A single-arm phase II study of nab-paclitaxel for patients with chemorefractory non-small cell lung cancer

This clinical trial was an open-label, multicenter, single-arm study involving 3 institutions in Aomori, Japan. This study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. This study was approved by the institutional review boards at each institution. Patients selected whether they would participate in this trial after detailed explanation; written informed consent was obtained from all patients before the study entry. This study was registered with the University Hospital Medical Information Network (UMIN). Clinical trial number UMIN000011696.

Patient eligibility required compliance with the following criteria: histologically or cytologically confirmed NSCLC. The patients were ≧ 20 years, had chemorefractory disease, measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1), an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2. Patients also had adequate bone marrow function (peripheral leukocyte count ≧ 3000/mm³, neutrophil count ≧ 1500/mm³, hemoglobin ≧ 9.0 g/dL, and platelet count ≧ 100,000/mm³), an adequate function of other organs includes aspartate transaminase and alanine transaminase levels ≦ 2.0 × the upper limit of normal, creatinine ≦ 1.5 mg/dl, total bilirubin concentration ≦ 1.5 mg/dl, and PaO2 ≧ 60 Torr or SpO2 ≧ 95%. The life expectancy more than 8 weeks was required. Patients who had undergone thoracic radiation therapy were required to finish their last treatment at least 12 weeks prior to registration in the protocol. Patients with symptomatic central nervous system metastasis, uncontrolled pleural effusion, pregnancy or lactation, the use of corticosteroid or immunosuppressive drugs or medical problems such as active peptic ulcer, heart disease, interstitial pneumonia or pulmonary fibrosis, cerebrovascular disease, and diabetes mellitus were excluded.

Patients were received nab-PTX, 100 mg/m² i.v. on days 1, 8, and 15 every 4 weeks. Treatment was discontinued when the patients had disease progression, and observed unacceptable toxicity and the patient refused protocol treatment. Restarting was approved when adequate organ function was recovered and fulfilled the following criteria: the neutrophil count was ≧ 1500/mm³, the platelet count was ≧ 100,000/mm³, total bilirubin was ≦ 1.5 mg/dl, the ECOG PS was ≦ 2, and the grade of any non-hematologic toxicity was ≦ 2, there was no infection. Before administration of nab-paclitaxel on days 8, 15, the neutrophil count ≧ 500/mm³ and the platelet count ≧ 50,000/mm³ were required. The dose of nab-PTX was reduced to 75 mg/m² in case of leukopenia or neutropenia of grade 4 persisting for ≧ 5 days, thrombocytopenia of grade 4 or requiring platelet transfusion, febrile neutropenia, or non-hematologic toxicity of grade ≧ 3 during the previous courses. Second dose reduction 50 mg/m² was done if these toxicities occurred after the reduction of the dose to 75 mg/m². The third dose reduction was not permitted, and the protocol treatment was finished.

The primary endpoint was the overall response rate (ORR). Secondary endpoints were the progression-free survival time (PFS), overall survival (OS), and toxicity profiles. Simon’s two-stage minimax design was chosen to determine the number of patients required for our study. The ORR 20% was set for the target activity level, with 5% as the lowest response rate of interest. The study was designed to have 90% power to accept and a 1-sided level of type I error of 5% significance to reject the hypothesis. If one or more out of 13 patients responded in the first stage, this trial could be continued to the second stage. The estimated accrual number was 27 patients. Allowing 10% of the patients to be ineligible, we planned to enroll 30 patients in the study. If ≧5 responses were observed by the end of the study, we considered that the primary endpoint was met. The PFS time and OS were estimated using the Kaplan–Meier method. The PFS has been defined as the time from the date of the start of treatment to the date of disease progression or death or the date of last contact. If neither event is observed, it is considered to be censored with the latest observation date. If the date on which the exacerbation on the image has been confirmed has exceeded 8 weeks since the last examination date, it shall be censored with the previous examination date. If post-treatment is started, it is considered to be censored with the treatment start date. If the event is unknown because it is a transfer or a non-arrival, it will be terminated with the date of the final survival confirmation. The OS time has been defined as the time from the date of the start of treatment to the date of death or last contact. In patients who cannot follow up, they are censored on the day that survival is confirmed before becoming impossible to pursue. Statistical analyses were performed using JMP 10 (SAS Institute, Cary, NC, USA). Tumor responses were assessed using chest radiography, computed tomography scan at every cycle until disease progression. Unidirectional measurements were adopted on the basis of the RECIST, version 1.1. Toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 4.0.

From July 2013 to July 2015, a total of 31 patients were enrolled from 3 participating institutions in Aomori. Table 1 showed the characteristics of the 31 eligible patients. There were 24 male (77.4%) patients and 7 female (22.6%) patients, with a median age of 66 years (range, 48–81 years). All patients included in this study were Asian. Most patients (87.1%) had a good ECOG PS score of 0–1. The most common histology was adenocarcinoma (51.6%), followed by 12 squamous cell carcinoma (38.7%), non-small cell carcinoma not otherwise specified (NOS) (9.7%). Fourteen patients (45.1%) received nab-paclitaxel as a second-line therapy and 17 patients (54.9%) received it as an over third-line therapy. Only 3 patients (9.6%) were positive and 28 patients (90.4%) were negative or unknown for the EGFR mutation.

Thirty-one patients were deemed eligible for evaluation of treatment response. Six patients attained a partial response (PR), and no patients attained a complete response (CR). The ORR was 19.3% (95% confidence interval: CI, 9.1%–36.2%), (90% CI, 10.3%–33.2%) (Table 2). Seventeen patients (54.8%) had stable disease (SD) a disease control ratio (DCR) was 74.1%. Eight patients (25.8%) had progressive disease. By the time of analysis, 26 patients had the disease progression events. The OS events occurred in 15 patients. The median PFS was 4.5 months (95% CI, 3.5–6.3 months) (Fig. 1), and the median OS was 15.7 months (95% CI, 11.7 months, not reached) (Fig. 2). The one-year survival rate was 54.8%. Clinical data of post-study treatment were available in 25 patients (80.6%). Twenty-one patients (84.0%) received salvage chemotherapy regimens as post-study treatment. Nine patients in the 1 prior line group received post-study treatment, 3 patients in the 2 prior lines group received post-study treatment and 9 patients in the 3 or more lines group received post-study treatment. Nineteen patients were treated with single agent cytotoxic drug. The three most common agents were vinorelbine (42.0%), S-1 (31.0%) and gemcitabine (21.0%). Two patients with known driver genes were treated with molecular target agents.

The median number of treatment cycles was 5 (range, 1–11 cycles). Fifteen patients (48%) required dose reduction. The primary reasons for dose reduction were grade 4 neutropenia, febrile neutropenia, and grade 3 anemia or neuropathy.

The major toxicities are showed in Table 3. Grade 3 and higher hematologic toxicities included leukopenia (22.5%), neutropenia (38.6%), anemia (3.2%), and thrombocytopenia (0%). No patients received a packed red blood cell transfusion. Febrile neutropenia were observed in 4 patients (12.9%). Grade 3 or 4 non-hematologic toxicities were nausea or vomiting (6.4%), infection (12.9%), sensory neuropathy (9.6%), anorexia (3.2%), and liver dysfunction (3.2%). Most non-hematologic toxicities were generally mild and reversible. No treatment-related deaths were founded in this study.