is linked HERE. We are incredibly disappointed by this news given the promising data from the earlier Phase 1b portion of the trial. At this time, not a great deal of information is available for us to understand the result. I've tried to answer a few questions that I've received below, to the extent that it is possible at this time. However, the most that I can really say is that we are committed to understanding these results more fully, both from a biological and a clinical standpoint.
What exactly does this mean?
An interim analysis is one performed before a trial is complete, after a certain amount of data is available. In this case, an independent data monitoring group was in charge of following the outcomes of the two randomized arms of the trial. They reported that, based on the early data from the study, one arm was living longer than the other. It was a complete surprise and disappointment to all involved to learn that, in fact, the arm that was living longer was the control arm. Given those early results, the decision was made to stop the trial.
Question: Where can I get more data about the results of the trial?
At this stage, the full data from the trial are not available. The decision was made to try to get the best, most informative data from the trial. To do this, it is critical to wait until the full dataset is complete before performing a full analysis. Once all the data are available, they will be carefully analyzed to learn as much as possible about what happened.
Question: Does this mean that the approach failed?
From a clinical trials standpoint, yes, the trial failed. From the point of view of a scientist trying to understand what happened, it's impossible to say without the full set of data. It is possible hedgehog inhibitors could still have an application in treating pancreatic cancer. But this is certainly a setback. It will be absolutely critical to understand the results more fully. Did some patients benefit, while other fared less well? Was there some unintended bias in the enrollment? Did any of the patients treated with IPI-926 + gemcitabine respond in the way that was observed in the Phase 1b trial? These questions (and a hundred others) can only be answered when the full data set is available.
Question: When will we hear more?
Honestly, I don't know. I'm committed to understanding what happened, but realistically, it is going to take some time to get the full data set, analyze it, and then do experiments to follow up on the results.
What exactly does this mean?
An interim analysis is one performed before a trial is complete, after a certain amount of data is available. In this case, an independent data monitoring group was in charge of following the outcomes of the two randomized arms of the trial. They reported that, based on the early data from the study, one arm was living longer than the other. It was a complete surprise and disappointment to all involved to learn that, in fact, the arm that was living longer was the control arm. Given those early results, the decision was made to stop the trial.
Question: Where can I get more data about the results of the trial?
At this stage, the full data from the trial are not available. The decision was made to try to get the best, most informative data from the trial. To do this, it is critical to wait until the full dataset is complete before performing a full analysis. Once all the data are available, they will be carefully analyzed to learn as much as possible about what happened.
Question: Does this mean that the approach failed?
From a clinical trials standpoint, yes, the trial failed. From the point of view of a scientist trying to understand what happened, it's impossible to say without the full set of data. It is possible hedgehog inhibitors could still have an application in treating pancreatic cancer. But this is certainly a setback. It will be absolutely critical to understand the results more fully. Did some patients benefit, while other fared less well? Was there some unintended bias in the enrollment? Did any of the patients treated with IPI-926 + gemcitabine respond in the way that was observed in the Phase 1b trial? These questions (and a hundred others) can only be answered when the full data set is available.
Question: When will we hear more?
Honestly, I don't know. I'm committed to understanding what happened, but realistically, it is going to take some time to get the full data set, analyze it, and then do experiments to follow up on the results.
A brief explanation of the science...
This trial arose from earlier research performed by Dr. Olive as a postdoctoral fellow in David Tuveson's laboratory at the Cambridge Research Institute, in Cambridge, England. The topic of the research was to understand why tumors DO NOT respond to chemotherapy. What we learned is that pancreatic tumor cells recruit normal cells from the rest of the body to aid in their growth. These other normal cells are called "stromal cells" and they perform a variety of functions. For example, they help prevent the tumor from being attacked by the immune system, they support the growth of tumor cells, and they manufacture fibrous proteins that form and thick, dense jacket around the tumor cells. This jacket has the effect of preventing drugs from getting into the tumor, which helps to explain why drugs fail to work in pancreatic cancer. [A more detailed explanation of this concept is coming in the future]
After identifying this barrier to drug delivery, Dr. Olive and his collaborators learned that a particular molecular signal called the Hedgehog pathway was responsible for building the barrier. Tumor cells use proteins in the Hedgehog pathway to "call to" stromal cells and recruit them into the tumor. We reasoned that turning off this pathway might break down the stroma of pancreatic tumors, allowing other drugs to have better access to the tumor.
At this point we were fortunate to build a scientific collaboration with Infinity Pharmaceuticals, a small biotech company in Cambridge, MA. They had developed a drug that could turn off the Hedgehog pathway and were developing it for other clinical applications. They collaborated with us to test this drug in our mice that get pancreatic cancer. When we did this, we found that their drug, called IPI-926, caused the stroma of pancreatic tumors to break down. It also allowed higher concentrations of chemotherapy, such as gemcitabine, to be delivered into the tumors. Most importantly, the mice lived more than twice as long when treated with the combination of IPI-926 + gemcitabine, compared to controls.
After identifying this barrier to drug delivery, Dr. Olive and his collaborators learned that a particular molecular signal called the Hedgehog pathway was responsible for building the barrier. Tumor cells use proteins in the Hedgehog pathway to "call to" stromal cells and recruit them into the tumor. We reasoned that turning off this pathway might break down the stroma of pancreatic tumors, allowing other drugs to have better access to the tumor.
At this point we were fortunate to build a scientific collaboration with Infinity Pharmaceuticals, a small biotech company in Cambridge, MA. They had developed a drug that could turn off the Hedgehog pathway and were developing it for other clinical applications. They collaborated with us to test this drug in our mice that get pancreatic cancer. When we did this, we found that their drug, called IPI-926, caused the stroma of pancreatic tumors to break down. It also allowed higher concentrations of chemotherapy, such as gemcitabine, to be delivered into the tumors. Most importantly, the mice lived more than twice as long when treated with the combination of IPI-926 + gemcitabine, compared to controls.
