A phase II trial of dose-reduced nab-paclitaxel for patients with previously treated, advanced or recurrent gastric cancer (OGSG 1302)

Background For unresectable or recurrent advanced gastric adenocarcinoma (AGC), tri-weekly administration of nanoparticle albumin-bound paclitaxel (nab-PTX) at 260 mg/m2 achieved a response rate of 27.8% in a phase II trial in Japan. However, frequent neutropenia and peripheral neuropathy limit its use in clinical settings. We, thus, conducted a single-arm phase II trial to investigate the efficacy and safety of a reduced dose (220 mg/m2) of tri-weekly nab-PTX. Methods Eligible patients included those with AGC and ECOG performance status of 0–2 who had received one or more prior chemotherapy containing fluoropyrimidine regimens. A reduced dose of nab-PTX (220 mg/m2) was administered tri-weekly. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity (RDI) and proportion of patients receiving subsequent chemotherapy. Results Among 33 patients enrolled, 32 were treated with protocol therapy. RR was 3.1% [95% confidence interval (CI), 0–16.2%], which did not reach the protocol-specified threshold (p = 0.966). DCR was 37.5% (95% CI, 21.1–56.3%). Median OS and PFS were 6.3 (95% CI, 4.4–14.2) and 2.2 (95% CI, 1.8–3.1) months, respectively. RDI was 97.8%. Twenty (62.5%) patients received subsequent chemotherapy. Toxicity was relatively mild with the most common grade ≥ 3 adverse events being neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). Conclusion Tri-weekly nab-PTX with a reduced dose (220 mg/m2) is not recommended for AGC in a second-line or later setting, despite demonstrating less toxicity than at 260 mg/m2. Clinical trial registration The OGSG1302 trial was registered with UMIN-CTR as UMIN000000714.


Introduction
Combination of chemotherapy with platinum agents and fluoropyrimidine has been regarded as the standard of care in a first-line setting for unresectable or recurrent advanced gastric adenocarcinoma (AGC) [1], to which trastuzumab, an anti-HER2 monoclonal antibody, is added in HER2-positive cases [2,3]. Recently, oral fluoropyrimidine including S-1 and capecitabine, has generally been utilized instead of infusional 5-FU because of their convenience and tolerability [4][5][6]. The combination of S-1 and cisplatin is now accepted as the standard regimen for first-line chemotherapy for patients with AGC in Japan, based on the result of the SPIRITS trial [4].
For second-line chemotherapy, until weekly solvent-based paclitaxel (sb-PTX) plus ramucirumab, an anti-VEGFR antibody, demonstrated superiority over sb-PTX alone [7], sb-PTX alone was widely utilized in this setting based on a phase III study in which sb-PTX showed comparable efficacy to CPT-11 with less toxicity [8]. This was also supported by promising results of several phase II studies, yielding overall response rates (RRs) that ranged from 16 to 27% and overall survival (OS) times of 5-11 months [8][9][10][11][12]. However, sb-PXT can cause hypersensitivity and anaphylactic reactions in certain patients, mostly because of polyethoxylated castor oil contained in it [13]. To use this drug safely, premedication with steroids and histamine H-2 blockers is generally required. Moreover, sb-PTX contains alcohol. These factors limit the general use of sb-PTX in a certain subset of AGC patients.
A phase I trial of nab-PTX in patients with advanced solid tumors determined the maximum tolerated dose to be 300 mg/m 2 [19]. In MBC, the dose of nab-PTX was initially set as 300 mg/m 2 [20], and then deduced to 260 mg/m 2 in the subsequent phase III Ca012 trial, where tri-weekly nab-PTX demonstrated significantly superior RR as well as a longer time to progression compared to the conventional sb-PTX at a dose of 175 mg/m 2 [15]. This study also identified grade 3 or higher CIPN as a considerable adverse event of nab-PTX [15]. To reduce such toxicity, low-dose tri-weekly nab-PTX (160-175 mg/m 2 ) was examined in several phase II studies for MBC, showing good overall RR (23-39.5%) without CIPN of grade 3 or higher [21,22].
These results reveal the need to develop a low-dose nab-PTX regimen in AGC. To this end, we conducted a phase II trial to evaluate the efficacy and safety of low-dose triweekly nab-PTX (220 mg/m 2 ) in AGC patients in secondline or later setting.

Study objectives and design
This study was conducted in accordance with the international ethical recommendations stated in the Declaration of Helsinki. The protocol was approved by the institutional ethics committees of each participating hospital and registered in the University Hospital Medical Information Network (UMIN) database (ID000000714). Written informed consent was obtained from each patient before enrollment.
This was a non-randomized, multicenter phase II study for patients with AGC for whom more than one regimen including fluorinated pyrimidine antineoplastic agents had failed. The primary endpoint was RR, and the secondary endpoints were OS, PFS, time to treatment failure (TTF), disease-control rate (DCR), safety, relative dose intensity and proportion of patients who received subsequent therapy. This trial was carried out in accordance with the Japanese Classification of Gastric Carcinoma of the 14th edition from the Japanese Gastric Cancer Association.

Eligibility criteria
The eligibility criteria of this study were as follows; (1) histologically confirmed unresectable or recurrent gastric or esophagogastric junction adenocarcinoma; (2) history of failure of one or more prior chemotherapy containing fluoropyrimidine regimens for HER2-negative cases or both fluoropyrimidine and Trastuzumab for HER2-positive cases; (3) age 20-80 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2; (5) one measurable lesion according to RECIST ver. 1.1 criteria as determined via computed tomography (CT) within 4 weeks before enrollment; (6) no previous treatment with PTX; (7) adequate organ function, including leukocyte count under 12,000 mm 3 , neutrophil count over 2,000 mm 3 , platelet count over 100,000 mm 3 , hemoglobin level over 9.0 g/dl, serum bilirubin level under 1.5 mg/dl, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of under 100 or 200 IU/L of patients with liver metastasis, a serum creatinine level under 1.5 mg/dl; (8) expected to survive for at least 90 days from the date of registration; and (9) cases with the provision of informed consent.
Exclusion criteria were as follows: (1) with a history of severe drug sensitivity; (2) with infection or suspected infection with a fever over 38.0 °C; (3) serious complications, such as interstitial pneumonia or lung fibrosis, uncontrolled diabetes, or renal or hepatic failure; (4) suffering more than four bouts of diarrhea; (5) a history or complication of heart disease, for example, congestive heart failure, myocardial infarction, ischemic heart disease requiring treatment, arrhythmia or valvular disease; (6) active double cancer; (7) peripheral neuropathy over grade 2; (8) difficulty enrolling due to a psychiatric or neurological disorders; (9) brain metastasis; (10) positivity for HBs antigen or HCV antibody, and (11) the a presence of any other condition that would make the treatment unsafe.
Written informed consent was obtained from each patient before enrollment and the protocol was approved by the institutional ethics committee of each participating centers.

Study design
Treatment nab-PTX was administered intravenously on an outpatient basis by a 30-min infusion at a dose of 220 mg/m 2 on day 1 of each 21-day cycle. No premedication, such as steroid or antihistamine premedication, was administered. Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal.
Two dose-reduction levels (level 1, 180 mg/m 2 and level 2, 150 mg/m 2 ) and one dose escalation level (260 mg/m 2 ) were implemented under the dose-reduction or escalation criteria: if the number of neutrophils was 1500/mm 3 or more after the administration of 220 mg/m 2 nab-PTX in the previous course and the dose-reduction criteria were not violated, the dose of nab-PTX could be increased up to 260 mg/m 2 in the next course.

Follow-up
Patients underwent hematological tests and assessments of clinical symptoms at least once during each course of chemotherapy. However, in the first course, hematological tests were conducted on the 1st, 8th and 15th day. The severity of adverse drug reactions was judged in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Thoracoabdominal CT scans were repeated at least every 6 weeks (± 2 weeks) after treatment initiation and at the end of the treatment in this study. The objective disease status was assessed in accordance with the RECIST guidelines, version1.1. An independent review board organized by the Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG) objectively identified treatment responses and drug-related adverse events.

Statistical analysis
RR was reported to be 27.8% (95% CI: 16.5-41.3) in a phase II study of nab-PTX (260 mg/m 2 , q3w) with almost the same objective as the present study [18] and 23% in a phase II study of PTX (210 mg/m 2 ; 95% CI: 13-36%) [9]. The calculation of the sample size for the study was based on an expected response rate of 25% and a threshold response rate of 10%, using a one-sided alpha error of 0.05 and statistical power of 80%. The planned sample size was 35 patients, allowing for four patients dropping out.
The analysis focused on patients who were enrolled in this study and received at least one course of nab-PTX treatment. Background data were summarized as frequency with proportion for categorical variables, and median with range for continuous variables. The response rate was evaluated using exact binomial test. Confidence intervals of response rate and disease-control rate were estimated by the Clopper-Pearson method. OS, PFS and TTF were estimated using the Kaplan-Meier method and the 95% CIs for survival rate were calculated using Greenwood's formula. p values less than 0.05 were considered statistically significant. All statistical analyses were performed with S-plus version 3.6.1 (R Foundation for Statistical Computing, Vienna Austria).

Results
Between April 2014 and December 2018, 33 patients with AGC and ECOG PS of 0-2 who had received one or more prior chemotherapy containing fluoropyrimidine regimens were enrolled from 10 institutions in Japan. As one patient withdrew consent before the initial treatment, 32 patients received the study treatment and were evaluated for clinical response and safety. The patients' characteristics are listed in Table 1. Twenty-seven patients were male (84.4%) and the median age was 70 years (range 48-82). Most of the patients had an ECOG PS of 0 or 1, whereas ECOG PS 2 was seen in two patients (6%). Twenty patients involved advanced cases and 12 involved relapse. The stages at initial treatment of the relapse cases were stage II for 1 patient, stage III for 9, and stage IV for 2. Twenty-three patients (72%) were enrolled as second-line treatment and nine patients (28%) as third-line treatment.

Discussion
In patients with AGC, the efficacy of tri-weekly nab-PTX at 260 mg/m 2 without anti-allergic premedication was demonstrated with an overall RR of 27.8% in a phase II trial in Japan [18]. However, relatively high toxicities, such as neutropenia and CIPN, were indicated, which was the limitation of the general use of nab-PTX for patients with AGC. Therefore, we investigated the safety and efficacy of a reduced dose (220 mg/m 2 ) of tri-weekly nab-PTX for patients with AGC with PS-0, 1 plus 2 in a second-line or later setting. At the time when the current study was ongoing, a result of the phase III ABSOLUTE study was reported [23], in which the survival benefits of tri-weekly nab-PTX (260 mg/m 2 ) or weekly nab-PTX (100 mg/m 2 ) were compared with weekly sb-PTX (80 mg/m 2 ) in patients with previously treated AGC. The results showed that weekly nab-PTX showed non-inferiority to weekly sb-PTX, whereas tri-weekly nab-PTX failed to demonstrate non-inferiority to sb-PTX. Interestingly, the study also showed that weekly nab-PTX had considerably lower grade 3 or higher toxicity than tri-weekly nab-PTX especially in terms of neutropenia (41.1 vs. 64.8%) and CIPN (2.5 vs. 20.1%). As a result of these findings, tri-weekly nab-PTX (260 mg/m 2 ) is not commonly utilized in a clinical setting in AGC.
In the current study, we observed grade 3 or higher neutropenia at a rate of 38%, febrile neutropenia at 3%, and grade 3 or higher CIPN at 13%, whereas previous trials in AGC evaluating tri-weekly nab-PTX at 260 mg/m 2 showed grade 3 or higher neutropenia and CIPN at rates of 49.1-64.8% and 20.1-23.6%, respectively. These results suggest that tri-weekly nab-PTX at 220 mg/m 2 achieved the expected reduction of adverse events, consistent with previous trials in MBC [21,22] With regard to the efficacy, however, RR, the primary endpoint of this study, was only 3.1%, in addition to the relatively short median PFS and OS of 2.2 and 6.3 months, respectively. In contrast, previous studies evaluating triweekly nab-PTX at 260 mg/m 2 showed RR of 25-27.8% as well as PFS and OS of 2.9-3.8 months and 9.2-10.3 months, respectively [18,23]. These data indicate that the efficacy of the reduced dose of nab-PTX is not satisfactory, unlike in MBC [14,20], despite the considerably low toxicities, so it is not recommended in clinical practice. Potential reasons for the poorer efficacy in the current study than in previous ones in AGC [18,23] include the difference in the treatment line (second line or later vs. exclusively second line) and the relatively poor patients background in our study.   In comparison with the other studies, our study population tended to be older (median age, 70 vs. 63.5 and 66 years) and had poorer ECOG PS (PS-0, 56 vs. 58.9 and 69%; as shown in Table 5). Indeed, the RDIs of phase II study and ABSOLUTE study were 93.4% (243 mg/m 2 ) and 88.06% (229 mg/m 2 ), respectively, which were higher than that in our study (97.8%: 215 mg/m 2 ). Furthermore, the poorer patients' background might lead to lower frequency of subsequent chemotherapy in the current study (62.5%) vs. others (81.5% [18] and 71% [23]) as was the number of patients administered CPT-11-based chemotherapy as subsequent therapy (53.7% and 51% [18] vs. 37.5% [23]). These results may support the hypothesis that the insufficient efficacy in the current study was derived from the inadequate treatment dose and the lower rate of subsequent treatment that may due to the difference in baseline patient characteristics between this study and the others.
In summary, the present study failed to show a clinical benefit of a reduced dose of tri-weekly nab-PTX in AGC and indicated that such treatment is not recommended, despite being potentially less toxic than the original dosing. Tri-weekly nab-PTX has little currency in the treatment of AGC as of the ABSOLUTE study [23], whereas the weekly administration of nab-PTX is now widely accepted. Following the success of the RAINBOW trial [7], weekly nab-PTX in combination with ramucirumab was examined in a phase II trial [24], showing promising activity with an RR of 54.8% and manageable toxicities. Given that the clinical benefit of weekly nab-PTX was pronounced in patients with peritoneal metastasis [23], a randomized phase II study comparing sb-PTX plus ramucirumab with nab-PTX plus ramucirumab is ongoing in AGC patients with peritoneal metastasis in a second-line setting (WJOG_P-SELECT study, jRCTs031180022), and the results of which are awaited.  Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.