A phase I trial of intraperitoneal nab-paclitaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity
Mihaela C Cristea, Paul Frankel, Timothy Synold, Saul Rivkin, Dean Lim, Vincent Chung, Joseph Chao, Mark Wakabayashi, Benjamin Paz, Ernest Han, Paul Lin, Lucille Leong, Amy Hakim, Mary Carroll, Neal Prakash, Thanh Dellinger, Min Park, Robert J Morgan, Mihaela C Cristea, Paul Frankel, Timothy Synold, Saul Rivkin, Dean Lim, Vincent Chung, Joseph Chao, Mark Wakabayashi, Benjamin Paz, Ernest Han, Paul Lin, Lucille Leong, Amy Hakim, Mary Carroll, Neal Prakash, Thanh Dellinger, Min Park, Robert J Morgan
Abstract
Purpose: To evaluate intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies that are primarily confined to the peritoneal cavity in a phase I trial.
Methods: Using a 3 + 3 dose escalation of IP nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle, we evaluated six dose levels (35-175 mg/m2/dose). Maximum tolerated dose (MTD) and pharmacokinetics (PK) of IP nab-paclitaxel were determined.
Results: There were no dose-limiting toxicities (DLTs) in cohorts 1-3. There was a DLT in one of six patients in cohort 4 (112.5 mg/m2) (grade 3 neutropenia causing treatment delay > 15 days) and a DLT in one of three patients in cohort 6 (175 mg/m2) (grade 4 neutropenia and grade 3 abdominal pain). A second patient in cohort 6 experienced a serious adverse event (cycle 1, grade 4 ANC ≤ 7 days, cycle 4, grade 2 left ventricular dysfunction). This dose level was determined to be above the MTD. No DLTs were seen in seven patients treated in cohort 5 (140 mg/m2). The MTD of IP nab-paclitaxel was established at 140 mg/m2 on days 1, 8, and 15 of a 28-day cycle. There was a PK advantage for IP nab-paclitaxel, with an IP plasma area under the concentration-time curve (AUC) ratio of 147-fold (range 50-403) and therapeutic range systemic drug levels. Eight of 27 enrolled patients had progression-free survival ≥ 6 months. One patient experienced complete response, and one patient experienced partial response. Six patients had stable disease.
Conclusions: Weekly IP nab-paclitaxel has a favorable toxicity profile, a significant pharmacologic advantage, and promising clinical activity.
Clinical trial registration: NCT00825201.
Keywords: Intraperitoneal chemotherapy; Nab-paclitaxel; Peritoneal carcinomatosis; ovarian cancer; Pharmacologic advantage.
Conflict of interest statement
Conflict of interest
MC receives personal fees from Astra Zeneca and VC is a member of the Celgene Speaker’s Bureau.
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Source: PubMed