PD-1 Antibody Plus GEMOX as Postoperative Adjuvant Therapy in Perihilar Cholangiocarcinoma

Official title

PD-1 Antibody Plus Gemcitabine and Oxaliplatin (GEMOX) as Postoperative Adjuvant Therapy in Perihilar Cholangiocarcinoma Patients With Positively Metastatic Lymph Nodes : a Single Arm, Phase II Trial

Overview

This is an open-label,single center,non-randomized,single arm exploratory study. The objective of this study is to evaluate the efficacy and safety of PD-1 antibody plus GEMOX as postoperative adjuvant therapy in perihilar cholangiocarcinoma with positively metastatic lymph nodes.

Detailed description

For perihilar cholangiocarcinoma, radical surgical treatment, such as major hepatectomy combined with total caudate lobe and extrahepatic bile duct resection, remain the potential modality for cure. However, the lymph node tumor metastasis is an independent risk factor for prognosis after radical resection for this disease without distant metastasis. As reported by Nagoya University, Japan, the patients without lymph node tumor metastasis, the 5-year survival rate could reach as high as 67.1% after R0 resection, but the 5-year survival rate was only 22.1% for the patients with lymph node tumor metastasis after R0 resection. Thus, it is urgent to look for an effective adjuvant therapy treatment for these patients with lymph node tumor metastasis. Fluoropyrimidine-based or gemcitabine-based chemotherapy was recommended for these patients by NCCN guidelines. Studies have shown that Gemox chemotherapy (oxaliplatin + gemcitabine) in patients with resected biliary tract cancer has a good benefit in overall survival. However, for extrahepatic cholangiocarcinoma with lymph nodes metastasis, the benefit was limited. In recent years, immunotherapy, such as PD-1 or PD-L1 monoclonal antibody, combined with chemotherapy have shown better results in the palliative treatment of un-resectable biliary tract tumor. However, there is no report on combined immunotherapy with chemotherapy as adjuvant therapy in perihilar cholangiocarcinoma with lymph node tumor metastasis after R0 resection.

Interventions

• Drug PD-1antibody plus GEMOX
  1. PD-1 antibody，200mg，D1，intravenous infusion, the administration time is 60 (+15) minutes. 2. GEMOX chemotherapy : gemcitabine 1000mg/m2,D1，D8；oxaliplatin 100mg/m2,D1，intravenous infusion. 3. Three weeks is a course of treatment,a total of 6-8 courses.

Primary outcome measures

• The 12-month relapse-free survival rate [Time frame: 12 months]

Secondary outcome measures (5)

• The 12-month overall survival rate [Time frame: 12 months]
• The 60-month overall survival rate [Time frame: 60 months]
• Relapse-free survival [Time frame: 60 months]
• Overall survival [Time frame: 60 months]
• Percentage of participants with adverse events (AEs) [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• The patient must sign an informed consent form;
• Age 18-75 years old, both male and female;
• ECOG performance status score (PS score) 0 or 1 point;
• Child-Pugh score A period;
• Perihepatic cholangiocarcinoma with negative margins and positively metastatic lymph nodes confirmed by histopathology. Abdominal positively metastatic lymph nodes region is not limited. The 16 groups of microscopically positively metastatic lymph nodes can be included.
• Have not received any systemic treatment within 6 months;
• The functional indicators of important organs meet the following requirements (1)Neutrophils≥1.5\*109/L; platelets≥100\*109/L; hemoglobin≥9g/dl; serum albumin≥3g/dl; (2)Thyroid-stimulating hormone (TSH) ≤ 2 times the upper limit of normal, and T3 and T4 are in the normal range; (3)Bilirubin ≤ 1.5 times the upper limit of normal; ALT and AST ≤ 3 times the upper limit of normal; (4)Serum creatinine ≤ 1.5 times the upper limit of normal, and creatinine clearance ≥ 60ml/min (calculated by Cockcroft-Gault formula); 8. The subject has at least 1 measurable lesion (according to RECIST1.1);
• For women who are not breastfeeding or pregnant, use contraception during treatment or 12 months after the end of treatment.

Exclusion criteria

• Unresectable PHC patients or postoperative diagnosis of PHC recurrence and metastasis ;
• Past or simultaneous suffering from other malignant tumors, except for fully treated non-melanoma skin cancer, cervical carcinoma in situ, and thyroid papillary carcinoma;
• Have used gemcitabine-based chemotherapy or have used PD-1 monoclonal antibody or PD-L1 monoclonal antibody treatment within 6 months;
• Severe cardiopulmonary and renal dysfunction;
• Hypertension that is difficult to control with drugs (systolic blood pressure (BP) ≥140 mmHg and/or diastolic blood pressure ≥90mmHg) (based on the average of ≥3 BP readings obtained by ≥2 measurements);
• Abnormal coagulation function (PT>14s), have bleeding tendency or are receiving thrombolysis or anticoagulation therapy;
• After antiviral treatment, HBV DNA>2000 copies/ml, HCV RNA>1000;
• A history of esophageal and gastric varices, significant clinically significant bleeding symptoms or a clear tendency to appear within 3 months before enrollment;
• Active infections requiring systemic treatment; patients with active tuberculosis infection within 1 year before enrollment; a history of active tuberculosis infection more than 1 year before enrollment, and no formal anti-tuberculosis treatment or tuberculosis Still in the active period;
• Human immunodeficiency virus (HIV, HIV1/2 antibody) positive;
• A history of psychotropic drug abuse, alcohol or drug abuse;
• Known to have a history of severe allergies to any monoclonal antibodies, platinum drugs, or gemcitabine;
• Other factors judged by the investigator may affect the safety of the subjects or the compliance of the trial. Such as serious diseases (including mental illness) that require combined treatment, serious laboratory abnormalities, or other family or social factors.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

China · 1 center

• Sun Yat-sen Memorial Hospital, Sun Yat-sen University — Guangzhou

Publications

• DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ, Schulick RD. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007 May;245(5):755-62. doi: 10.1097/01.sla.0000251366.62632.d3. PMID 17457168
• Kang MJ, Lee JL, Kim TW, Lee SS, Ahn S, Park DH, Lee SS, Seo DW, Lee SK, Kim MH. Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma. Acta Oncol. 2012 Sep;51(7):860-6. doi: 10.3109/0284186X.2012.682628. Epub 2012 May 6. PMID 22559158
• Groot Koerkamp B, Wiggers JK, Allen PJ, Besselink MG, Blumgart LH, Busch OR, Coelen RJ, D'Angelica MI, DeMatteo RP, Gouma DJ, Kingham TP, Jarnagin WR, van Gulik TM. Recurrence Rate and Pattern of Perihilar Cholangiocarcinoma after Curative Intent Resection. J Am Coll Surg. 2015 Dec;221(6):1041-9. doi: 10.1016/j.jamcollsurg.2015.09.005. Epub 2015 Sep 15. PMID 26454735
• Abdel-Rahman O, Elsayed Z, Elhalawani H. Gemcitabine-based chemotherapy for advanced biliary tract carcinomas. Cochrane Database Syst Rev. 2018 Apr 6;4(4):CD011746. doi: 10.1002/14651858.CD011746.pub2. PMID 29624208
• Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, Ozawa F, Fukutomi A, Ando M, Nimura Y, Nagino M; Bile Duct Cancer Adjuvant Trial (BCAT) Study Group. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018 Feb;105(3):192-202. doi: 10.1002/bjs.10776. PMID 29405274
• Nassour I, Mokdad AA, Porembka MR, Choti MA, Polanco PM, Mansour JC, Minter RM, Wang SC, Yopp AC. Adjuvant Therapy Is Associated With Improved Survival in Resected Perihilar Cholangiocarcinoma: A Propensity Matched Study. Ann Surg Oncol. 2018 May;25(5):1193-1201. doi: 10.1245/s10434-018-6388-7. Epub 2018 Feb 27. PMID 29488187
• Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve JL, Faroux R, Guerin-Meyer V, Kurtz JE, Assenat E, Seitz JF, Baumgaertner I, Tougeron D, de la Fouchardiere C, Lombard-Bohas C, Boucher E, Stanbury T, Louvet C, Malka D, Phelip JM. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 1 PMID 30707660
• Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): PMID 30922733

Identifiers

NCT: NCT05430698 · LX-GY-2022010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗