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Hello, my name is Dr. Rachna Shroff, I'm an assistant professor of GI Medical Oncology at the University of Texas, MD Anderson Cancer Center. On behalf of my colleagues, I'm excited to present the results of our phase two trial of gemcitabine, cisplatin, and nab-paclitaxel, in advanced biliary tract cancers.
This study was multi-center, open labels, single-arm, phase two clinical trial. It involved treatment of advanced, untreated biliary tract cancers, to include Cholangiocarcinoma and gall bladder cancer, being treated with the standard of care, gemcitabine and cisplatin, with the addition of nab-paclitaxel. The overall prognosis of biliary tract cancers is actually quite dismal, with the median overall survival in advanced patients being just under one year, with the treatment of gemcitabine and cisplatin.
This study was designed to look at the efficacy in terms of adding nab-paclitaxel to the backbone of gemcitabine in a platinum therapy. Initially, 30 patients were enrolled that were treated with gemcitabine at a starting dose of 1,000 milligrams per meter squared, cisplatin at 24 milligrams per meter squared, and nab-paclitaxel at 125 milligrams per meter squared, all given intravenously on days one and eight of a 21 day cycle.
Every cycle was repeated every 21 days for a total of three cycles, prior to re-staging CT imaging. However, owing to the incidence of grade three/four toxicities, primarily hematologic, we subsequently dose reduced the gemcitabine and nab-paclitaxel, and enrolled 29 additional patients with the doses of gemcitabine at 800 milligrams per meter squared, cisplatin was kept stable at 25 milligrams per meter squared, and nab-paclitaxel at 100 milligrams per meter squared, again given on days one and eight of a 21 day cycle.
Patients were enrolled sequentially at both MD Anderson Cancer Center, and at Mayo Clinic, Arizona. All patients were allowed to have dose modifications and interruptions based on treatment related toxicities, and treatment was continued until disease progress or unacceptable toxicities were noted. All treated patients included a data cut of April 2017, which was a total of 59 of the 60 patients. The patients were initially seen to have a median progression free survival of 8.6 months, with a median overall survival of 18.8 months. However, a total of nine of those 59 patients actually received less than one full cycle of therapy, and as a result, we excluded them from the response evaluable population.
When we look at the response evaluable population with an N of 50 patients, the median progression free survival is 11.8 months. Our initial null hypothesis was based on the ABCO2 study, where gemcitabine and cisplatin have a median progression free survival of eight months, and we were looking for an improvement to ten months of median progression free survival. With progression free survival being our primary endpoint, and secondary endpoints include overall survival as well as overall response rate.
When we look at the response rate, the initial partial response rate in all treated patients was 28.8%, however when we look at the response evaluable patients, it was 34%. This, too, compare favorably with the historical control of gemcitabine and cisplatin, where the response rate is approximately 25%. When you look at the patients who also had stable disease, which was 42.4% of patients in the all-treated population, and 50% of patients in the evaluable population, you come to a disease control rate of 84% in the 50 response evaluable patients. Progressive disease was seen in 16% of these 50 patients.
I think it's also important to note that a total of seven patients who initially had unresectable or locally advanced disease, were converted to potentially operable patients and were taken to the operating room for a surgery. Three of those patients were in the initial high-dose group, and four patients were in the reduced dose group. One of the actual patients that was treated in the high-dose group achieved a pathologic complete response when we looked at their surgical pathology.
This is the Kaplan–Meier curve that summarizes progression free survival in all evaluable patients, meaning the 50 patients that received over one cycle of therapy. The dashed lines represent the confidence intervals of 7.9 to 16.1 months. This is our Kaplan–Meier curve that looks at the overall survival of all treated patients, which shows an impressive median overall survival of 18.8 months, with a 95% confidence interval of 13.6 to not reached. The one year overall survival rate was 70.2%.
When we look at treatment discontinuations, all treated patients, the median number of treatment cycles was 5.24. However you will see that the range goes all the way up to 29 cycles of therapy. In the high-dose group, the treatment related discontinuations was approximately 20% of patients, however once we dose-reduced, those toxicity related discontinuations dropped to just about 13.8%.
The grade three and four hematologic toxicities are summarized here. As you can see, the primary issues were in the range of neutropenia and thrombocytopenia. The high dose-group with 30 patients actually saw a 36.7% of patients having grade three to four neutropenia. However, with the dose reduction, this was dropped to 17.2% in the dose-reduced group. Thrombocytopenia went from 16.7% in the high-dose group, down to 10.3%. There were a total of three deaths on study, none of which were thought to be related to treatment. One was a cardiac arrest, one was an embolic stroke, and the other one was sepsis. Grade three non-hematologic toxicities were seen in 12 patients in the high-dose group, and four in the low-dose group, with the most common ones being diarrhea and vomiting. Surprisingly, we did not see any significant grade three or four neuropathy in these patients, and no grade four non-hematologic toxicities were reported.
Based on this data, we feel that the combination of gemcitabine, cisplatin and nab-paclitaxel demonstrate a promising efficacy in the treatment of patients with advanced biliary tract cancer, to include cholangiocarcinoma and gall bladder cancer. A median PFS of 8.6 months in the intention to treat population, and 11.8 months in the PFS evaluable population show a promising result compared to the historical median PFS of eight months with gemcitabine and cisplatin.
Gemcitabine, cisplatin, and nab-paclitaxel at the lower dose of 800 milligrams per meter squared of gemcitabine, 25 milligrams per meter squared of cisplatin, and 100 milligrams per meter squared of nab-paclitaxel on days one and eight of a 21 day cycle was well tolerated. Almost 60% of these patients started at this dose level and had no further dose reductions that were required. Given these provocative findings, we feel that randomized control trial data is really needed to clarify the potential role for gemcitabine, cisplatin, with the addition of nab-paclitaxel in the treatment of advanced biliary tract cancers.
Thank you so much for your attention.