Phase II trial of biologically optimized schedule of gemcitabine and nab-paclitaxel in metastatic pancreatic cancer.
Authors: Noonan Anne M. , Noonan Anne M. , Abushahin Laith I. , Wei Lai , Malalur Pannaga G. , Manne Ashish , Mittra Arjun , Roychowdhury Sameek , Jin Ning , Hays John L. , Babcook Melissa A. , Risch Zachary , Rahman Shafia , Hazard Brooke , Williams Terence Marques 
Published: July 2024

e16325 Background: Metastatic pancreatic adenocarcinoma (PDAC) has a poor prognosis and limited therapeutic options. In addition to efforts to develop novel agents, there is a need to optimize and maximize the benefit of currently approved drugs such as gemcitabine (G) + nab-paclitaxel (NP). NP is albumin–bound, hence albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. We have shown that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of PDAC cells to G resulted in up-regulation of Cav-1 peaking 48 hours after G exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, we noted that exposure of PDAC cells to G resulted in a time–specific re-entry of cells into the G2/M phase (NP cytotoxicity phase) between 48-60 hours after G treatment. Collectively this data suggest that infusing NP 48 hours after G infusion would be optimal for both increased uptake as well as increased susceptibility to apoptosis of tumor cells. We have shown this effect on multiple cell lines and mouse models. Methods: This is a phase II trial (NCT04115163) where patients (pts) receive G + NP every 2 weeks with modification of the schedule to deliver NP 48 hours (2 days) after G infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs a target of 35%. Employing a 2-stage minimax design minimax and assuming 80% power and a 0.05 significance level, a total of 53 pts are required. In the first stage, if at least 7/31 pts respond to therapy, an additional 22 pts will be added for a total of 53 pts. The study will be terminated early if ≤ 6 pts respond in the first stage. Observation of response in at least 16/53 pts would be required to warrant further investigation of this infusion schedule. Secondary endpoints include safety of the regimen schedule, relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrolment in June 2020. Results: Interim analysis was conducted after 43 pts had been enrolled. 29 pts were found to be evaluable for the primary endpoint of response. Objective response was seen in 11 out of 29 (37.9%) evaluable pts thus meeting statistical criteria to continue enrolment on stage 2 of the study. The regimen was well tolerated with no new safety signals. Toxicities are summarized in table. Conclusions: Biologically optimized G + NP was well tolerated with interim analysis revealing response rate of 37.9%. Enrolment is ongoing with plans for correlative analysis related to Cav-1. Clinical trial information: NCT04115163 . [Table: see text]