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

Phase 1

Interventions: Drug: Manganese Chloride
Drug: nab-paclitaxel
Drug: Gemcitabine
Drug: anti-PD-1 antibody

Brief Summary: 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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Manganese primed anti-PD-1 antibody plus nPG chemotherapy	Manganese Chloride	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.
Manganese primed anti-PD-1 antibody plus nPG chemotherapy	anti-PD-1 antibody	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.
Manganese primed anti-PD-1 antibody plus nPG chemotherapy	nab-paclitaxel	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.
Manganese primed anti-PD-1 antibody plus nPG chemotherapy	Gemcitabine	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.

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS) at 6 months	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
Number of Subjects with treatment-related adverse events (AEs)	12 months	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.

Secondary Outcome Measures

Name	Time	Method
Disease control rate (DCR)	12 months	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.
Overall survival (OS)	24 months	OS time was measured from the study entry to the date of death.
Object response rate (ORR)	12 months	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.
Number of participants with laboratory test abnormalities	12 months	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.

Locations (1): Biotherapeutic Department of Chinese PLA General Hospital
🇨🇳
Beijing, Beijing, China