Pembrolizumab plus lenvatinib in the treatment of unresectable cutaneous angiosarcoma: a study protocol of multicentre, open-label phase II study (NCCH2213, PLAS)

Abstract

Introduction

Cutaneous angiosarcoma (cAS) is a rare and aggressive malignancy with a poor prognosis. The disease most commonly occurs in older adults, with a peak age of 79–85 years and its incidence is expected to increase with population ageing. Standard treatments include radical surgery, radiation therapy, chemotherapy and combinations thereof. Paclitaxel is a commonly used systemic therapy; however, the 5-year overall survival (OS) rate remains approximately 32%. Therefore, the development of more effective treatments is urgently needed. Preclinical studies suggest that lenvatinib exerts immunomodulatory effects that may enhance the efficacy of programmed cell death protein 1/programmed cell death protein 1 inhibitors. Clinically, the combination of pembrolizumab and lenvatinib has been approved for uterine corpus cancer and renal cell carcinoma. We aim to evaluate the efficacy and safety of pembrolizumab plus lenvatinib in patients with unresectable cAS.

Methods and analysis

The PLAS study (NCCH2213) is a multicentre, open-label, phase II, investigator-initiated trial comprising two cohorts: cohort A (patients who have not been treated) and cohort B (patients who have previously received chemotherapy). Pembrolizumab (200 mg) is administered intravenously on day 1 of each 21-day cycle, and lenvatinib is administered orally at a dose of 20 mg daily on days 1–21 of each cycle. Treatment will continue for up to 35 cycles unless discontinuation criteria are met. The primary endpoint is the objective response rate, as assessed by central review. Secondary endpoints include objective response rate assessed by site investigators, progression-free survival, OS, disease control rate, duration of response, time to response and the incidence of adverse events and adverse drug reactions. An interim analysis will be conducted according to the Southwest Oncology Group two-stage design. The design emphasises feasibility in a rare cancer population and prioritises patient safety while pursuing therapeutic innovation. An independent Data and Safety Monitoring Committee and external reviewers will oversee safety and central tumour assessments.

Ethics and dissemination

This study (NCCH2213_protocol_en_ver.5.0) was approved by the institutional review boards of the National Cancer Center, Japan (number: NCCH2213). The results will be published in a peer-reviewed journal within 1 year of the study’s completion.

Trial registration number

NCT06673628.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Prospective multicentre phase II trial of pembrolizumab plus lenvatinib for unresectable cutaneous angiosarcoma.

• Conducted across six specialised centres with central independent response assessment and safety monitoring.

• Includes both treatment-naïve and previously treated patients, reflecting real-world clinical practice.

• Embedded translational research may identify genomic and immunological biomarkers of treatment response.

• Single-arm design and small sample size inherent to this ultra-rare disease limit direct comparisons with standard therapies.

Introduction

Cutaneous angiosarcoma (cAS) is an exceedingly rare form of sarcoma that originates from vascular endothelial cells¹ and frequently occurs in elderly individuals, with a high incidence of recurrence and metastasis after surgery. Patients with cAS account for 2–3% of all soft-tissue and visceral sarcomas.^{2 3} Angiosarcomas can be classified into five subtypes: cAS not associated with lymphedema (primary cAS), cAS associated with lymphoedema, radiation-induced cAS, angiosarcoma of the deep soft tissue and angiosarcoma of the parenchymal organs.⁴ The site with the highest incidence is the cutaneous site, accounting for approximately 49.6% of cases. This is followed by the breast parenchyma (14.4%), soft tissue (11.2%), heart (6.7%), bone (4.1%) and other sites (14%).⁵ cAS has a poor prognosis, with reported 5-year overall survival (OS) rates of 11–53%.^5–12 The most prevalent age range for cAS is 79–85 years.¹³ Given the increasing incidence of cAS in an ageing population and its poor prognosis, the development of effective treatments is imperative.

The standard treatment regimens for cAS include radical surgery, radiation therapy, chemotherapy and their combinations. While conventional therapeutic modalities are widely used, their efficacy remains limited. A previous clinical study indicated that paclitaxel administration resulted in an 18% (5 of 27) reduction in cancer lesions in patients after 2 months of treatment.¹⁴ Consequently, paclitaxel has become one of the most widely used agents for advanced cAS based on its clinical activity. Other treatment options in Japan include anthracyclines, pazopanib, eribulin, trabectedin and gemcitabine plus docetaxel. However, the prognosis of advanced cAS remains poor despite these treatments, with a recently reported 5-year OS rate of 32%.¹⁵ Therefore, the establishment of novel therapeutic strategies is urgently needed.

Recent studies have suggested that immune checkpoint inhibitors (ICIs) may have clinical activity in angiosarcoma. Several retrospective analyses and prospective studies have reported durable responses to anti-programmed cell death protein 1 (PD-1) therapy, particularly in cAS of the scalp and face.^16–19 Genomic analyses have demonstrated that a subset of head and neck cAS exhibits a high tumour mutational burden and ultraviolet mutational signatures, which may contribute to enhanced immunogenicity and sensitivity to ICIs.^{17 20 21} In addition, programmed cell death protein 1 (PD-L1) expression and tumour-infiltrating lymphocytes have been observed in some angiosarcoma cases, further supporting the rationale for immunotherapy in this disease.^{17 22 23}

Antiangiogenic therapies also represent a biologically relevant approach for angiosarcoma because these tumours originate from vascular endothelial cells and are highly dependent on angiogenic signalling pathways.^{24 25} Clinical activity of vascular endothelial growth factor (VEGF)-targeted therapies, including pazopanib and bevacizumab-based regimens, has previously been reported in angiosarcoma.^26–29 Lenvatinib is a multikinase inhibitor targeting VEGF receptors and other angiogenesis-related kinases and has also been shown to exert immunomodulatory effects within the tumour microenvironment. Preclinical studies demonstrated that lenvatinib reduces tumour-associated macrophage populations and enhances activated cytotoxic T-cell responses through interferon-γ signalling. These findings suggest potential synergistic effects when lenvatinib is combined with PD-1/PD-L1 blockade.³⁰

The combination of pembrolizumab and lenvatinib has demonstrated promising efficacy across multiple malignancies. The phase III KEYNOTE-775 study³¹ reported significantly prolonged progression-free survival (PFS) and OS with pembrolizumab plus lenvatinib compared with chemotherapy in advanced endometrial cancer. Similarly, the phase III CLEAR study³² demonstrated significantly improved PFS with this combination compared with sunitinib in advanced renal cell carcinoma. Furthermore, pembrolizumab plus lenvatinib has shown antitumour activity in other refractory solid tumours, including melanoma and hepatocellular carcinoma.^{33 34}

Therefore, in March 2025, we initiated a single-arm confirmatory study (NCCH2213/PLAS study) to evaluate the efficacy and safety of pembrolizumab combined with lenvatinib in patients with unresectable cAS.

Methods and analysis

Aim

We aim to evaluate the efficacy and safety of the combination of pembrolizumab and lenvatinib in previously untreated and treated patients with unresectable cAS (figure 1).

Figure 1. Study schema for the PLAS study (NCCH2213). IV, intravenous; ORR, objective response rate; PO: Product Owner; q3w, Every 3 weeks; PS, performance status.

Study setting

This is an investigator-initiated, single-arm, open-label, multicentre, phase II study. In this study, the results of the ANGIOTAX study¹⁴ will be considered historical data for comparison, and patients will be enrolled regardless of their history of chemotherapy for cAS. However, 11 of the 30 enrolled patients in the ANGIOTAX study were previously treated, and 19 were not, which represents a ratio of approximately 1:2. The threshold ORR was set at 18% based on the ORR reported for paclitaxel in the ANGIOTAX study.¹⁴ The expected ORR was set at 35%, considered the minimum clinically meaningful efficacy to warrant further clinical development of the investigational treatment. Under these assumptions, a total of 35 patients in full analysis set (FAS) are required to achieve a power of 70% with a one-sided alpha of 5%. The planned sample size is 38 patients in total, accounting for a small number of ineligible patients and those without the protocol treatment. To align with the patient group ratio of the ANGIOTAX study, this study sets a maximum enrolment limit of 13 and 25 for previously treated and previously untreated patients to ensure comparability. This study is conducted at six sites in Japan. The first author serves as the study chair.

The Data and Safety Monitoring Committee is responsible for providing the coordinating committee with an opinion on the appropriateness of continuing this study in the event of serious adverse events (AEs), other safety issues, interim analysis results or revisions to the study protocol.

Endpoints

The primary endpoint of this study is the objective response rate (ORR) to combination therapy with pembrolizumab and lenvatinib for unresectable cAS based on Response Evaluation Criteria in Solid Tumours V.1.1 at central review. The secondary endpoints are ORR (as determined by the site investigators), PFS, OS, disease control rate, duration of response, time to response, incidence of adverse events (AEs), incidence of drug-related AEs (adverse drug reactions, ADRs) and incidence of serious AEs/ADRs.

The central review will be conducted by three independent external evaluators, comprising one radiologist and two dermatologists specialising in oncology.

Characteristics of the participants

Inclusion criteria

The inclusion criteria will be as follows:

1. Histological diagnosis of cAS (if a histopathological examination is performed before the date of enrolment, a diagnosis can be established at any time. However, if a histopathological examination had been performed at another hospital, a pathological specimen should be obtained and the pathological diagnosis should be established again at each study site).

2. Unresectable primary or metastatic disease.

3. Absence of spinal metastases that require radiotherapy or surgical intervention.

4. Absence of pericardial or pleural effusion or ascites that requires treatment.

5. Age at enrolment: ≥18 years and ≤85 years.

6. Most recent Eastern Cooperative Oncology Group performance status score of 0 or 1 within 14 days before enrolment (including the same calendar day 2 weeks prior to enrolment).

7. A contrast-enhanced CT/MRI (head, neck, chest, abdomen, pelvis: slice thickness ≤5 mm) performed within 14 days prior to enrolment or having at least one measurable lesion^* that can be confirmed to be present on the surface of the body by visual inspection (for patients with contrast allergy or renal function deterioration, plain CT is allowed). ^*Measurable lesion: non-nodal lesion with a large diameter of ≥10 mm or nodal lesion with a short diameter of ≥15 mm. Irradiated lesions are considered measurable if disease progression is confirmed and the size criteria are met.

8. Cohort A (untreated patients): cAS without prior chemotherapy Cohort B (previously treated patients): cAS with prior chemotherapy (except for those described in exclusion criteria 1 and 2)

9. Adequately controlled blood pressure (BP) with or without antihypertensive medications^*1, defined as BP ≤150/90 mm Hg^*2 with no change in antihypertensive medications within 7 days prior to enrolment. ^*1 The number of antihypertensive drugs counted by components should be ≤2. ^*2If the patient’s first BP measurement of the current assessment is elevated (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 5 min later. One BP assessment will be defined as the mean value of two measurements taken at least 5 min apart. If the BP assessment (ie, the mean of the two BP measurements obtained at least 5 min apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 30 min later by performing two measurements (at least 5 min apart) to yield a mean value.

10. Wounds (eg, those after a surgical procedure or trauma) that have healed at enrolment.

11. No major surgery performed within 21 days of the first dose of the study intervention. (Note: Adequate wound healing after major surgery must be assessed clinically independent of the time elapsed for eligibility).

12. Laboratory tests performed within 14 days before the enrolment date meeting the following (1) to (10). (However, patients should not receive granulocyte colony-stimulating factor or blood transfusions within 14 days before the day of blood collection):

    1. Neutrophil count ≥1,500/mm³

    2. Platelet count ≥10×10⁴/mm³

    3. Hemoglobin ≥9.0 g/dL

    4. Aspartate aminotransferase ≤100 U/L

    5. Alanine aminotransferase ≤100 U/L

    6. Total bilirubin ≤1.5 mg/dL

    7. Serum creatinine ≤1.5 mg/dL

    8. Creatinine clearance ≥30 mL/min (Cockcroft–Gault) (Even if the calculated value is <30 mL/min, it can be registered if the value is ≥30 mL/min using the 24-h urine collection method).

    9. Urine protein levels (<1 g/24 h) (Note: Patients with proteinuria ≥2+ on urine dipstick testing [urinalysis] will undergo 24-h urine collection for quantitative assessment of proteinuria)

    10. Prothrombin time-international normalized ratio ≤1.5

• 13 1Male patients who agree to use highly effective contraception and do not donate sperm during treatment or for at least 120 days after the last dose of the investigational drugs. Female patients who agree to use contraception methods consistent with local regulations for those participating in clinical studies, are not pregnant or breastfeeding and meet at least one of the following conditions:

  1. Not a woman of childbearing potential (WOCBP)

  2. Is a WOCBP who tested negative by pregnancy test (highly sensitive serum or urinary human chorionic gonadotropin test) within 14 days prior to enrolment and using a contraceptive method that is highly effective (with a failure rate of <1% annually), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least 120 days after pembrolizumab or 30 days after lenvatinib, whichever occurs last (The investigator should evaluate the potential for contraceptive method failure (i.e. noncompliance, recently initiated) in relation to the first dose of the study intervention).

• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 h before the first dose of the study intervention.

• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the patient must be excluded from participation if the serum pregnancy result is positive.

  • The investigator is responsible for reviewing medical history, menstrual history and recent sexual activity to decrease the risk of inclusion of women with an early undetected pregnancy.

• 14 1At least 28 days have elapsed since the last day of prior chemotherapy, if applicable, and the patient has recovered from all treatment-related toxicities, except alopecia and haematological toxicities (≤Grade 1 or returned to baseline). Endocrine-related toxicities are permitted if appropriately managed with hormone replacement therapy. Patients with neuropathy ≤Grade 2 may be included in this study.
• 14 2Written informed consent for study participation being obtained from the patient.

Exclusion criteria

The exclusion criteria are as follows:

1. Previous treatment with anti-PD-1, anti-PD-L1 or anti-programmed cell death-ligand 2 (PD-L2) agents, or agents targeting other co-inhibitory T-cell receptors (eg, cytotoxic T-lymphocyte-associated protein 4, OX-40 or cluster of differentiation 137).

2. Previous treatment with lenvatinib or other angiogenesis inhibitors, including treatment for other types of cancer.

3. Considered likely to be cured with chemoradiotherapy at the discretion of the treating physician.

4. Receipt of radiation therapy within 14 days before the enrolment date or the presence of radiation therapy-related toxicities at enrolment. Note: Palliative radiotherapy (duration ≤14 days) for non-central nervous system diseases is permitted if performed after completion of a 7-day washout period.

5. Positive for human immunodeficiency virus antibody, hepatitis B surface (HBs) antigen or hepatitis C virus (HCV) antibody. Patients who are HCV antibody-positive but HCV-RNA-negative are not excluded.

6. HBs antigen-negative but HBs antibody-positive or HBc antibody-positive with detectable HBV-DNA (patients with undetectable HBV-DNA are not excluded).

7. Receipt of live or live attenuated vaccines within 30 days before enrolment. Patients who receive inactivated vaccines are not excluded.

8. Receipt of other investigational products or use of investigational medical devices within 28 days before enrolment.

9. Diagnosis of immunodeficiency or treatment with long-term systemic steroid therapy (>10 mg/day prednisolone equivalent) or other immunosuppressive therapies within 14 days before enrolment.

10. Presence of other malignancies requiring progressive or aggressive treatment within the past 3 years. However, even when the disease-free interval is <3 years, the following are not considered active double or multiple cancers if curatively treated: clinical stage 0 or stage I laryngeal cancer, clinical stage I prostate cancer, and other cancers with a 5-year relative survival rate ≥95%, including the following pathological stages:

• Gastric carcinoma (adenocarcinoma, common type): stage 0–I.

• Colon carcinoma (adenocarcinoma): stage 0–I.

• Rectal carcinoma (adenocarcinoma): stage 0–I.

• oesophageal carcinoma (squamous cell carcinoma, adenosquamous carcinoma, basaloid carcinoma): stage 0.

• Breast carcinoma (ductal carcinoma in situ or lobular carcinoma in situ): stage 0.

• Breast carcinoma (invasive ductal carcinoma, lobular carcinoma in situ, Paget’s disease): stage 0–IIA.

• Carcinoma of the uterine body (endometrioid adenocarcinoma, mucinous adenocarcinoma): stage I.

• Prostate carcinoma (adenocarcinoma in situ): stage I–II.

• Cervical carcinoma (squamous cell carcinoma): stage 0.

• Thyroid carcinoma (papillary carcinoma, follicular carcinoma): stage I–III.

• Renal carcinoma (clear cell carcinoma, chromophobe cell carcinoma): stage I.

• Skin carcinoma (squamous cell carcinoma, basal cell carcinoma): stage 0–I.

• Skin carcinoma (malignant melanoma): stage 0–I.

• Other lesions equivalent to intramucosal carcinoma.

NOTE: Staging is based on the Union for International Cancer Control Tumour-Node-Metastasis eighth edition or equivalent cancer staging systems.

1. Active central nervous system metastases or carcinomatous meningitis. However, patients with previously treated brain metastases may be included if imaging shows stable disease (no progression for ≥28 days), re-imaging is performed within 28 days prior to enrolment, the patient is clinically stable and no steroid treatment has been required for at least 14 days before enrolment.

2. Severe (≥Grade 3) hypersensitivity to pembrolizumab, lenvatinib or their excipients.

3. Active autoimmune disease requiring systemic treatment within the past 2 years, except for replacement therapies (eg, thyroxine, insulin or physiological doses of steroids).

4. History of interstitial lung disease or pneumonitis, or pneumonitis requiring steroid treatment (non-infectious).

5. Active infection requiring systemic treatment at the time of enrolment.

6. Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula at enrolment. Includes active gastrointestinal ulcers or other fistulas requiring invasive treatment.

7. Gastrointestinal malabsorption or other conditions that may affect lenvatinib absorption (eg, history of total gastrectomy).

8. History of acute coronary syndrome (including myocardial infarction or unstable angina), coronary angioplasty or coronary stenting within 6 months prior to enrolment.

9. Clinically significant cardiovascular disease within 12 months prior to enrolment, including New York Heart Association class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident or cardiac arrhythmia associated with haemodynamic instability. NOTE: Medically controlled arrhythmia is permitted.

10. Left ventricular ejection fraction <50% as determined by multigated acquisition scan or echocardiography within 14 days prior to enrolment.

11. Complications requiring hospitalisation (eg, intestinal palsy, intestinal obstruction, pulmonary fibrosis, poorly controlled diabetes mellitus, cardiac failure, myocardial infarction, unstable angina, renal failure, hepatic failure, psychiatric disorders or cerebrovascular disorders).

12. Radiographic evidence of encasement or invasion of a major blood vessel, or intratumoural cavitation. NOTE: Proximity to major blood vessels should be carefully evaluated due to the potential risk of severe haemorrhage associated with tumour shrinkage or necrosis following lenvatinib treatment.

13. QTcF prolongation >480 ms within 14 days prior to enrolment.

14. Active haemoptysis (≥0.5 teaspoon of bright red blood) within 21 days prior to enrolment.

15. Psychotic or psychiatric disorders or substance use disorders that interfere with daily functioning and are considered likely to impair participation in the study.

16. History of allogeneic transplantation.

Treatment

Pembrolizumab (200 mg) will be administered intravenously on day 1 of each 21-day cycle. Lenvatinib will be administered orally at a daily dose of 20 mg on days 1–21 of each cycle. Pembrolizumab and lenvatinib will be administered for up to 35 cycles, unless the protocol treatment discontinuation criteria are met. For patients who have completed the protocol treatment with a complete response (CR) and experienced recurrence afterwards, pembrolizumab and lenvatinib can be administered at the same dose and frequency as the protocol treatment up to 17 cycles (21 days per cycle) in addition. This additional treatment is called the second treatment.

Evaluation of adverse events

Pembrolizumab should only be administered at a dose of 200 mg, if an infusion reaction or immune related adverse event (irAE) induced by pembrolizumab occurs, administration of pembrolizumab should be withheld or discontinued depending on the severity (Common Terminology Criteria for Adverse Events (CTCAE) grade). Treatment with lenvatinib should be suspended, the dose reduced or treatment discontinued depending on the severity of any lenvatinib-related AEs, as defined by the CTCAE grading system. In particular, if hypertension develops, patients should be monitored frequently and antihypertensive therapy initiated. To manage the risk of bleeding and ensure a certain level of safety, patient selection criteria should be employed and these events managed in the same manner as lenvatinib-related AEs. A four-step dose reduction protocol should be established for lenvatinib at 20, 14, 10 and 8 mg. The Japanese translation of the CTCAE V.5.0 Japanese Translated Japanese Clinical Oncology Group (JCOG) Version (NCI-CTCAE V.5.0 (hereafter referred to as CTCAE V.5.0-JCOG) will be used to evaluate AEs.

Follow-up

The follow-up observation of patients who have completed and discontinued the protocol treatment will be conducted concurrently, on a 6-month basis, based on the date of enrolment of the first patient. Surveys will include survival confirmation, defined as the date or cause of death, if applicable. Additionally, surveys will document the initial progression following protocol treatment, subsequent treatment for cAS, date of treatment initiation and specific treatment administered.

Interim analysis and monitoring

An interim analysis will be performed in accordance with the Southwest Oncology Group two-stage design.^{35 36} In the first stage, enrolment will be suspended on the 20th patient. The data, including response evaluation results, used for the interim analysis will be locked approximately 12 weeks after the enrolment of the 20th patient. Even if the 20th patient is not evaluated 12 weeks after treatment initiation, the timing of the data lock will remain unaltered.

In the interim analysis, ORR will be calculated based on the best overall response (BOR) by the central review in FAS at the time. The PLAS study will be continued if three or more of the 20 patients are confirmed to have the BOR of CR or partial response (PR). However, if this criterion is met before the 20th patient is enrolled, an interim analysis will be performed. In this case, the enrolment process will not be suspended until the 20th patient is enrolled. Even if enrolment is suspended, an interim analysis will be performed if three or more patients are confirmed to have the BOR of CR or PR by central review before the BOR for all 20 patients are confirmed.

Statistical analyses

The primary analysis will be performed using data collected 6 months after accrual completion to determine whether pembrolizumab plus lenvatinib is an adequately active treatment. The primary endpoint, ORR by central review, will be analysed in the FAS, defined as all eligible patients who have received at least one dose of both investigational drugs. The null hypothesis for primary endpoint is ‘the true ORR is less than or equal to the threshold ORR (18%), which is considered ineffective’. If the null hypothesis is rejected based on the binomial test with a one-sided alpha of 5%, pembrolizumab plus lenvatinib is judged as an effective treatment, while the results of the secondary endpoints are also taken into consideration. If this combination treatment is judged as effective enough, regulatory application to expand the indication of this combination treatment will be planned.

Data sharing plan

The individual participant data will be made available on reasonable request.

Patient and public involvement

Patients or the public were not involved in the design.

Discussion

This study addresses the unmet need for effective systemic therapy for cAS. The combination of pembrolizumab and lenvatinib is therefore expected to offer synergistic benefits. The study design reflects feasibility within a rare cancer population and prioritises patient safety while aiming for therapeutic innovation.

The results of a phase II study (Alliance A091902) evaluating cabozantinib plus nivolumab for advanced angiosarcoma previously treated with taxane-based anticancer agents were presented at ASCO 2023. The study reported an ORR of 54% for cAS (n=13) among the 22 patients enrolled overall.³⁷ As the PLAS study employs a similar therapeutic concept, it is anticipated that the treatment regimen may also achieve a meaningful response rate.

Given the limited treatment options for unresectable cAS, this study provides patients who complete the protocol treatment with a CR an opportunity for a second course of treatment with pembrolizumab and lenvatinib. This second treatment regimen will be administered for up to 17 cycles. An interim analysis will be conducted during the accrual period. If the ORR is significantly lower than expected, enrolment will be terminated because of insufficient efficacy.

As the PLAS study targets cAS, an ultra-rare cancer, suspension of enrolment for interim analysis could negatively affect patient accrual. To minimise interruption of enrolment, the interim analysis will be conducted without suspending enrolment once three or more patients demonstrate a PR or CR based on central imaging review, as previously described.

Since this study is single-arm, it is not possible to directly compare the protocol treatment with other treatments within the same population. Furthermore, the open-label nature of this study may introduce information bias, and results from a small number of participants may be variable and unreliable. While efficacy will be assessed by comparing data from this study with the historical control, ANGIOTAX study, these two participant populations are not strictly identical, which limits comparability and may introduce selection bias. In addition, although this study is planned to be conducted at six large hospitals selected for case accumulation, it may not accurately reflect population characteristics, including cAS patients treated in clinics and smaller hospitals. Among these limitations, we hope that the results of this clinical trial will lead to new treatment options for cAS. Furthermore, we seek to identify biomarkers associated with the efficacy of the investigational treatment. To this end, integrated genomic and immunological analyses will be conducted to investigate their associations with clinical outcomes.

Trial status

This study is currently recruiting patients. The first patient was enrolled in March 2025, and 15 patients were enrolled by the end of July 2025. The planned accrual period is 2 years, and the study will be completed in November 2029.

Ethics and dissemination

This study is approved by the institutional review boards of all participating institutions. The results will be published in a peer-reviewed journal within 1 year of the study’s completion.