A phase II clinical trial on the efficacy and safety of carboplatin plus nab-paclitaxel in chemotherapy-naive advanced or recurrent thymic epithelial tumors: protocol of Nab-TET

Introduction

Background

According to the statistics from the Japanese Regional Cancer Registry Project for the years 2011–2015, the age-adjusted incidence rate for thymic epithelial tumors (TETs), rare mediastinal tumors (1), is approximately 0.6 per 100,000 population per year, while that for thymic carcinoma (2) is 0.29–0.38 per 100,000 population per year. However, with advancements in imaging evaluation and increased awareness of the disease, the number of surgeries for thymoma in Japan rose from 1,712 cases in 2008 to 2,098 cases in 2018, while for thymic carcinoma cases increased from 240 to 325 during the same period. Surgical resection is the standard therapy for early-stage TETs (3), whereas systemic treatment is required for advanced or recurrent TETs (4).

According to the National Comprehensive Cancer Network (NCCN) guidelines (5), cisplatin (CDDP)- and anthracycline-based regimens are recommended for first-line chemotherapy in advanced or recurrent TETs. However, these treatment regimens have significant adverse effects, including nephrotoxicity caused by CDDP, cardiotoxicity caused by anthracyclines, and a decline in the performance status owing to the use of multiple drugs. Carboplatin plus paclitaxel therapy is preferred and commonly used as a regimen without anthracyclines. Recent trials have demonstrated the usefulness of adding ramucirumab to carboplatin and paclitaxel for thymic carcinoma (6). However, there are challenges in clinical use, such as the risk of hypersensitivity reactions due to the polyoxymethylene castor oil in paclitaxel, requiring premedication to suppress these reactions, inclusion of anhydrous ethanol as an additive, and frequent occurrence of peripheral neuropathy.

Rationale and knowledge gap

To address these issues, nab-paclitaxel, a nanoparticle formulation that binds paclitaxel to human serum albumin, was developed. Several clinical trials have been conducted on this drug in non-small-cell lung cancer (NSCLC), and it has been frequently used for the treatment of NSCLC because of its fewer adverse events, such as peripheral neuropathy, neutropenia, and myalgia (7,8). Regarding carboplatin plus nab-paclitaxel therapy for TETs in Japan, only four case reports of thymic carcinoma (9-12) and one case of thymoma (13) have been published to date.

Objective

Therefore, treatment with carboplatin and nab-paclitaxel may show similar effectiveness and reduced toxicity in patients with TETs. Based on this clinical background, we will conduct this phase II trial to clarify the efficacy and safety of carboplatin plus nab-paclitaxel for patients with TETs ( Nab-TET). We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1110/rc).

Methods

Study design

In this multicenter, single-arm phase II study, we aim to evaluate the efficacy and safety of investigational therapies—carboplatin and nab-paclitaxel—in chemotherapy-naïve patients with advanced or recurrent TETs. The study will be conducted at Nagasaki University Hospital and its affiliated institutions in Japan. A total of 44 patients is planned for enrollment over a 4-year period beginning in June 2024.

To date, no prospective interventional trials have explored response rates for the combination of carboplatin and nab-paclitaxel in TETs, although isolated case reports have documented individual responses. Given the rarity of TETs and the limited number of confirmatory phase III trials, establishing a predefined efficacy threshold based on historical data remains challenging. As such, this study is designed as an exploratory investigation. And to enhance feasibility and ensure adequate enrollment, the study sample will not be restricted to a single histological subtype but is designed to include both thymic carcinomas and thymomas.

The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Clinical Review Board of Nagasaki University (No. CRB24-001) and registered in the Japan Registry of Clinical Trials (No. jRCTs071240019) on June 6^th, 2024. The investigators will explain the concept of the trial to the patients and obtain written informed consent from all participating patients. Any changes to the study protocol or related procedures are subject to consultation with the Clinical Review Board, including an explanation of the content and rationale for the modifications. Following this process, approval was also obtained from the administrators of the participating institutions. The initial protocol was approved on April 1^st, 2024, and patient recruitment commenced in June 2024. The most recent version of the protocol (version 1.1) was approved on August 5^th, 2024.

Investigators will explain the study to all prospective participants and obtain written informed consent. The consent form includes a detailed explanation of the background, objectives, methods, and duration of the study and expected number of participants. It also outlines the potential benefits and risks of participation. Patients will be informed of their right to withdraw from the study at any time without penalty. Measures to protect personal data confidentiality are established, with clear guidelines for data storage, handling, and disposal. Contact information for inquiries or reporting adverse events will also be provided.

Inclusion criteria

• Written consent to participate in the study has been obtained from the patient.
• Patient is at least 18 years of age at the time consent is obtained.
• Pathological diagnosis of TETs, including thymoma or thymic carcinoma confirmed by histological or cytological analysis [tissue classification was determined based on the World Health Organization (WHO) classification of thoracic tumor histology, 5^th edition] (14).
• Patients with unresectable clinical staging (Masaoka-Koga classification) III, IVa/b, or postoperative recurrence requiring chemotherapy.
• Patients with or without measurable disease.
• No brain metastases requiring urgent irradiation or surgery (regardless of the presence or absence of symptoms).
• No uncontrolled pericardial effusions, pleural effusions, ascites, superior vena cava syndrome, or spinal cord compression. However, patients may be enrolled if they do not have grade three pleural effusion 14 days after intrapleural infusion of talc, antimicrobial agents, or OK432 (other anticancer agents are not acceptable) after the cessation of drainage.
• Expected survival of at least 3 months from the date of initiation of treatment.
• Patients with TETs who have not received prior chemotherapy other than molecular-targeted agents or radical radiotherapy within 3 months.
• Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1.
• Patients with preserved major organ function, such as bone marrow, liver, and kidney, and who meet the following criteria on examination within 2 weeks prior to enrollment (examination on the same weekday 2 weeks prior to the enrollment date is acceptable): (i) neutrophil count of ≥1,500/µL; (ii) hemoglobin value of ≥9 g/dL; (iii) platelet count of ≥100,000/µL; (iv) total bilirubin (T-Bil) level of ≤1.8 mg/dL (except for constitutional jaundice); (v) aspartate aminotransferase (AST) value of ≤100 U/L, however, if the patient has liver metastases, AST value must be <5 times the upper limit of the facility standard range; (vi) alanine aminotransferase (ALT) value of ≤100 U/L, however, if the patient has liver metastases, this limit should be ≤5 times the upper limit of the facility’s reference range; (vii) serum creatinine value of ≤2 mg/dL; (viii) peripheral oxygen saturation (SpO₂) level ≥90% in room air; however, if SpO₂ level <90%, the patient is eligible if partial pressure of oxygen (PaO₂) of 60 Torr or more is met.

Exclusion criteria

• Active multiple carcinomas (synchronous or heterochronic multiple carcinomas with a disease-free interval of ≤2 years that require treatment). Carcinoma in situ (intraepithelial carcinoma) and intramucosal carcinoma-equivalent lesions, considered curable by local treatment, are excluded from this criterion.
• Patients having infectious diseases requiring systemic treatment.
• Patients must have an axillary temperature of ≥38 ℃ at the time of enrollment.
• Patients with symptoms of superior vena cava syndrome requiring urgent radiotherapy.
• Patients with poorly controlled angina (angina with onset or worsening within the last 3 weeks) or a history of myocardial infarction within the past 3 months.
• Patients with diabetes mellitus or hypertension that are difficult to control.
• Pulmonary fibrosis evident on chest computed tomography.
• Grade two or higher peripheral neuropathy.
• Women who are pregnant, possibly pregnant, or lactating.
• Patients with psychiatric disorders or psychiatric symptoms that interfere with daily life and make it difficult for them to participate in the study.
• Patients receiving continuous systemic administration of steroids or immunosuppressive drugs (infliximab, cyclophosphamide, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, or tocilizumab) exceeding an oral prednisolone equivalent of 10 mg/day.
• History of severe drug allergy or hypersensitivity to therapeutic agents, polysorbate 80-containing products, or albumin. Patients who did not undergo localized in situ irradiation within 2 weeks of enrollment.
• Positive for hepatitis B surface (HBs) antigen or hepatitis C virus antibody (acceptable if antiviral therapy has been completed and the patient’s condition is stable).
• Human immunodeficiency virus antibody positive (if tested).
• Patients participating in another clinical trial that may affect the endpoints of this study (patients participating in other clinical trials must be confirmed by the study office at the time of enrollment).
• Other cases deemed inappropriate by the investigator.

Interventions

Carboplatin [area under the blood concentration-time curve (AUC) of 5 or 6] will be intravenously administered on day 1 and nab-paclitaxel (100 mg/m²) on days 1, 8, and 15, every 3 weeks for four cycles or until disease progression or the development of unacceptable toxicity. If a grade ≥3 toxicity occurs, the dose will be reduced by one level: carboplatin (AUC-1) and nab-paclitaxel (75 mg/m²). If the toxicity persists or worsens, the dose could be further reduced to a second level: carboplatin (AUC-2) and nab-paclitaxel (50 mg/m²). For patients who test positive for the HBs antibody or hepatitis B core antibody, supportive therapy will be provided in accordance with the Guidelines for Countermeasures for Hepatitis B Caused by Immunosuppression and Chemotherapy. Febrile neutropenia will be managed based on the Guidelines for the Management of Febrile Neutropenia. Antiemetic treatment could include 5-HT₃ receptor antagonists, NK1 receptor antagonists, corticosteroids, metoclopramide, and other agents, administered as clinically indicated. Interstitial pneumonia will be treated using corticosteroids or other appropriate therapies as needed. Insulin administration will be permitted in patients with steroid-induced hyperglycemia during chemotherapy. On the day of granulocyte colony-stimulating factor (G-CSF) administration, radiation exposure to the lung fields and administration of anticancer drugs will not be permitted. The use of investigational drugs, anticancer agents, immunosuppressants, or immunotherapies that might interfere with the treatment protocol will also be prohibited throughout the study period. Following completion of the treatment protocol, no additional therapy for TETs, including surgical intervention, will be administered unless clear evidence of disease progression exists. No specific restrictions will be imposed on follow-up treatment in cases of progression, recurrence, or non-evaluable outcomes. If any health-related harm occurs as a result of participation in this study, the principal investigator will ensure that appropriate medical care is provided in accordance with the condition of the patient and covered under standard health insurance as in routine clinical practice.

Endpoints

This study is expected to demonstrate efficacy comparable to or greater than that of the current standard treatment, carboplatin plus paclitaxel. Therefore, the primary endpoint will be the overall response rate (ORR), calculated using a 95% confidence interval (CI). The secondary endpoints will be overall survival (OS), progression-free survival (PFS), incidence of adverse events, and quality of life (QOL). We also plan to conduct subgroup analyses based on histological subtype to evaluate whether the response rate to chemotherapy varies across different tumor classifications. Efficacy will be assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. OS will be defined as the time from enrollment to the last confirmed day the patient was alive or to death from any cause, whereas PFS will be defined as the time from enrollment to either disease progression or death from any cause. The Kaplan-Meier method will be used to estimate OS and PFS after final data confirmation upon completion of follow-up. Reports on QOL after chemotherapy for TETs are limited. In this study, we will conduct a QOL analysis and present the mean values and their standard errors at each time point using the FACT-L. If a patient withdraws from the study for any reason, the study secretariat will determine whether the patient should be included in or excluded from the safety analysis. When inclusion is deemed appropriate, the secretariat will review the circumstances of the withdrawal and make a final decision following appropriate consultation.

Data collection and management

A schematic of the study is shown in Figure 1. If eligible, patients will be enrolled with a clinical trial subject number and anonymized by the study administration prior to the initiation of protocol treatment. The detailed schedule of measurements is presented in Figure 2. All collected data will be securely stored by the study administration for 5 years following the completion of the study. If a patient discontinues participation for any reason, the test results and data collected up to the point of withdrawal will be retained to the greatest extent possible. The observation period will continue until completion of the treatment course or until the date of discontinuation for those who stop protocol treatment early. The follow-up period will extend until 1 year after the date of death or 1 year after the last patient is registered, whichever comes first.

Figure 1 Schema of the study. If the eligibility criteria are met, carboplatin (AUC 5 or 6) will be administered on day 1, and nab-paclitaxel (100 mg/m²) will be administered intravenously on days 1, 8, and 15, every 3 weeks for four cycles. AUC, area under the blood concentration-time curve; PD, progressive disease; TET, thymic epithelial tumor.

Figure 2 Overview of measurements. ○^pre: performed within 1 year prior to enrollment. ○¹⁴: within 14 days before enrollment. ○²⁸: within 28 days before enrollment. ○: performed. ●: performed every 6 weeks. ◎: imaging for efficacy assessment: every 6 weeks for the first 6 months after treatment initiation until progression or death. After 6 months, the procedure was performed every 9 weeks. If protocol treatment is discontinued for reasons other than progression, the same imaging schedule applies until progression or death is confirmed, unless post-treatment begins before progression, in which case the schedule continues until the start of post-treatment. △: performed as needed if symptoms appear or new lesions are suspected. ○*: performed at four time points—at enrollment, and at 6, 12, and 18 weeks after treatment initiation. CT, computed tomography; HBc, hepatitis B core; HBs, hepatitis B surface; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; MRI, magnetic resonance imaging; PET, positron emission tomography; QOL, quality of life; SpO₂, peripheral oxygen saturation.

Data collection will occur at the following time points: (I) at registration; (II) 6 weeks after the start of treatment; (III) 12 weeks after the start of treatment; and (IV) 18 weeks after the start of treatment. Case report forms (CRFs) will be used for documentation, and the original CRFs will be submitted to the study secretariat by mail or hand delivery. After the follow-up period, data will be collected and analyzed. The study secretariat will prepare an analysis report and submit it to the principal investigator. The results of the study will be reported in full, regardless of the outcome.

Adverse events will be assessed using the Common Terminology Criteria for Adverse Events version 5.0. The causal relationship between adverse events and the investigational treatment will be classified into five categories: definite, probable, possible, unlikely, and unrelated. Events classified as definite, probable, or possible will be considered causally related to the treatment, while those assessed as unlikely or unrelated will be considered not causally related. Any event determined to be a serious adverse event will be immediately reported to the principal investigator. If the adverse events reported urgently by the facility fall into any of the following categories, the principal investigator will notify the Efficacy and Safety Evaluation Committee Secretariat by email:

• Death;
• Potential to lead to death;
• Requires hospitalization or extended hospitalization at a medical institution for treatment;
• Disability;
• Potential to lead to disability;
• Serious events equivalent to (I) to (V) above;
• Congenital disease or abnormality in future generations;
• Malignancy.

If the Efficacy and Safety Evaluation Committee Secretariat determines that an adverse event is causally related and warrants reporting, it will be reported it to the Clinical Review Board of Nagasaki University. The study may be terminated early due to adverse events, insufficient enrollment, or other unforeseen circumstances. The decision to terminate the study prematurely will be made by the Efficacy and Safety Evaluation Committee.

Quality control

The monitoring manager will be responsible for ensuring that the human rights of the subjects are protected, the study will be conducted in accordance with the protocol, and the data are accurately collected. Central monitoring will be conducted twice a year based on the CRF data collected from each facility. The monitoring manager will prepare a report that includes a summary of important findings such as diseases, nonconformities, or other facts, and shall report the results of such monitoring to the principal investigator. An independent expert, serving as the monitoring director, will be responsible for safety oversight and will conduct safety monitoring, including comparisons of adverse event incidences. This study will not include on-site audits.

Discussion

Advanced or recurrent TETs are primarily treated with cytotoxic chemotherapy as the first-line therapy, while second-line regimens often include molecular-targeted agents, such as lenvatinib, everolimus, and sunitinib (5). However, cytotoxic agents are not curative, and the efficacy of molecular-targeted therapies remains limited owing to the lack of obvious driver mutations (15), such as epidermal growth factor receptor (EGFR) mutations in NSCLC (16). Promising therapeutic targets, including general transcription factor 2-I (GTF2I), rat sarcoma viral oncogene (RAS), and additional sex combs like 1 (ASXL1), have been reported (17). In addition, the efficacy of immune checkpoint inhibitors has garnered increasing attention, and recent clinical trials have begun investigating their potential in the treatment of thymic carcinoma (18). However, the rarity of TETs poses challenges in advancing research, preventing the establishment of standard treatments.

This is the first prospective trial to evaluate the efficacy and safety of carboplatin plus nab-paclitaxel for TETs. TETs are rare diseases, and in a previously planned study, analyzing them was not possible because of low accruals (19). Therefore, to increase the number of cases, we decided to target both thymic carcinoma and thymoma, and set a relatively long enrollment period of 4 years.

Previously, the NCCN guidelines for thymomas and thymic carcinomas recommended a regimen of three or more drugs based on CDDP and anthracycline for unresectable or post-surgical recurrent TETs. Regarding thymoma, intensive regimens such as CDDP, doxorubicin, vincristine, and cyclophosphamide therapy and CDDP, doxorubicin, and cyclophosphamide therapy—comprising three or more cytotoxic agents—are commonly used in clinical practice (20,21). As a regimen without anthracyclines, carboplatin plus paclitaxel therapy was reported in 2011, with a response rate of 42.9% (90% CI: 24.5–62.8%). The same guidelines recommend this regimen for thymic carcinoma, with response rates of 21.7% (90% CI: 9.0–40.4%) to 36% (95% CI: 21–53%) (22,23). Based on these results, this regimen has been recommended as the first-line therapy for TETs and for cases where anthracyclines are intolerable (5). However, paclitaxel-induced peripheral neuropathy is often encountered in clinical practice, which can significantly lower a patient’s QOL.

In a phase III international randomized trial (CA031 trial) comparing carboplatin plus nab-paclitaxel therapy with carboplatin plus paclitaxel therapy for advanced/recurrent NSCLC, the primary endpoint of the response rate was significantly higher (33.0% vs. 25.0%; 95% CI: 1.082–1.593; P=0.005), demonstrating the superiority of the nab-paclitaxel regimen. Additionally, the median time to improvement of grade ≥3 sensory neuropathy to grade one was shorter with nab-paclitaxel (38 days) than with paclitaxel (104 days). Sensory neuropathy (all grades) occurred in 46% of patients in the nab-paclitaxel group and 62% in the paclitaxel group, with 54% and 38% of patients not developing neuropathy, respectively (P<0.001) (24). Considering these points, carboplatin plus nab-paclitaxel therapy may be a promising first-line regimen with a relatively mild side-effect profile and expected efficacy for rare TETs.

Thymic carcinoma and thymoma exhibit significant biological differences (25), which may contribute to distinct responses to chemotherapy. Therefore, we plan to conduct subgroup analyses according to histological subtype and compare our results with those in previous reports, while acknowledging differences in patient populations and study designs. We acknowledge that a significant imbalance between thymomas and thymic carcinomas in this subgroup analysis could limit the interpretation and generalizability of the findings. However, given the rarity of TETs, we believe the chosen analytical approach remains reasonable. Compared to these regimens, our regimen may provide a less toxic alternative while maintaining efficacy. In conclusion, we conducted a phase II trial to evaluate the efficacy and safety of this regimen in patients undergoing TETs.

Acknowledgments

The authors are grateful to all patients, oncologists, allied healthcare professionals, research concierges, and research assistants who participated or will participate in this study.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1110/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1110/prf

Funding: This study was supported by the Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1110/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Clinical Review Board of Nagasaki University (No. CRB24-001) and registered in the Japan Registry of Clinical Trials (No. jRCTs071240019) on June 6^th, 2024. The investigators will explain the concept of the trial to the patients and obtain written informed consent from all participating patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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