Skip to main content
Download PDF

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial)

BMC Cancer volume 23, Article number: 729 (2023) Cite this article

Abstract

Background

Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients.

Methods

The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China.

Discussion

The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research.

Trial registration

Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Peer Review reports

Background

Patients with advanced biliary tract cancer (BTC) have limited options for second-line treatment [1]. The ABC-06 study, the only phase 3 trial conducted in this setting, demonstrated that the median overall survival (mOS) of active symptom control (ASC) plus FOLFOX (folinic acid, fluorouracil, and oxaliplatin) group is merely 0.9 months longer than that of the ASC group (6.2months vs. 5.3months; P = .031) [2].

Previous studies have suggested the clinical benefit of nanoparticle albumin-bound (nab)-paclitaxel in BTC [3, 4]. In a single-arm, multicenter trial, combination chemotherapy with capecitabine and nab-paclitaxel demonstrated feasibility as a regimen for advanced BTC in patients who had progressed on first-line chemotherapy, with a disease control rate of 80% and overall survival of 12.1 months [5]. Recently, early-phase data from the ongoing phase 3 SWOG S1815 trial demonstrated improvements in median PFS and OS when nanoparticle albumin–bound (nab) paclitaxel is combined with gemcitabine-cisplatin (GC) in the first-line setting [6].

Sintilimab, an anti-PD-1 antibody, has exhibited high affinity to human PD-1 and superior PD-1 occupancy in circulating T cells [7]. Pembrolizumab or nivolumab monotherapy was well tolerated and provided modest efficacy with durable response in patients with BTC [8, 9].

It is well-accepted that chemotherapy enhances antitumor activity through direct or indirect immune-system stimulation [10]. Martin JD, et al. further demonstrated the potential of nanomedicines to enable durable responses to immunotherapy [11]. Improved outcomes and manageable safety profiles have been observed with immune checkpoint inhibitors (ICIs) combined with nab-paclitaxel in breast cancer, pancreatic adenocarcinoma, urothelial carcinoma, and other malignancies [12,13,14]. Currently, durvalumab is approved in combination with gemcitabine and cisplatin for the first-line treatment of advanced BTC. Based on these findings, investigating the efficacy and safety of sintilimab in combination with nab-paclitaxel as a second-line treatment for advanced BTC is warranted.

The NapaSinti trial aims to challenge the standard second-line therapy for advanced BTC by evaluating the combination of sintilimab and nab-paclitaxel, and it also provides an opportunity for translational research.

Methods and design

This is a prospective, single-arm, open-label, phase 2 study designed to evaluate the efficacy and safety of second-line treatment with sintilimab in combination with nab-paclitaxel in patients with advanced biliary tract cancer (BTC).

Patient selection

The main inclusion criteria for this study are as follows: histologically or cytologically confirmed advanced adenocarcinoma in the biliary tract; previous treatment with gemcitabine or fluorouracil-based chemotherapy as first-line therapy; not received taxane or immunotherapy; age between 18 and 75 years; life expectancy of at least 3 months; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; measurable lesions according to the Response Evaluation Criteria in Solid Tumors guidelines version 1.1 (RECIST 1.1); and adequate organ function. Complete inclusion and exclusion criteria are detailed in Table 1.

Table 1 Eligibility criteria
Full size table

Treatment

  1. 1.

    Sintilimab: 200 mg, administered as a 30–60 min intravenous infusion on day 1, every three weeks.

  2. 2.

    Nab-paclitaxel: 125 mg/m2, initiated ≥ 30 min after sintilimab, administered as a 30–40 min intravenous infusion on day 1 and day 8, every three weeks.

Eligible patients will receive a total of eight cycles of sintilimab plus nab-paclitaxel. Patients who do not experience disease progression or unacceptable toxicity will continue with sintilimab monotherapy maintenance for up to 24 months. Treatment must adhere to all protocol-related requirements. The planned enrollment period for the study is two years, from March 30, 2022, to March 30, 2024, and the planned follow-up period is two years from the date of enrollment of the last patient. The study design is illustrated in Fig. 1.

Fig. 1
figure 1

Outline of the study design

Full size image

Treatment discontinuation

Treatment will be discontinued for any of the following reasons:.

  1. 1.

    The patient declines further study treatment or withdraws consent to participate.

  2. 2.

    Progressive disease is confirmed by the investigator.

  3. 3.

    Unacceptable toxicity is determined by the patient or investigator.

  4. 4.

    Exclusion criteria are met.

  5. 5.

    The patient fails to comply with the protocol.

  6. 6.

    The investigator determines that the continuation of treatment is not in the best interest of the patient.

The reasons for discontinuing treatment will be documented in the patient’s medical records.

Study endpoints

Primary endpoint

Objective response rate (ORR), defined as the proportion of complete responses (CRs) and partial responses (PRs).

Secondary endpoints

  1. 1.

    Overall survival (OS), defined as the time from starting second-line therapy until death or last follow-up.

  2. 2.

    Progression-free survival (PFS), defined as the time from starting second-line therapy until progression or last follow-up or death from any cause.

  3. 3.

    Safety assessment according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Assessments

Complete blood cell count (red blood cell, hemoglobin, platelet count, white blood cell), measurement of liver and renal function, and electrolyte panel are performed weekly. The following assessments are performed before each cycle: a complete blood cell count, measurement of liver and renal function, electrolyte panel, coagulation parameters, myocardial enzymogram, thyroid-related hormones, 12-lead electrocardiogram. Morphological imaging (contrast-enhanced computed tomography (CT) of the abdomen and chest) and biological tumor assessments (carcinoembryonic antigen (CEA), carbohydrate antigen 19 − 9 (CA199), carbohydrate antigen 125 (CA125)) are conducted every six weeks. The response is determined using CT scanning based on RECIST 1.1.

Health-related quality of life (HRQoL) questionnaires will be completed before each cycle. HRQoL questionnaires are based on assessments using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21)..

The investigators will monitor adverse events in every circle. All adverse events observed during the study treatment period are appropriately registered in the subjects’ medical records and electronic case report forms. Adverse events will be assessed according to the CTCAE version 5.0.

Follow-up

After treatment, regular follow-up is scheduled every three months. If necessary, follow-up may be conducted more frequently through telephone interviews or face-to-face visits. The follow-up period continues until death or the end of the study, regardless of the duration of treatment. The following procedures are performed during follow-up:.

  1. 1.

    Assessment of survival status.

  2. 2.

    Completion of health-related quality of life (HRQoL) questionnaires.

  3. 3.

    Recording of all adverse events.

Biomarker analysis

Tumor tissue and blood samples are collected before treatment. The serum is analyzed for cytokines, while the tumor tissue is used to explore immune cell populations and the expression of selected tumor markers. Tumor samples will also be analyzed with next-generation sequencing (NGS), which allows comprehensive genomic profiling of critical targeted therapy and immunotherapy biomarkers, such as tumor mutation load, programmed cell death ligand 1 (PD-L1) expression, and microsatellite status. This analysis aims to identify biomarkers and molecular signatures that can predict treatment response or prognosis.

Sample size calculation and statistical analysis

The sample size calculation was performed using Simon’s optimal two-stage design [15] with an α error of 5% and a power of 80%. ABC-06 clinical trial showed that the ORR for second-line treatment of advanced biliary tract cancer was 5% [2]. The expected number of patients was calculated according to the alternative hypothesis that the objective response rate would be 15% or higher and the null hypothesis that the ORR would be 5% or lower. The trial consists of two stages: stage 1 requires the enrolment of at least 23 patients, with at least 1 patient achieving PR or CR. Once this criterion is met, stage 2 will be initiated, with the enrolment of at least 33 additional participants to achieve a sample size of 56 patients. Considering a 10% loss to follow-up rate, the actual study requires a total sample size of 63 subjects. Overall, if at least five patients had a response, the treatment regimen would be deemed a success. The analysis will be performed on an intention-to-treat basis, where all patients will be included in the analysis, and missing data will be considered as treatment failure. The sample size calculation was performed using the “Two-stage designs for tests of one proportion (Simon)” in PASS 2021 software (version 21.0.3 NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass).

Confidentiality

All study-related information will be securely stored at the study site. Participants’ information will be kept in locked file cabinets located in restricted-access areas. To maintain participant confidentiality, all laboratory specimens, reports, data collection, process, and administrative forms will be identified only by a coded identification number.

Discussion

Patients with advanced biliary tract cancer (BTC) have a poor prognosis, with a median OS of approximately 12 months [16]. A systematic review of second-line chemotherapy for advanced BTC that included 761 patients reported an OS of 7.2 months [95% confidence interval (CI) 6.2–8.2], a PFS of 3.2 months (95% CI 2.7–3.7), and response rate of 7.7% (95% CI 4.6–10.9) [17]. Although patients with molecular alterations such as HER2, BRAF, FGFR2, and IDH1 may benefit from targeted therapies, drugs are expensive and poorly accessible in China. Additionally, only a small number of patients have these specific genetic mutations [18,19,20,21]. A study has revealed the presence of CD8 + tumor-infiltrating lymphocytes and PD-L1 expression on cancer cells in BTC [22], providing support for the potential use of ICIs in BTC. Nevertheless, patients with advanced BTC failing standard treatment have shown limited benefits from pembrolizumab monotherapy, with durable antitumor activity observed in only 6–13% of patients [8]. Although combination immunotherapy with PD-1/PD-L1 and CTLA-4 blockade has shown some advantages over single-agent immunotherapy, it has not resulted in substantial improvements in overall survival [23]. Furthermore, the combination of immunotherapy and targeted therapy has demonstrated minimal benefits in BTC [24,25,26]. Therefore, the development of novel therapeutic combinations that can extend the clinical benefits for advanced BTC remains a significant challenge.

Sintilimab, a highly selective, fully humanized, anti-PD-1 antibody, blocks the interaction between PD-1 and its ligands. The ORIENT-12 and ORIENT-32 studies indicated that the addition of sintilimab offers clinical benefits for non-small cell lung cancer and unresectable hepatocellular carcinoma, with an acceptable safety profile [27, 28]. It has been suggested that chemotherapy and immunotherapy have a synergistic effect by overcoming the immunosuppressive effects of the tumor microenvironment, increasing the cross-presentation of tumor antigens, and facilitating better penetration of immune cells into the tumor core [29]. Another study revealed that the immune response stimulated by durvalumab could be further enhanced by chemotherapy-induced immunogenic cell death [30]. Of note, chemoimmunotherapy has already shown encouraging results in advanced BTC. A phase 1 study demonstrated that nivolumab plus gemcitabine-cisplatin (GC) in patients with unresectable or recurrent biliary tract cancer were associated with signs of antitumor activity [31]. Additionally, the TOPAZ-1 phase 3 study indicated that durvalumab plus GC as first-line treatment significantly improved overall survival and progression-free survival compared to placebo plus GC, with manageable safety [32].

The identification of biomarkers might lead to improved outcomes for patients with biliary tract cancer. The European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) ranked genomic alterations in advanced cholangiocarcinoma based on therapeutic implications, and level I alterations included IDH1 mutations, FGFR2 fusions, microsatellite instability-high (MSI-H), and NTRK fusions [33]. The expression of PD-L1 in tumors has been proven to be associated with prolonged progression-free survival (hazard ratio, 0.23; 95% CI, 0.10–0.51; P < .001) [9]. Pembrolizumab is FDA-approved for advanced solid tumors, including BTC, that are mismatch-repair-deficient (dMMR)/ MSI-H or have a tumor mutational burden (TMB); TMB of 10 mutations per megabase or higher. Furthermore, exploratory subgroup analyses from the chemotherapy plus immunotherapy groups have indicated that mutations in CDKN2A and ARID1A might be associated with reduced progression-free survival compared to wild-type genes [34]. Therefore, further translational research is required to identify biomarkers that can help predict treatment response and prognosis.

This study is the first phase 2 study evaluating the efficacy and safety of sintilimab plus nab-paclitaxel in the second-line setting for advanced BTC, while also exploring predictive and prognostic biomarkers for treatment.

Data Availability

Not applicable.

Abbreviations

BTC:

Biliary tract cancer

ECOG:

Eastern Cooperative Oncology Group

PS:

Performance status

ORR:

Objective response rate

mOS:

Median overall survival

PFS:

Progression-free survival

NAB:

Nanoparticle albumin-bound

ASC:

Active symptom control

FOLFOX:

Folinic acid, fluorouracil, and oxaliplatin

GC:

Gemcitabine-cisplatin

ICI:

Immune checkpoint inhibitor

RECIST:

Response Evaluation Criteria in Solid Tumors guidelines

ULN:

Upper limit of normal

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death-ligand 1

HIV:

Human immunodeficiency virus

CRs:

Complete responses

PRs:

Partial responses

CTCAE:

Common Terminology Criteria for Adverse Events

CT:

Computed tomography

CEA:

Carcinoembryonic antigen

CA199:

Carbohydrate antigen 19 − 9

CA125:

Carbohydrate antigen 125

HRQoL:

Health-related quality of life

EORTC QLQ-C30:

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

QLQ-BIL21:

Cholangiocarcinoma and Gallbladder Cancer module

NGS:

Next-generation sequencing

ChiCTR:

Chinese Clinical Trial Registry (ChiCTR)

dMMR/MSI-H:

Mismatch-repair-deficient/microsatellite instability-high

TMB:

Tumor mutational burden

References

  1. Ellis H, Raghavan S, Wolpin BM, Cleary JM. How we treat advanced biliary tract cancers in the second-line setting. Clin Adv Hematol Oncology: H&O. 2023;21(1):35–42.

    Google Scholar 

  2. Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cheon J, Lee C-k, Sang YB, Choi HJ, Kim MH, Ji JH, et al. Real-world efficacy and safety of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancers: a multicenter retrospective analysis. Therapeutic Adv Med Oncol. 2021;13:17588359211035983.

    CAS  Google Scholar 

  4. Talwar V, Raina S, Goel V, Dash P, Doval DC. Nab-paclitaxel: an effective third-line chemotherapy in patients with advanced, unresectable gallbladder cancer. Indian J Med Res. 2020;152(5):475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Woodford R, Brungs D, Leighton C, Grimison P, Sjoquist KM, Becker T, et al. Combination chemotherapy with NAB(®) -paclitaxel and capecitabine for patients with advanced biliary tract cancer (NAP-CAPABIL pilot study). Asia Pac J Clin Oncol. 2022;18(5):e220–e6.

    Article  PubMed  Google Scholar 

  6. Shroff RT, Guthrie KA, Scott AJ, Borad MJ, Goff LW, Matin K, et al. SWOG 1815: a phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. American Society of Clinical Oncology; 2023.

  7. Wang J, Fei K, Jing H, Wu Z, Wu W, Zhou S, et al. Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit. MAbs. 2019;11(8):1443–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Piha-Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147(8):2190–8.

    Article  CAS  PubMed  Google Scholar 

  9. Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, et al. A phase 2 multi-institutional study of Nivolumab for patients with Advanced Refractory biliary tract Cancer. JAMA Oncol. 2020;6(6):888–94.

    Article  PubMed  Google Scholar 

  10. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25.

    Article  CAS  PubMed  Google Scholar 

  11. Martin JD, Cabral H, Stylianopoulos T, Jain RK. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Reviews Clin Oncol. 2020;17(4):251–66.

    Article  Google Scholar 

  12. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative breast Cancer. N Engl J Med. 2018;379(22):2108–21.

    Article  CAS  PubMed  Google Scholar 

  13. Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, Schütz E, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Investig New Drugs. 2018;36(1):96–102.

    Article  CAS  Google Scholar 

  14. Giannatempo P, Raggi D, Marandino L, Bandini M, Fare E, Calareso G, et al. Pembrolizumab and nab-paclitaxel as salvage therapy for platinum-treated, locally advanced or metastatic urothelial carcinoma: interim results of the open-label, single-arm, phase II PEANUT study. Ann Oncol. 2020;31(12):1764–72.

    Article  CAS  PubMed  Google Scholar 

  15. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  16. Marin JJG, Prete MG, Lamarca A, Tavolari S, Landa-Magdalena A, Brandi G, et al. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br J Cancer. 2020;123(7):1047–59.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Annals of Oncology: Official Journal of the European Society For Medical Oncology. 2014;25(12):2328–38.

    Article  CAS  PubMed  Google Scholar 

  18. Javle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22(9):1290–300.

    Article  CAS  PubMed  Google Scholar 

  19. van Golen RF, Dekker TJA. Dabrafenib plus trametinib in patients with BRAF-mutated biliary tract cancer. Lancet Oncol. 2020;21(11):e515.

    Article  PubMed  Google Scholar 

  20. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim R, Coppola D, Wang E, Chang YD, Kim Y, Anaya D, et al. Prognostic value of CD8CD45RO tumor infiltrating lymphocytes in patients with extrahepatic cholangiocarcinoma. Oncotarget. 2018;9(34):23366–72.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Doki Y, Ueno M, Hsu CH, Oh DY, Park K, Yamamoto N, et al. Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. Cancer Med. 2022;11(13):2550–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Villanueva L, Lwin Z, Chung HCC, Gomez-Roca CA, Longo F, Yanez E, et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase 2 LEAP-005 study. Wolters Kluwer Health; 2021.

  25. Cousin S, Cantarel C, Guegan J-P, Mazard T, Gomez-Roca C, Metges J-P, et al. Regorafenib–avelumab combination in patients with biliary tract cancer (REGOMUNE): a single-arm, open-label, phase II trial. Eur J Cancer. 2022;162:161–9.

    Article  CAS  PubMed  Google Scholar 

  26. Yarchoan M, Cope L, Ruggieri AN, Anders RA, Noonan AM, Goff LW et al. Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. J Clin Invest. 2021;131(24).

  27. Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, et al. Sintilimab Plus Platinum and Gemcitabine as First-Line treatment for Advanced or metastatic squamous NSCLC: results from a Randomized, Double-Blind, phase 3 trial (ORIENT-12). J Thorac Oncol. 2021;16(9):1501–11.

    Article  CAS  PubMed  Google Scholar 

  28. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22(7):977–90.

    Article  CAS  PubMed  Google Scholar 

  29. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol. 2015;26(9):1813–23.

    Article  CAS  PubMed  Google Scholar 

  30. Loibl S, Untch M, Burchardi N, Huober J, Sinn B, Blohmer J-U, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30(8):1279–88.

    Article  CAS  PubMed  Google Scholar 

  31. Ueno M, Ikeda M, Morizane C, Kobayashi S, Ohno I, Kondo S, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. lancet Gastroenterol Hepatol. 2019;4(8):611–21.

    Article  PubMed  Google Scholar 

  32. Oh D-Y, Ruth He A, Qin S, Chen L-T, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8):EVIDoa2200015.

    Article  Google Scholar 

  33. Mosele F, Remon J, Mateo J, Westphalen CB, Barlesi F, Lolkema MP, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2020;31(11):1491–505.

    Article  CAS  PubMed  Google Scholar 

  34. Oh DY, Lee KH, Lee DW, Yoon J, Kim TY, Bang JH, et al. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Lancet Gastroenterol Hepatol. 2022;7(6):522–32.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The phase 2 trial commenced in March 2022 and is currently ongoing, with patient recruitment still in progress. Further study information can be found at chictr.org.cn (ChiCTR2100052118). Outlines of the protocol were presented as a poster at ASCO 2023.

Funding

This research was funded by the Health Commission of Sichuan Province Program, grant number 21PJ007. The funding source had no control over the interpretation, writing, or publication of this paper.

Author information

Author notes

  1. Nan Zhou and Xiaofen Li contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China

    Nan Zhou, Xiaofen Li, Yu Yang, Sirui Tan, Shunyu Zhang, Qiyue Huang & Hongfeng Gou

  2. Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Xiaofen Li & Yu Yang

  3. Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Nan Zhou, Sirui Tan, Shunyu Zhang, Qiyue Huang & Hongfeng Gou

Authors
  1. Nan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaofen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sirui Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shunyu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiyue Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongfeng Gou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HG conceived and designed the study. NZ and XL drafted the protocol. HG and NZ conducted statistical trial planning. HG, XL, and YY are responsible for recruitment. NZ, ST, and SZ handled ethics and regulatory affairs. NZ, QH, SZ, and ST contributed to data and sample collection, follow-up, and data analysis. All authors have approved the final version of the manuscript.

Corresponding author

Correspondence to Hongfeng Gou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study is being conducted in accordance with the Good Clinical Practice guidelines and the guiding principles outlined in the Declaration of Helsinki. All prospective patients must provide written informed consent for participation in the study procedures. The trial is registered in the Chinese Clinical Trial Registry under registration number ChiCTR2100052118. The study received approval from the Ethics Committee on Biomedical Research at West China Hospital of Sichuan University (approved on March 30, 2022).

Consent for publication

Not applicable.

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

Zhou, N., Li, X., Yang, Y. et al. Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial). BMC Cancer 23, 729 (2023). https://doi.org/10.1186/s12885-023-11188-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-023-11188-4

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us