Skip to main content
Download PDF

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib

BMC Cancer volume 23, Article number: 219 (2023) Cite this article

Abstract

Background

Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS.

Methods

The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial.

Discussion

This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD.

Trial registration

This study was registered with the Japan Registry of Clinical Trials (jRCTs031190152) on December 5, 2019.

Peer Review reports

Background

Soft tissue sarcomas (STS) are rare malignancies that comprise a variety of histological diagnoses [1]. The standard treatment for STS is mainly based on the clinical stage and resectability of the tumor [2]. The standard treatment for resectable cases is surgical resection, whereas that for unresectable or metastatic advanced STS is chemotherapy.

Doxorubicin alone or in combination with ifosfamide or dacarbazine is widely accepted as first-line chemotherapy for advanced STS [2]. Doxorubicin induces irreversible cumulative cardiotoxicity, and second-line chemotherapy is required when the total dose approaches the upper limit or in tumors that are refractory to doxorubicin.

Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD) form the standard treatment options for second-line chemotherapy for advanced STS; however, there are no clear recommendations regarding the choice of regimen. The U.S. National Comprehensive Cancer Network guidelines list pazopanib, trabectedin, and eribulin as preferred regimens; other recommended regimens include dacarbazine, ifosfamide, temozolomide, vinorelbine, and regorafenib; pembrolizumab is also listed as a useful agent in specific cases [3]. The ESMO-EURACAN-GENTURIS guidelines recommend that second-line chemotherapy should be based on histopathology: trabectedin is a treatment option for all histological types, pazopanib should be used for non-liposarcoma, eribulin for liposarcoma only, and the GD and gemcitabine-dacarbazine combinations are preferred in patients who underwent prior treatment with doxorubicin-containing agents [2].

The results of clinical trials conducted to date {Table 1 [4,5,6,7,8,9,10,11,12,13,14,15]} indicate that trabectedin is highly effective for translocation-related sarcomas [6], liposarcoma and leiomyosarcoma (L-sarcoma) [4], eribulin for L-sarcoma, especially liposarcoma [9], pazopanib for other histological types besides liposarcoma[12], and GD for leiomyosarcoma [16], based on the histological inclusion criteria of each trial. These results have influenced the approval of each drug. While trabectedin is approved for L-sarcoma in the U.S.A., eribulin is approved exclusively for liposarcoma in the U.S.A and Europe, and pazopanib is approved for STS, excluding liposarcoma in the U.S.A and Europe. All three agents are approved for all histologic types of STS in Japan. Recent research, including that conducted using real-world data, has shown that all of these agents are effective against a wider range of histological types [17,18,19]. However, there is no clear evidence demonstrating the superiority of any one of these agents as second-line chemotherapy for advanced STS, since no randomized controlled trials have been conducted with these agents.

Table 1 Summary of median PFS and OS in clinical trials of trabectedin, eribulin, and pazopanib for advanced STS
Full size table

Therefore, the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG) planned to establish a standard second-line treatment for advanced STS from among the widely used regimens such as trabectedin, eribulin, pazopanib, and GD. First, we plan to conduct a selection design, randomized, phase II study using trabectedin, eribulin, and pazopanib, which are relatively new drugs for STS that have been approved since the 2010s. A randomized phase III study comparing the best second-line agent determined by this JCOG1802 study with GD, which has been in use since the 2000s and is currently deemed standard therapy for STS, will be planned.

Methods/design

Study design

The objective of this clinical trial (JCOG1802, 2ND-STEP) is to determine the most promising regimen among trabectedin, eribulin, and pazopanib, which will be designated as the test arm in a future phase III trial of second-line treatment for patients with metastatic or unresectable STS that has progressed after first-line chemotherapy with doxorubicin.

This multicenter, randomized, open-label, parallel-arm, selection design phase II trial aims to examine the efficacy and safety of trabectedin, eribulin, and pazopanib, which are widely used anticancer agents for advanced STS.

At commencement, this study will be conducted across 37 institutions in Japan, all of which are participants in the BSTTSG of the JCOG. Patients with advanced STS are being treated at all participating institutions, and potentially eligible patients will be registered by investigators. The study protocol was approved by the National Cancer Center Hospital Certified Review Board for Clinical Trials (CRB Certification No. CRB3180008) prior to the initiation of patient accrual.

The inclusion and exclusion criteria for this study are summarized in Table 2.

Table 2 Inclusion and exclusion criteria of JCOG1802
Full size table

After confirming participant eligibility, patients will be randomly assigned to the treatment arms at the JCOG Data Center. Random allocation to trabectedin, eribulin, and pazopanib will be performed using a minimization method in a ratio of 1:1:1. The institution, histology (liposarcoma vs. leiomyosarcoma vs. translocation-related sarcoma vs. other), and distant metastases (N1 and/or M1 vs. other) will serve as factors for allocation adjustment (Fig. 1).

Fig. 1
figure 1

Flowchart of JCOG1802 (2ND-STEP) study. STS: Soft tissue sarcoma; LPS: Liposarcoma; LMS: Leiomyosarcoma; TRS: Translocation-related sarcoma; IV: Intravenous drip; PO: Per os (Oral administration)

Full size image

Interventions

Patients will be randomized to arms A, B, or C (Fig. 1) as follows. arm A, intravenous drip infusion of trabectedin 1.2 mg/m2 (body surface area) on day 1 for 24 h every 3 weeks; arm B, intravenous drip infusion of eribulin 1.4 mg/m2 (of body surface area) on days 1 and 8 for 2–5 min every 3 weeks; and arm C, oral administration of pazopanib 800 mg/day more than 1 h before meals or more than 2 h after meals every day.

The criteria for dose reduction for each arm are set as follows. There are three dose levels of trabectedin in arm A: level 0 (full dose), 1.2 mg/m2; level 1, 1.0 mg/m2; and level 2, 0.8 mg/m2. There are three dose levels for eribulin in arm B: level 0 (full dose), 1.4 mg/m2; level 1, 1.1 mg/m2; and level 2, 0.7 mg/m2. There are four dose levels for pazopanib in arm C: level 0 (full dose), 800 mg/body; level 1, 600 mg/body; level 2, 400 mg/body; and level 3, 200 mg/body. The dose will be lowered by one level in the next course, in the event of severe myelosuppression, liver dysfunction, or cardiac dysfunction. The treatment protocol will be terminated if any toxicity is observed even at the lowest dose level.

The concomitant use of any of the following therapies is prohibited during administration of the treatment protocol: (1) anticancer drugs other than the treatment regimen, (2) radiation therapy (including particle therapy) for the target lesion, and (3) immunotherapy.

Participant timeline

The participant timeline is summarized in Table 3. Candidates who consent to participate will be checked for eligibility based on the inclusion/exclusion criteria, and enrollment will be completed after confirmation of participant eligibility. Physical examination, Eastern Cooperative Oncology Group performance status (PS), body weight, body height, complete blood count (CBC), serum biochemistry, activated partial prothrombin time, prothrombin time-international normalized ratio, thyroid stimulating hormone, free T4, and urine analyses are performed within 14 days before registration. Echocardiography, electrocardiography, contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis, and additional CT/magnetic resonance imaging (MRI) of the lesions will be performed within 28 days before registration. Plain CT is acceptable when contrast agents cannot be administered due to allergies, asthma, etc.

Table 3 The study schedule
Full size table

Participants will commence the treatment protocol within 14 days of registration. The treatment protocol is continued until one of the following termination criteria are met: (1) exacerbation of disease (judged as ineffective treatment); (2) the treatment protocol cannot be continued due to adverse events including grade 4 non-hematologic toxicity and delay of 56 days before the start of the next course; (3) the patient requests termination of treatment for reasons related to adverse events; (4) the patient requests termination of treatment for reasons unrelated to adverse events; (5) death during treatment; and (6) post-enrollment exacerbation prior to the initiation of treatment (inability to start the treatment protocol due to rapid progression), discovery of protocol violation, change of treatment due to a change in the pathological diagnosis after enrollment, or other reasons that make the patient ineligible for treatment.

Treatment efficacy will be determined by performing contrast-enhanced chest-abdomen-pelvis CT and additional CT/MRI of the lesions every 4 weeks on the first four occasions after initiation of the treatment protocol, and every 6 weeks thereafter. After termination of the treatment protocol, physical examination, PS, body weight, CBC, serum biochemistry, and adverse events will be assessed every 6 months. If treatment is terminated for reasons other than progression of the disease, 6-weekly CT examination will be continued until disease progression.

Primary endpoint

The primary endpoint is progression-free survival (PFS). PFS is defined as the period from the date of registration until the date of progression or the date of death from any cause, whichever is earlier. Herein, progression includes both progressive disease as determined by imaging based on the revised Response Evaluation Criteria in Solid Tumours (RECIST) guidelines, and clinical progression without confirmation by imaging studies.

Secondary endpoints

The secondary endpoints include overall survival, disease-control rate, response rate, and proportion of adverse events (adverse reactions). Overall survival is defined as the period from the date of registration to the date of death from any cause. The disease-control rate is defined as the proportion of patients with either complete response (CR), partial response (PR), or stable disease according to the RECIST criteria from amongst all eligible patients with measurable disease. The response rate is defined as the proportion of patients whose best overall response is either CR or PR amongst all eligible patients with measurable disease. The proportion of adverse events (adverse reactions) is defined as the frequency of adverse events (toxicity) of the worst severity according to the Common Terminology Criteria for Adverse Events v5.0-JCOG during the entire course.

Sample size calculation

The required sample size to accurately ascertain the most favorable treatment based on the point estimate of the hazard ratio (HR) was calculated using Monte Carlo simulation corresponding to the instance where an exponential distribution is assumed for Liu’s selection design [20]. Based on previous studies [4,5,6,7,8,9,10,11,12,13,14,15], we established an accrual period of 3 years, follow-up period of 6 months, and the median PFS for each arm to be 2, 2, and 4 months in condition 1; 2, 3, and 4 months in condition 2; and 3, 3, and 4 months in condition 3. Under these conditions, the required sample size to correctly select the most favorable treatment arm with a probability of 80% was 7 for condition 1, 20 for condition 2, and 34 for condition 3. To maintain the probability of correct selection of at least 80% in any condition, the planned sample size was set at 40 for each arm and the total sample size was 120, where the probability was 99.7% for condition 1, 88.8% for condition 2, and 83.0% for condition 3.

Data collection, management, monitoring, and auditing

Data entry into the electronic case report form is performed by investigators using an electronic data capture (EDC) system via the JCOG Web Entry System. Adverse events are closely monitored by investigators. Investigators will report severe adverse events to the institutional administrator and principal investigator, and then to the CRB of the National Cancer Center Hospital, as appropriate.

Clinical data entry, data management, and central monitoring will be performed using the EDC system, E-DMS Online (EPS Corporation, Tokyo, Japan). All statistical analyses will be conducted at the JCOG Data Center. Interim analysis is not planned for this study because the follow-up period for the primary analysis is short and any safety issues with participants can be ascertained through periodic monitoring. In-house monitoring will be performed every 6 months by the JCOG Data Center to evaluate the study progress and improve the quality of the data.

Statistical analysis

Statistical analysis will be performed at the JCOG Data Center. The primary analysis will be performed 6 months after the end of accrual, when collection of the primary endpoint data for all enrolled patients is expected to be complete. The treatment protocol with the best point estimate of the HR for PFS, which is the primary endpoint of this study, will be the test treatment arm in a subsequent phase III trial. However, the treatment arm for the phase III trial will be decided comprehensively if the following results are obtained, taking into consideration endpoints other than PFS. First, the PFS obtained is substantially lower than expected (insufficient results for promising therapy). Second, the overall survival results differ significantly from those of PFS. Third, the frequency of adverse events among the arms differs significantly from the expected frequency.

For the primary analysis of PFS, the respective HRs of arms A to B and A to C will be calculated using an unstratified Cox proportional-hazards model for all enrolled patients, and the treatment with the best HR will be judged to be the most promising regimen. Since this study does not make judgments based on hypothesis testing, no significance level is set a priori, and no adjustment will be made for multiplicity.

Subgroup analyses based on the factors mentioned below are to be conducted, as necessary. The factors for which subgroup analyses are planned include age group 1 (< 40/ ≥ 40 years), age group 2 (< 70/ ≥ 70 years), sex (male/female), PS (0/1 and 2), histological type (liposarcoma/leiomyosarcoma/translocation-related sarcoma/other), distant metastasis 1 [(M1 and/or N1)/other], distant metastasis 2 [M1/(N1 and M0)/other], and doxorubicin (perioperative chemotherapy/palliative chemotherapy).

Discussion

Most guidelines state that first-line chemotherapy for advanced STS should include doxorubicin alone or in combination with ifosfamide or dacarbazine; however, there are no clear guidelines for standard second-line therapy. One of the chief factors preventing the establishment of clear drug selection criteria for second-line chemotherapy for advanced STS is the lack of clinical trials that directly compare the efficacy and safety of drugs used for this purpose. Therefore, data from clinical trials with different types of participants are used as a reference for drug selection based on indirect comparison. We intend to overcome this problem by conducting this multicenter, randomized, open-label, parallel-arm, selection design phase II trial of the three major treatment options for second-line chemotherapy for advanced STS, viz. trabectedin, eribulin, and pazopanib. The JCOG 1802 trial (a randomized phase II trial of trabectedin, eribulin, and pazopanib as second-line treatment for advanced soft-tissue sarcoma after doxorubicin, which is also known as the 2ND-STEP trial) will be the first randomized trial using trabectedin, eribulin, and pazopanib for STS worldwide. This trial is expected to determine the most promising regimen from amongst trabectedin, eribulin, and pazopanib as the test arm regimen in a future phase III trial of second-line treatment for advanced STS patients.

Availability of data and materials

Not applicable.

Abbreviations

GD:

Gemcitabine plus docetaxel

L-sarcoma:

Liposarcoma and leiomyosarcoma

STS:

Soft tissue sarcoma

JCOG:

Japan Clinical Oncology Group

BSTTSG:

Bone and Soft Tissue Tumor Study Group

PFS:

Progression-free survival

RECIST:

Response Evaluation Criteria in Solid Tumours

EDC:

Electronic data capture

CR:

Complete response

PR:

Partial response

HR:

Hazard ratio

PS:

Performance status

CBC:

Complete blood count

CT:

Computed tomography

MRI:

Magnetic resonance imaging

References

  1. The WHO Classification of Tumours Editorial Board. WHO Classification of Tumours Soft Tissue and Bone Tumours, 5th ed. Lyon: IARC Press; 2020. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Soft-Tissue-And-Bone-Tumours-2020.

  2. Gronchi A, Miah Ab, Dei Tos Ap, Abecassis N, Bajpai J, Bauer S, Biagini R, Bielack S, Blay Jy, Bolle S, et al. soft tissue and visceral sarcomas: esmo-euracan-genturis clinical practice guidelines for diagnosis. Treatment And Follow-Up Ann Oncol. 2021;32(11):1348–65.

    CAS  PubMed  Google Scholar 

  3. Nccn: Nccn Clinical Practice Guidelines In Oncology Soft Tissue Sarcoma Version 2.2022. 2022. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf.

  4. Demetri Gd, von Mehren M, Jones Rl, Hensley Ml, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase iii randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786–93.

    Article  CAS  PubMed  Google Scholar 

  5. Demetri Gd, Sp Chawla, von Mehren M, Ritch P, Baker Lh, Blay Jy, Hande Kr, Keohan Ml, Samuels Bl, Schuetze S, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase ii study of two different schedules. J Clin Oncol. 2009;27(25):4188–96.

    Article  CAS  PubMed  Google Scholar 

  6. Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol. 2015;16(4):406–16.

    Article  CAS  PubMed  Google Scholar 

  7. le Cesne A, Blay Jy, Judson I, van Oosterom A, Verweij J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, et al. Phase Ii study of et-743 in advanced soft tissue sarcomas: a european organisation for the research and treatment of cancer (eortc) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005;23(3):576–84. https://pubmed.ncbi.nlm.nih.gov/15659504/.

  8. le Cesne A, Ray-Coquard I, Duffaud F, Chevreau C, Penel N, Bui Nguyen B, Piperno-Neumann S, Delcambre C, Rios M, Chaigneau L et al: Trabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of the french sarcoma group. Eur J Cancer 2015, 51(6):742–750.

    Article  PubMed  Google Scholar 

  9. Schoffski P, Chawla S, Maki Rg, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha Sy, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629–37.

    Article  CAS  PubMed  Google Scholar 

  10. Kawai A, Araki N, Naito Y, Ozaki T, Sugiura H, Yazawa Y, Morioka H, Matsumine A, Saito K, Asami S.  Phase 2 study of eribulin in patients with previously treated advanced or metastatic soft tissue sarcoma. Jpn J Clin Oncol. 2017;47(2):137–44.

    Article  PubMed  Google Scholar 

  11. Schoffski P, Ray-Coquard IL, Cioffi A, Bui NB, Bauer S, Hartmann JT, Krarup-Hansen A, Grunwald V, Sciot R, Dumez H, et al. Activity Of Eribulin Mesylate In Patients With Soft-Tissue Sarcoma: A Phase 2 Study In Four Independent Histological Subtypes. Lancet Oncol. 2011;12(11):1045–52.

    Article  PubMed  Google Scholar 

  12. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schoffski P, Aglietta M, Staddon AP, Beppu Y, et al. Pazopanib for metastatic soft-tissue sarcoma (palette): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–86.

    Article  PubMed  Google Scholar 

  13. Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schoffski P, Collin F, Pandite L, Marreaud S, De Brauwer A, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase ii study from the european organisation for research and treatment of cancer-soft tissue and bone sarcoma group (eortc study 62043). J Clin Oncol. 2009;27(19):3126–32.

    Article  CAS  PubMed  Google Scholar 

  14. Bl Samuels, Sp Chawla, Somaiah N, Staddon Ap, Skubitz KM, Milhem MM, Kaiser PE, Portnoy DC, Priebat DA, Walker MS, et al. Results of a prospective phase 2 study of pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma. Cancer. 2017;123(23):4640–7.

    Article  Google Scholar 

  15. Nakamura T, Matsumine A, Kawai A, Araki N, Goto T, Yonemoto T, Sugiura H, Nishida Y, Hiraga H, Honoki K, et al. The clinical outcome of pazopanib treatment in japanese patients with relapsed soft tissue sarcoma: a japanese musculoskeletal oncology group (jmog) study. Cancer. 2016;122(9):1408–16.

    Article  CAS  PubMed  Google Scholar 

  16. Hensley Ml, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase ii trial. J Clin Oncol. 2002;20(12):2824–31.

    Article  CAS  PubMed  Google Scholar 

  17. Lee Atj, Jones Rl, Huang Ph: Pazopanib In advanced soft tissue sarcomas. signaltransduct target ther 2019, 4:16.

  18. Kobayashi E, Naito Y, Asano N, Maejima A, Endo M, Takahashi S, Megumi Y, Kawai A. interim results of a real-world observational study of eribulin in soft tissue sarcoma including rare subtypes. Jpn J Clin Oncol. 2019;49(10):938–46.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kobayashi H, Iwata S, Wakamatsu T, Hayakawa K, Yonemoto T, Wasa J, Oka H, Ueda T, Tanaka S. Efficacy and safety of trabectedin for patients with unresectable and relapsed soft-tissue sarcoma in japan: a japanese musculoskeletal oncology group study. Cancer. 2020;126(6):1253–63.

    Article  CAS  PubMed  Google Scholar 

  20. Py Liu, Dahlberg S, Crowley J. Selection designs for pilot studies based on survival. Biometrics. 1993;49(2):391–8.

    Article  Google Scholar 

Download references

Acknowledgements

This study protocol has been presented as “Trials in Progress” at the 2021American Society of Clinical Oncology Annual Meeting (Abstract No: TPS11580). We would like to thank all involved in planning and launching of JCOG1802 study in the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the JCOG, JCOG Data Center and the JCOG Operations Office. Participating institutions in JCOG1802 (from north to south) will be: Hokkaido Cancer Center, Tohoku University Hospital, Saitama Prefectural Cancer Center, Jichi Medical University Saitama Medical Center, Saitama Medical University International Medical Center, National Cancer Center Hospital East, Chiba Cancer Center, National Cancer Center Hospital, Kyorin University Hospital, Keio University Hospital, Cancer Institute Hospital of Japanese Foundation for Cancer Research, University of Tokyo Hospital, Juntendo University Hospital, Teikyo University Hospital, Yokohama City University Hospital, Kanagawa Cancer Center, Niigata Cancer Center Hospital, Niigata University Hospital, Kanazawa University Hospital, Fukui University Hospital, Shinshu University Hospital, Gifu University, Shizuoka Cancer Center, Aichi Cancer Center Hospital, Nagoya University Hospital, Mie University Hospital, Kyoto University Hospital, Osaka University Hospital, Osaka International Cancer Center, Kobe University Hospital, Okayama University Hospital, Hiroshima University Hospital, Kagawa University Hospital, Kurume University Hospital, Kyushu University Hospital, Kyushu Rosai Hospital, and Oita University Hospital.

Funding

The JCOG1802 (2ND-STEP) study is supported by Japan Agency for Medical Research and Development (AMED: Grant number JP21ck0106507 and JP22ck0106764), and the National Cancer Center Research and Development Fund (2020-J-3). The funders have no control over the interpretation, writing, or publication of this paper.

Author information

Author notes

  1. Makoto Endo and Tomoko Kataoka contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Makoto Endo & Toshifumi Fujiwara

  2. JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan

    Tomoko Kataoka, Ryunosuke Machida, Yuta Sekino & Haruhiko Fukuda

  3. Department of Orthopaedic Surgery, Aichi Cancer Center, Nagoya, Japan

    Satoshi Tsukushi

  4. Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Masanobu Takahashi

  5. Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan

    Eisuke Kobayashi

  6. Department of Breast and Medical Oncology, Saitama Cancer Center, Saitama, Japan

    Yoko Yamada

  7. Department of Orthopaedic Surgery, Fukui University School of Medicine, Fukui, Japan

    Takaaki Tanaka

  8. Department of Musculoskeletal Tumor Surgery, Kanagawa Cancer Center, Yokohama, Japan

    Yutaka Nezu

  9. Department of Musculoskeletal Oncology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan

    Hiroaki Hiraga

  10. Division of Orthopaedic Oncology, Shizuoka Cancer Center, Nagaizumi, Japan

    Junji Wasa

  11. Department of Orthopaedic Surgery, Gifu University School of Medicine, Gifu, Japan

    Akihito Nagano

  12. Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan

    Kenji Nakano

  13. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan

    Robert Nakayama

  14. Department of Orthopaedic Surgery, Kurume University School of Medicine, Kurume, Japan

    Tetsuya Hamada

  15. Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Yufu City Oita, Hasama, 879-5593, Japan

    Masanori Kawano & Kazuhiro Tanaka

  16. Department of Orthopaedic Oncology and Surgery, Saitama Medical University International Medical Center, Hidaka, Japan

    Tomoaki Torigoe

  17. Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Akio Sakamoto

  18. Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan

    Kunihiro Asanuma

  19. Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Mitaka, Japan

    Takeshi Morii

  20. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yoshinao Oda

  21. Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Toshifumi Ozaki

  22. Department of Advanced Medical Sciences, Oita University, 1-1 Idaigaoka, Yufu City Oita, Hasama, 879-5593, Japan

    Kazuhiro Tanaka

Authors
  1. Makoto Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoko Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshifumi Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoshi Tsukushi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masanobu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eisuke Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoko Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takaaki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yutaka Nezu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroaki Hiraga
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Junji Wasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Akihito Nagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kenji Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Robert Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tetsuya Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Masanori Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tomoaki Torigoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Akio Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kunihiro Asanuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Takeshi Morii
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Ryunosuke Machida
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Yuta Sekino
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Haruhiko Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Yoshinao Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Toshifumi Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Kazuhiro Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ME and KT were involved in conception of trial. ME, TK, KT, RM, and HF were involved in trial design. ME, TK, KT and RM wrote the first draft of this manuscript. All authors contributed to revisions of this manuscript and approved the final manuscript.

Corresponding author

Correspondence to Kazuhiro Tanaka.

Ethics declarations

Ethics approval and consent to participate

All patients receive verbal and written information and provide their written informed consent before enrolment. This study is conducted in accordance with the ethical principles stipulated in the “Declaration of Helsinki” (revised October 2013) and “Clinical Trials Act” (announced April 14, 2017, enacted April 1, 2018) established by Japan’s Ministry of Health, Labour, and Welfare. This study was approved by the National Cancer Center Hospital CRB (CRB3180008) on October 3, 2019 (approval number: T2019003).

The results of the study will be submitted to international peer-reviewed journals, and the main findings will be presented at international scientific conferences. The authors are attributed according to the guidance of the International Committee of Medical Journal Editors.

Any amendments to the protocol will undergo a review by the National Cancer Center Hospital CRB. This study protocol was lately corrected in December 2021 (ver. 1.4.0) due to the minor amendment.

Consent for publication

Not applicable.

Competing interests

ME receives honoraria from Daiichi Sankyo Co., Ltd., Kyowa Kirin Co., Ltd., Bayer AG, Boehringer Ingelheim International GmbH, Taiho Pharmaceutical Co., Ltd., Novartis AG, and Eisai Co., Ltd. MT receives grants from MSD, Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim International GmbH, and honoraria from Daiichi Sankyo Co., Ltd., Bristol Myers Squibb Company, and Ono Pharmaceutical Co., Ltd. EK receives honoraria from Eisai Co., Ltd. HF receives honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., CMIC Co., Ltd., and m3, Inc. KT is an advisory board member of Taiho Pharmaceutical Co., Ltd., and receives honoraria from Taiho Pharmaceutical Co., Ltd., Novartis AG, and Eisai Co., Ltd. The other authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Endo, M., Kataoka, T., Fujiwara, T. et al. Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib. BMC Cancer 23, 219 (2023). https://doi.org/10.1186/s12885-023-10693-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-023-10693-w

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us