A Phase I/II Study of the Pan-immunotherapy in Patients With Local Advanced/Metastatic BTC

Study Overview
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Brief Summary
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Biliary tract cancer (BTC) is a rare heterogeneous collection of malignancies arising within the biliary tract, characterized by innate chemoresistance and abysmal prognosis. PD-1 blockade has been developed to a new class of cancer immunotherapy that could restore an adequate immunosurveillance against the neoplasm and enhance T-cell-mediated anticancer immune responses. Manganese has been confirmed to activate antigen-presenting cells and function as mucosal immunoadjuvants in pre-clinical studies. This open-label, phase I/II study is designed to assess the safety and efficacy of Manganese primed combined therapy of anti-PD-1 antibody and gemcitabine/cisplatin chemotherapy.

Official Title
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A Phase I/II, Open-label, Single-center Study to Evaluate the Safety and Efficacy of the Pan-immunotherapy in Subjects With Local Advanced/Metastatic Biliary Tract Cancer

Conditions
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Biliary Tract Cancer (BTC)

Intervention / Treatment
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* Drug: Manganese Chloride
* Drug: nab-paclitaxel
* Drug: Gemcitabine
* Drug: anti-PD-1 antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years old. Life expectancy of at least 3 months. Subjects must have Histopathological/cytological diagnosis of unresectable or recurrent /metastatic biliary tract carcinoma (intra-hepatic, extrahepatic or gall bladder). Eastern Cooperative Oncology Group performance status 0-2. Subjects must have at least one measurable lesion ≥ 1 cm as defined by response criteria. Subjects may have received prior radiotherapy, chemotherapy, or other local ablative therapies, which completed ≥ 4 weeks prior to registration AND patient has recovered to <= grade 1 toxicity. Subjects with Anti-PD-1 antibody treatment history are eligible which must be resistance. Adequate organ function. Participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug. Exclusion Criteria: Subjects with any autoimmune disease or history of syndrome that requires corticosteroids or immunosuppressive medications. Serious uncontrolled medical disorders or active infections, pulmonary infection especially. Prior organ allograft. Women who are pregnant or breastfeeding. Women with a positive pregnancy test on enrollment or prior to investigational product administration. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Manganese primed anti-PD-1 antibody plus nPG chemotherapy<br>Subject received Manganese primed anti-PD-1 antibody, nab-paclitaxel and gemcitabine every 3 weeks until achieving a second assessable stable disease or up to a maximum of 12 cycles. Treatment continued until progressive disease, development of unacceptable toxicity, or withdrawal of consent. | Drug: Manganese Chloride<br>* Administered by inhalation at 0.2 or 0.4mg/kg/d once daily in a 3-week cycle<br>Drug: nab-paclitaxel<br>* Administered intravenously, 125mg/m2/d on day1 and day8 in a 3-week cycle<br>* Other names: Paclitaxel For Injection (Albumin Bound);Drug: Gemcitabine<br>* Administered intravenously, 1g/m2/d on day1 and day8 in a 3-week cycle<br>Drug: anti-PD-1 antibody<br>* Administered intravenously, 2-4mg/kg on day 3 in a 3-week cycle<br>* Other names: Anti-PD-1 monoclonal antibody; PD-1 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with treatment-related adverse events (AEs) | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0. AEs were considered to be treatment-related if they had started or worsened within the interval from first study drug administration until the follow-up visit. | 12 months | 
| Progression-free survival (PFS) at 6 months | Progression free survival (PFS) at 6 months in patients with local advanced /metastatic BTCs treated with the combined regimen. Progression will be defined clinically or on imaging as per immune related response evaluation criteria in solid tumors (RECIST V1.1) definition | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | DCR is defined as the proportion of subjects who achieved a stable disease (SD), partial response (PR) or complete response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 12 months | 
| Object response rate (ORR) | ORR is defined as the proportion of subjects who achieved a partial response (PR) or complete response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 12 months | 
| Overall survival (OS) | OS time was measured from the study entry to the date of death. | 24 months | 
| Number of participants with laboratory test abnormalities | The laboratory tests of serum cytokines and chemokines will be performed on day 1 and 3 of each cycle, and the abnormality will be determined by the investigator. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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local advanced, metastatic, anti-PD-1 antibody, Manganese, gemcitabine, cisplatin