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BIDIRECTIONAL PACLITAXEL PLUS NILOTINIB FOR PERITONEAL CARCINOMATOSIS: PHASE II CLINICAL TRIAL RESULTS
Shruthi R. Perati
*, Amber F. Gallanis, Stephanie Canady, Molly Sullivan, Nancy Moore, Yvonne Mallory, Audra Satterwhite, Diane Ahn, Silvia Figueiroa Da Cruz, Stacy Joyce, John Lee, Andre De Souza, Jessica Mukherjee, Sarah Shin, Ning Ma, Lamin Juwara, Jibran Ahmed, Alice Chen, Jeremy L. Davis, Andrew Blakely
National Cancer Institute, National Institutes of Health, Bethesda, MD
Background: The efficacy of locoregional therapy with intraperitoneal (IP) drug delivery in combination with systemic chemotherapy for peritoneal carcinomatosis (PC) is understudied. Given preclinical evidence of therapeutic synergy, our study aimed to evaluate efficacy of bidirectional chemotherapy using IP and intravenous (IV) paclitaxel and oral nilotinib in patients with PC.
Methods: This was a single-institution phase II, single-arm clinical trial of IP and IV (bidirectional) paclitaxel plus nilotinib for PC (NCT05185947). Participants received 60-80 mg/m
2 IP paclitaxel and 60-80 mg/m
2 IV paclitaxel plus 300 mg oral nilotinib twice daily (Figure 1). The primary endpoint was downstaging of peritoneal disease burden to become potentially resectable, based on serial laparoscopic Peritoneal Carcinomatosis Index (PCI) scoring. Secondary endpoints included overall survival (OS), peritoneal progression-free survival (PFS), and safety/tolerability.
Results: Seven patients with PC from appendiceal (n=3), gastric (n=3), and small bowel (n=1) adenocarcinoma with median age 59 years (range 46-69) were enrolled from October 2022 through October 2024. Prior to enrollment, two patients had radiographically measurable disease, and all participants had received at least one line of systemic chemotherapy. Two participants suffered adverse events before completing a cycle of treatment and were taken off-study and excluded from endpoint analyses. The remaining five participants completed a median number of 4 cycles (range 3-7). Median PCI was 20 (range 13-26) at time of IP catheter placement, vs. 16 (range 9-20) upon re-staging laparoscopy (following Cycles 1-3). No patients met the primary endpoint of being downstaged to the point of resectability. 80% (4/5) of patients had stable disease (re-staging PCI within 3 points of baseline), and one patient exhibited an objective response (PCI reduction from 15 to 9 after completion of Cycles 1-3). Median PFS was 3.6 months (range 2.6-6.6), and median OS was 8.3 months (range 2.8-10.2) (Figure 2). No patients developed extra-peritoneal disease progression during the study period. All patients sustained at least one non-serious adverse event. 80% of patients (4/5) experienced at least one major toxicity (Grade III and above), and 40% (2/5) sustained a serious adverse event.
Conclusions: Bidirectional paclitaxel-based chemotherapy plus nilotinib was associated with mostly stable peritoneal disease but limited survival benefit in this small, heterogenous cohort with PC. Adverse events, particularly those related to nilotinib tolerability, were significant and frequent, ultimately leading to early trial closure. Larger clinical trials are needed to more thoroughly investigate the efficacy of bidirectional therapy for PC, and identification of oral agent(s) that are well-tolerated by patients with PC is paramount.
Figure 1. IP/IV paclitaxel plus nilotinib study design for enrolled patients. Created with biorender.com.
Kaplan-Meier curves for A) clinical progression-free survival and B) overall survival from start of IP/IV Paclitaxel plus nilotinib treatment, in months.
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