pyrimidinones and Biliary-Tract-Neoplasms

The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC.. Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm.. The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2.. This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Capecitabine; Female; Fluorouracil; Humans; Male; Middle Aged; Pyridones; Pyrimidinones

Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF. This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF. Between March 12, 2014, and July 18, 2018, 43 patients with BRAF. Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF. GlaxoSmithKline and Novartis.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Disease-Free Survival; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2-31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

Topics: Administration, Oral; Aged; Aged, 80 and over; Ampulla of Vater; Bile Duct Neoplasms; Biliary Tract Neoplasms; DNA-Binding Proteins; Exome Sequencing; Female; Gallbladder Neoplasms; Humans; Male; Middle Aged; Neurofibromin 1; Nuclear Proteins; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Survival Analysis; Transcription Factors; Treatment Outcome

Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients.. Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed.. IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response.. NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Biomarkers, Tumor; Combined Modality Therapy; Dasatinib; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Phthalazines; Piperazines; Prognosis; Prospective Studies; Pyridones; Pyrimidinones; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Biliary Tract Neoplasms; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Biliary Tract Neoplasms; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Biliary tract carcinomas (BTC) are malignant tumors with limited therapeutic options. Clinical experiences with anti-EGFR therapies have produced unsatisfactory results. The strategies of combined inhibition of EGFR and MEK1/2 could be a promising therapeutic option in BTC treatment. Preclinical activity of Panitumumab and Trametinib was tested in in vitro (EGI-1, MT-CHC01 and WITT cells) and in in vivo (xenograft) BTC models with different K-RAS mutational status. Trametinib reduced MAPK phosphorylation in wild type (WT) WITT cells and in both K-RAS mutated cells; in EGI-1 was also able to switch off EGFR activation. Panitumumab reduced the activation of its target only in EGI-1 cells, and of MAPK only in WITT cells. While Trametinib inhibited cell growth in K-RAS mutated cell lines, Panitumumab had no effect on proliferation independently by K-RAS status. The addition of Panitumumab to Trametinib did not significantly potentiate its anti-proliferative effect also in mutated cells. In vivo, Trametinib was able to significantly slow the tumor growth in K-RAS mutated xenograft models, but did not have effect on K-RAS WT cells; the addition of Panitumumab potentiated the Trametinib efficacy in MT-CHC01 and overcame the resistance to the anti-EGFR in WITT cells, in which the monotherapy was ineffective. Only in K-RAS mutated xenografts Trametinib alone or in combination with Panitumumab significantly decreased Ki67 positive cell fraction and CD31 angiogenesis markers. In conclusion, this preclinical study provides a rational to plan clinical trials assessing the efficacy of Trametinib in K-RAS mutated BTC patients and the combination with anti-EGFR in WT BTC patients.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Biliary Tract Neoplasms; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Female; Humans; MAP Kinase Kinase Kinase 1; MAP Kinase Kinase Kinase 2; Mice; Mice, Inbred NOD; Mice, SCID; Panitumumab; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

There is no standard palliative chemotherapy regimen in biliary tract cancers (BTC). Fluoropyrimidine or gemcitabine, with or without platinum, are most frequently used. We conducted this study to clarify the efficacy of palliative chemotherapy in BTC.. Patients with unresectable BTC treated with palliative chemotherapy between Oct 2001 and Aug 2006 at Seoul National University Hospital were reviewed retrospectively. Histologically confirmed cases of intrahepatic cholangiocarcinoma, gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater carcinoma were enrolled. We analyzed the efficacy of regimens: gemcitabine (G) versus fluoropyrimidine (F) and with or without platinum (P).. A total of 243 patients were enrolled. 159 patients (65%) were male and the median age of the patients was 60 years (range 26-81). Intrahepatic cholangiocarcinoma, gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater carcinoma were 92, 72, 58, and 21 cases, respectively. The median progression free survival (PFS) was 4.3 months (95% CI, 3.7-4.9) and median overall survival (OS) was 8.7 months (95% CI, 7.4-10.0). Ninety-nine patients received G-based chemotherapy (94 GP, 5 G alone), and 144 patients received F-based chemotherapy (83 FP, 61 F alone). The response rate (RR), disease control rate (DCR), PFS and OS of G-based chemotherapy versus F-based chemotherapy were 16.7% vs. 19.5% (P=0.591), 52.8% vs. 58.9% (P=0.372), 4.0 months vs. 4.3 months (P=0.816), and 7.8 months vs. 9.1 months (P=0.848), respectively. Sixty-six patients received F or G without P, and 177 patients received F or G with P. The RR, DCR, PFS and OS of chemotherapy without P versus chemotherapy including P were 12.7% vs. 20.6% (P=0.169), 46.0% vs. 60.6% (P=0.049), 3.3 months vs. 4.4 months (P=0.887), and 10.6 months vs. 8.1 months (P=0.257), respectively.. In unresectable BTC, F-based and G-based chemotherapy showed similar efficacy in terms of RR, DCR, PFS and OS. The benefit of adding P to F or G was not significant except for DCR. Further prospective studies which define the efficacy of various chemotherapeutic regimens in BTC are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Capecitabine; Cisplatin; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Palliative Care; Pyrimidinones; Retrospective Studies; Tegafur; Treatment Outcome; Uracil