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

Abstract

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).

Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

“…Our study evaluated a feasible dose de-escalation strategy involving two FDA-approved drugs, sorafenib and metformin, which can potentially reduce the side effects associated with these drugs as well as provide increased efficacy. Our results are supported by a recent study showing that reduced doses of sorafenib along with standard doses of atorvastatin and metformin led to reduced sorafenib-related side effects in advanced HCC [ 60 ].…”

Cancer biology in diabetes update: Focusing on antidiabetic drugs

“…Randomized efficacy trials evaluating the clinical benefit of metformin were also carried out in patients with bladder 105 , cervical 106 , esophageal 107 , liver 108 , ovary 109 , 110 , pancreas 111 , 112 and prostate cancer 113 , 114 , 115 . Although some human studies have shown the protective effect of metformin on cancer development, many prospective studies failed to show the improvement in primary endpoints, such as disease‐free survival (DFS) and overall survival, in cancer‐bearing patients treated with metformin plus standard cancer therapy.…”

“…Contrary to the possible risk of SGLT2is for cancer incidence, many preclinical studies have shown the protective effects of SGLT2 inhibition in cancer progression. Several basic and clinical investigations have elucidated that SGLT2is could mitigate the development of nonalcoholic steatohepatitis 108 , which is one of the important risk factors of liver cancer initiation or promotion. In this line, animal studies showed that a SGLT2i canagliflozin attenuates the development of hepatocellular carcinoma through the suppression of hepatic steatosis, inflammation, fibrosis and pro‐angiogenic activity 174 , 175 , 176 .…”

Comprehensive Review of Hepatocellular Carcinoma in India: Current Challenges and Future Directions

“… 50 In a phase I dose de-escalation study aimed to assess the safety and efficacy of sequentially decreasing doses of sorafenib in combination with atorvastatin (10 mg once daily) and metformin (500 mg twice daily), there was a marked reduction in sorafenib-related side effects. 51 Both these drugs show an inhibitory effect against chronic hepatitis and liver cirrhosis and also resensitize HCC cells to the action of sorafenib.…”