Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH).

BACKGROUND: This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10 mg) and metformin (M, 500 mg BD) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800 mg, 600 mg. 400 mg, and 200 mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE). RESULTS: The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600 mg dose, and the concentration threshold of 2400 ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI]: 3.2-14.5 months). CONCLUSION: The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID: CTRI/2018/07/014865).

Presentation and Outcomes with First-Line Chemotherapy in Advanced Cholangiocarcinomas-A Relatively Rare Component of Biliary Tract Cancers in India.

Background Biliary tract cancers (BTCs) are a rare group of cancers with limited data with respect to advanced unresectable cholangiocarcinoma (CCA). Materials and Methods The study is a retrospective study of patients with advanced unresectable/metastatic CCA, who received first-line palliative chemotherapy (CT1) from January 2014 to March 2019 at the Tata Memorial Hospital, Mumbai. Baseline clinical characteristics, chemotherapeutic regimens, and toxicities were evaluated. Results One hundred and forty patients satisfied criteria for evaluation. Median age of the entire cohort was 57 years (range: 32-80). There were 87 patients (62.1%) with intrahepatic CCA, 35 patients (25%) with perihilar CCA, and 14 patients (10%) with distal CCA. One hundred and twelve patients (80%) had metastatic disease at presentation. Commonest CT1 regimens were gemcitabine-cisplatin (GC) in 89 patients (63.5%) and gemcitabine-oxaliplatin (GO) in 34 patients (24.3%). Sixty-three patients (45%) received second-line chemotherapy. With a median follow-up of 27 months, median progression-free survival for the entire cohort was 7.56 months (95% confidence interval [CI]: 6.23-8.88), and median OS was 12.16 months (95% CI: 10.08-14.24). Common chemotherapy-related grade 3/4 side effects included vomiting in 25 patients (17.9%), diarrhea in 23 patients (16.4%), and thrombocytopenia in 22 patients (15.7%). Conclusion The current study in advanced CCAs is the largest of its nature from India. The common regimens used as first line were GC and GO. Tolerance and overall survival appear similar to previously published data.