Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma

Yan Huang, Wenhua Liang, Yunpeng Yang, Liping Zhao, Hongyun Zhao, Xuan Wu, Yuanyuan Zhao, Yang Zhang, Li Zhang, Yan Huang, Wenhua Liang, Yunpeng Yang, Liping Zhao, Hongyun Zhao, Xuan Wu, Yuanyuan Zhao, Yang Zhang, Li Zhang

Abstract

Background: This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC).

Methods: Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining.

Results: Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC.

Conclusions: Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study.

Trial registrations: ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Figures

Fig. 1
Fig. 1
Waterfall plot of maximum percentage change in the sum of the longest diameters of target lesions. PD was defined as an increase of > 20 % in tumor size; PR was defined as a decrease of > 30 % in tumor size
Fig. 2
Fig. 2
Kaplan-Meier analysis of median progression free survival in: a, all study patients; b, all 3 nab-paclitaxel dose cohorts; c, patients with ≤ 30 %, > 30 to < 50 %, and ≥ 50 % maximum decrease in the sum of the longest diameters of target lesions; and d, patients with complete EBV-DNA clearance at any time during treatment versus those with non-zero trough EBV-DNA. Cohort 1, cisplatin 75 mg/m2 day 1 + nab-paclitaxel 260 mg/m2 day 1 Q3W; Cohort 2, cisplatin 75 mg/m2 day 1 + nab-paclitaxel 140 mg/m2 day 1, 8 Q3W; Cohort 3, cisplatin 75 mg/m2 day 1 + nab-paclitaxel 100 mg/m2 day 1, 8, 15 Q3W. CI, confidence interval
Fig. 3
Fig. 3
SPARC protein expression. Panels a (20× magnification) and c (40× magnification) show high stromal expression and low expression on the tumor surface; panels b (20× magnification) and d (40× magnification) show that stromal expression is scarce, and there is little expression on the tumor surface

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