Anti-mitochondrial therapy in bile duct cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15661-e15661
Author(s):  
Angela Tatiana Alistar ◽  
Boris Pasche ◽  
Bonny Morris ◽  
Rodwige Desnoyer ◽  
Ralph D'Agostino
Keyword(s):  
Bile Duct ◽  
Bile Duct Cancer ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Biliary Duct ◽  
Duct Carcinoma ◽  
Duct Cancer

e15661 Background: Biliary duct carcinoma is a rare but highly fatal malignancy. The five-year survival rate for advanced bile duct cancer is 2%, per SEER data. As such, new treatment options are desperately needed. CPI-613, a novel anticancer agent that selectively inhibits mitochondrial metabolism in cancer cells, was employed in this study. Methods: This phase 1 study utilized a two-stage dose-escalation schema to determine the maximum-tolerated dose (MTD) and safety of single agent CPI-613 in patients with locally advanced or metastatic bile duct cancers. The 1st cohort enrolled 4 patients at 2300 mg/m2, with no dose-limiting toxicities (DLT) observed. The 2nd cohort enrolled patients at 1200 mg/m2/day for pre-cycle (days 1-5) and 3000 mg/m2 on days 1 and 4 weekly for 3 weeks (28 day cycle). The 5th and 6th patient experienced a DLT. The 3rd cohort was initiated at 600 mg/m2 pre-cycle and 3000 mg/m2 weekly with no other DLTs observed. Results: To-date, 14 patients have been enrolled in the study. The MTD was determined at 600 mg/m2/day pre-cycle and 3000 mg/m2 as per schedule. Once the MTD was determined, the cohort was expanded and, 8 patients have been treated at the MTD with no DLTs observed. Two additional patients are planned to be enrolled at this dose prior to trial completion. Of these 8 patients, 3 are still alive with 1 having prolonged survival (15 months) and the other 2 still on treatment. The most commonly observed toxicities were mild, such as anemia, anorexia, dehydration, fatigue, nausea and thrombocytopenia. Conclusions: Treatment with CPI-613 was well tolerated by patients with heavy tumor burden and refractory disease. CPI-613 has recently been shown to be well tolerated in combination with FOLFIRINOX in pancreatic cancer patients. Due to the low toxicity of CPI-613 in this study, even among highly symptomatic patients, it is anticipated that combination with other active agents is feasible in patients with advanced bile duct cancer. CPI-613 represents a novel treatment that could prove to be an exciting therapeutic alternative for patients with previously limited options and poor survival. Clinical trial information: NCT01766219.

A randomized study of gemcitabine/cisplatin versus single-agent gemcitabine in patients with biliary tract cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4579-4579 ◽  
Author(s):  
J. Furuse ◽  
T. Okusaka ◽  
M. Miyazaki ◽  
H. Taniai ◽  
Y. Nimura ◽  
...  
Keyword(s):  
Bile Duct ◽  
Biliary Tract ◽  
Bile Duct Cancer ◽  
Extrahepatic Bile Duct ◽  
Performance Status ◽  
Single Agent ◽  
Intrahepatic Bile Duct ◽  
Extrahepatic Bile Duct Cancer ◽  
Duct Cancer ◽  
Grade 3

4579 Background: Biliary tract cancers (BTC) are not common but increasing in the US and Europe, and more prevalent in South America and Asia including Japan. Gemcitabine (G) and cisplatin (C) are now deemed as key drugs based on the accumulated literature. This is the first study to compare GC combination with G alone in Japan, even though one phase 3 trial (ABC-02) is ongoing in UK. Methods: 84 Japanese pts, aged ≥ 20 years, with histologically or cytologically confirmed advanced BTC, Performance Status 0 - 1, with adequate bone-marrow, hepatic and renal function were randomized. 83 pts received either C 25 mg/m2 plus G 1000 mg/m2 on days 1, and 8 of each 21-day cycle (GC-arm) or G 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle (G-arm). Treatments were repeated up to a maximum of 16 cycles of GC or 12 of G until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using RECIST criteria by an independent review committee. The primary end-point of the study was 1- year survival rate. Safety, response rate, duration of progression-free survival were also evaluated. Results: A total of 83 pts (19 extrahepatic bile duct cancer, 28 intrahepatic bile duct cancer, 32 gallbladder cancer and 4 ampullary carcinoma) were eligible for the study protocol defined analysis set (Full Analysis Set, FAS); GC-arm n=41 and G-arm n=42. Baseline characteristics were similar between the two arms: median ages were 65.0 vs 66.5, females were 56.1 vs 50.0%. All pts completed at least one cycle of therapy, yielding a total of 247 cycles (median 6) in GC vs 203 (median 4) in G. The overall response rates were 19.5% (95% CI: 8.8, 34.9) vs 11.9 (95% CI: 4.0, 25.6). The results on survival will be determined and presented at the meeting. The most commonly reported grade 3 or 4 toxicities were: neutropenia (56.1 vs 38.1%), thrombocytopenia (39.0 vs 7.1%), leukopenia (29.3 vs 19.0%), hemoglobin decrease (36.6 vs 16.7%) and γ-GTP increase (29.3 vs 35.7%). Grade 3 acute renal failure was reported in 1 pt on GC. Conclusions: The combination therapy of GC would be an effective and well-tolerated chemotherapy regimen for Japanese pts with advanced BTC. [Table: see text]

scholarly journals Combined treatment options for resectable common bile duct cancer patients

2020 ◽  
Vol 25 (3) ◽  
pp. 123-130
Author(s):  
A. N. Polyakov ◽  
D. V. Podluzhny ◽  
Y. I. Patyutko ◽  
S. V. Chulkova ◽  
A. V. Egorova ◽  
...  
Keyword(s):  
Bile Duct ◽  
Common Bile Duct ◽  
Cancer Patients ◽  
Bile Duct Cancer ◽  
Treatment Options ◽  
Combined Treatment ◽  
Common Bile Duct Cancer ◽  
Duct Cancer

scholarly journals miR-122-5p Inhibits the Proliferation, Invasion and Growth of Bile Duct Carcinoma Cells by Targeting ALDOA

2018 ◽  
Vol 48 (6) ◽  
pp. 2596-2606 ◽  
Author(s):  
Zhuo Xu ◽  
Guangchao Liu ◽  
Meng Zhang ◽  
Zhilei Zhang ◽  
Yuming Jia ◽  
...  
Keyword(s):  
Bile Duct ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Bile Duct Cancer ◽  
Bile Duct Carcinoma ◽  
Carcinoma Cells ◽  
Duct Carcinoma ◽  
Clinical Specimens ◽  
Duct Cancer ◽  
Proliferation And Invasion

Background/Aims: Bile duct cancer, although not among the most common tumors, still accounts for more and more worldwide deaths each year. By attempting to verify an overexpression of ALDOA in cholangiocarcinoma tissues and cells and explore the underlying molecular mechanism regulated by miR-122-5p, this study was designed to provide a potential molecular target in bile duct cancer treatment. Methods: Western blot and immunohistochemistry were performed to detect the ALDOA protein level in duct carcinoma tissues. The transfection efficiency was confirmed by western blot and/or RT-qPCR assay. The proliferation of bile duct carcinoma cells was determined by MTT and colony formation assay. The invasion ability of bile duct carcinoma cells was evaluated with Transwell invasion assay. Flow cytometry detected cell apoptosis of bile duct carcinoma cells. The miRNAs which modulate ALDOA were filtrated from bioinformatics software and clinical specimens. The target relationship was confirmed by dual luciferase reporter assay. Furthermore, a xenograft model was completed to verify the impact of miRNA on inhibition growth of bile duct carcinoma cells. Results: ALDOA was found up-regulated in bile duct carcinoma tissues and cells. Knockdown of ALDOA promoted the apoptosis of cells and inhibited the proliferation and invasion of bile duct carcinoma cells. Bioinformatics and clinical specimens indicated the negative correlation and targeted regulation between miR-122-5p and ALDOA. By down-regulating ALDOA, overexpression of miR-122-5p appeared to promote cell apoptosis and significantly inhibit cell proliferation, invasion in vitro and suppress the tumor growth in vivo. Conclusion: miR-122-5p inhibited proliferation and invasion of bile duct carcinoma cells and promoted cell apoptosis by targeting ALDOA expression.

External beam and intraluminal radiotherapy for locally advanced bile duct cancer: role and tolerability

1996 ◽  
Vol 41 (1) ◽  
pp. 61-66 ◽  
Author(s):  
K.A. Vallis ◽  
I.S. Benjamin ◽  
A.J. Munro ◽  
A. Adam ◽  
C.S. Foster ◽  
...  
Keyword(s):  
Bile Duct ◽  
Bile Duct Cancer ◽  
Locally Advanced ◽  
External Beam ◽  
Duct Cancer

scholarly journals Prognostic Impact of Extracapsular Lymph Node Invasion and Myofibroblastic Activity in Extrahepatic Bile Duct Cancer

2017 ◽  
Vol 10 ◽  
pp. 117955571772965 ◽  
Author(s):  
Tadashi Yoshizawa ◽  
Keinosuke Ishido ◽  
Kensuke Saito ◽  
Toshihiro Haga ◽  
Hiroko Seino ◽  
...  
Keyword(s):  
Lymph Node ◽  
Bile Duct ◽  
Lymph Nodes ◽  
Bile Duct Cancer ◽  
Extrahepatic Bile Duct ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Duct Carcinoma ◽  
Extrahepatic Bile Duct Cancer ◽  
Duct Cancer

Extrahepatic bile duct carcinoma is a potentially malignant gastrointestinal lesion. Cancer cells spread via the lymphatic system to regional lymph nodes and help in tumor progression. However, there are no reports on the prognostic impact of extracapsular lymph node invasion and myofibroblastic activity in this cancer. Hence, we classified the histopathologic patterns of lymph nodes into 2 patterns: extracapsular lymph node invasion or not. Based on this, we investigated 32 cases of extrahepatic bile duct cancer with lymph node metastasis and classified 21 cases as positive and 11 cases as negative. The extracapsular lymph node invasion cases were associated with poor disease-free survival and overall survival. The myofibroblast density of the metastatic foci was significantly higher in the extracapsular lymph node invasion cases. This is the first study to demonstrate that extracapsular lymph node invasion cases were associated with poor prognosis and that the myofibroblast distribution contributed to malignancy.

402 DRAGON: Phase 1 trial of SRK-181, a latent TGFβ1 inhibitor in combination with anti-PD-(L)1 inhibitors for patients with solid tumors unresponsive to anti-PD-(L)1 therapy alone

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A427-A427
Author(s):  
Lu Gan ◽  
Johanna Bendell
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Immune Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Locally Advanced ◽  
Tumor Stroma ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Primary Resistance

BackgroundTGFβ1 is a key mediator of primary resistance to PD1 (programmed cell death protein 1) pathway blockade. SRK-181 is a high-affinity, fully humanized antibody that selectively binds to latent TGFβ1 and inhibits its activation on suppressive immune cells as well as within tumor stroma. Preclinical data demonstrated that selective inhibition of latent TGFβ1 with SRK-181 overcomes primary anti-PD-1 resistance and has an improved safety profile compared to broad inhibition of the TGFβ pathway.MethodsThe DRAGON trial is a multi-center, open-label, Phase 1, first-in-human (FIH), dose-escalation, and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered by IV infusion every 3 weeks (q3w) alone and in combination with an anti-PD-(L)-1 in adult patients with locally advanced or metastatic solid tumors. The study is divided into 3 parts: Part A1, a single agent dose escalation, will determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of SRK-181 as a single agent. Part A2, a combination dose escalation, will determine the MTD or MAD of SRK-181 in combination with anti-PD-(L)1 therapy and the RP2D of the combination treatment for use in Part B. Part B, the dose expansion, will enroll parallel cohorts of patients with non-small cell lung cancer, urothelial carcinoma, melanoma, or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the anti-tumor activity of SRK-181 in combination with an anti-PD-(L)1 therapy. Patients in Part A2 and Part B will have previously received anti-PD-(L)1 therapy and considered non-responders to anti-PD-(L)1 therapy alone. Patients will receive SRK-181 alone or in combination with anti-PD-(L)1 until disease progression, unacceptable toxicity, or other reasons for study discontinuation. Safety, PK, PD and efficacy data will be collected and monitored throughout the study. PD effects will be assessed by measuring modulation of tumor immune cells and TGFb pathway within the tumor microenvironment.ResultsN/AConclusionsAn enrollment update will be providedTrial RegistrationNCT04291079

Is there a difference in survival after photodynamic therapy of bile duct cancer depending on the sensitizer?

2008 ◽  
Vol 21 (01) ◽  
Author(s):  
A Dechêne ◽  
E Maldonado-Lopez ◽  
P Hilgard ◽  
G Gerken ◽  
T Zöpf
Keyword(s):  
Photodynamic Therapy ◽  
Bile Duct ◽  
Bile Duct Cancer ◽  
Duct Cancer
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