Phase Ⅰ Trail of Concurrent Nab-paclitaxel and Cisplatin with radiotherapy for locally advanced cervical cancer

Purpose: Concurrent chemoradiotherapy using platinum-containing chemotherapy is the treatment of choice for stages IB3-IVA cervical cancer. A preclinical evaluation of the radiation-modulating effects of nab-paclitaxel in tumor showed that nab-paclitaxel acted as a radiosensitizer and produced supra-additive effects when combined with radiation (1). However, the use of concurrent nab-paclitaxel and cisplatin with radiation has not been tested for cervical cancer. In this study we aimed to assess the maximum-tolerated dose (MTD) of nab-paclitaxel (Keaili®) in combination with a fixed dose of cisplatin when given concurrently with radiotherapy to patients for locally advanced cervical cancer.

Methodology: We conducted a single-center, open-label, single-arm, phase Ⅰ trial (ClinicalTrials.gov Identifier: NCT04017377). Chemotherapy was administered intravenously on day 1 of radiotherapy weekly. Chemotherapy consisted of at least four cycles of cisplatin 40 mg/m2 and nab-paclitaxel with escalating doses (10, 20, 33, 50, 70 mg/m2). Radiotherapy consisted of intensity modulated radiation therapy in a 50.4 Gy in 28 fractions for five days weekly and intracavitary brachytherapy in a 30 Gy in 5 fractions twice a week. Three patients were enrolled for each dose level. If one Dose-limiting toxicity (DLT) were recorded, three further patients were included for the same dose level. The DLT was defined as grade 3 or 4 nonhematologic toxicity, excluding nausea, vomiting and alopecia, decreased appetite and fatigue, or grade 4 hematologic toxicity.

Results: This study was initiated in September, 2019, and enrollment ended in October, 2021. Eighteen patients with stage ⅠB2-ⅣA cervical cancer were enrolled. Five levels of nab-paclitaxel were studied with three, three, three, six and three patients enrolled, respectively. The MTD of nab-paclitaxel was found at 50 mg/m2/week. At level 4, 1 patient experienced DLT because of grade 3 right upper extremity edema. At level 5, two DLTs (grade 3 rash and grade 3 perineal edema) were observed in two patients. Other major side effects included leukopenia, neutropenia, hypochromia, fatigue and nausea. Sixteen patients were evaluable for response: two complete and fourteen partial responses were obtained with an overall response rate of 100%.

Conclusions: Based on the results obtained from this study, weekly administration of 50 mg/m2 nab-paclitaxel when associated to cisplatin 40 mg/m2/week and concurrent radiotherapy can be considered a tolerable and safe dose for the treatment of locally advanced cervical cancer.

References: 1. Wiedenmann N, Valdecanas D, Hunter N, et al. 130-nm Albumin–Bound Paclitaxel Enhances Tumor Radiocurability and Therapeutic Gain[J]. Clinical Cancer Research, 2007, 13(6): 1868-1874.