azd-6244 and Biliary-Tract-Neoplasms

Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem.. Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity.. In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P > 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks.. Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bile Duct Neoplasms; Biliary Tract Neoplasms; Cisplatin; Deoxycytidine; Gemcitabine; Humans; Mitogen-Activated Protein Kinase Kinases

Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC.. Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m(2) intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment.. Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-t), AUC(0-∞) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem.. The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6(th) 2010).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biliary Tract Neoplasms; Cause of Death; Cisplatin; Combined Modality Therapy; Deoxycytidine; Female; Gemcitabine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Retreatment; Treatment Outcome

Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.. This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.. Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.. Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.

Topics: Adult; Aged; Benzimidazoles; Biliary Tract Neoplasms; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); ras Proteins

MEK inhibition has clinical activity against biliary cancers and might therefore be successfully combined with gemcitabine, one of the most active chemotherapy agents for these cancers. As gemcitabine is active in S-phase, and the extracellular signal-regulated kinase (ERK) pathway has a major role driving cell-cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 using a series of biliary cancer models.. Primary xenografts were established from patients with gallbladder and distal bile duct cancer and grown in severe combined immunodeficient (SCID) mice at the subcutaneous site. Plasma and tumor drug levels and the time course for recovery of ERK signaling and S-phase were measured in tumor-bearing mice treated for 48 hours with AZD6244 and then monitored for 48 hours off treatment. On the basis of these results, two different treatment schedules combining AZD6244 with gemcitabine were tested in four different biliary cancer models.. DNA synthesis was suppressed during treatment with AZD6244, and reentry into S-phase was delayed by approximately 48 hours after treatment. Strong schedule dependence was seen in all four biliary cancer models tested, suggesting that combined treatment with AZD6244 plus gemcitabine would be more active in patients with biliary cancer when gemcitabine is given following a 48-hour interruption in AZD6244 dosing, rather than concurrently.. The combination of AZD6244 plus gemcitabine is highly schedule dependent, and predicted to be more effective in the clinic using sequential rather than simultaneous dosing protocols.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biliary Tract Neoplasms; Cell Cycle; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Gemcitabine; Humans; Male; Mice; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Benzimidazoles; Biliary Tract Neoplasms; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins