Dose Of Sorafenib Research Articles

2402 Sorafenib (SOR) dose reduction attenuates its immunosuppressive effects and delays hepatocellular cancer (HCC) development in the woodchuck model of hepatitis B related HCC

2402 Sorafenib (SOR) dose reduction attenuates its immunosuppressive effects and delays hepatocellular cancer (HCC) development in the woodchuck model of hepatitis B related HCC

PP65 - Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation that limits the survival of tumor cells. We have recently shown that the overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoma cells. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in hepatoblastoma cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic markers in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced cell death in HepG2 cells. However, low concentration of the drug (10 nM) increased the expression of cell death receptors and extrinsic apoptotic pathway (caspase-8) that both diminished at higher concentrations of the drug (10 µM). High doses of Sorafenib correlated to a rise of caspase-9 and caspase-3 activities, as well as DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in cells treated with Sorafenib. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death shift from the extrinsic to intrinsic apoptotic signaling in hepatoblastoma cells.

FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib‐mediated cytotoxicity

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 4′,6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and – independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.

Abstract 5144: Low dose sorafenib delays hepatocellular cancer (HCC) development in the woodchuck model of hepatitis B related HCC

Abstract Introduction: The eastern woodchuck is an established model of human hepatitis B viral infection and spontaneously develops HCC in the context of chronic woodchuck hepatitis viral infection (WHV) at a median age of 24 months. In this translational model of angiogenesis driven HCC, we evaluated the impact of sorafenib on delaying HCC development. Methods: Woodchucks were bred and inoculated at birth with titered infectious WHV pools obtained from chronic WHV carriers. By 12 months of age, the rate of chronic WHV infection was >60%. Animals were trained to receive drug orally mixed in a liquid diet. After an initial single dose woodchuck PK study it was predicted that sorafenib given orally M-F at 2.5 mg/kg once daily or 5mg/kg daily would achieve exposure in woodchucks ∼ 2x IC50 and 5X IC50 for all targets of sorafenib. This is within the exposure achieved in humans where the starting dose achieves exposures that are ∼ 10-12X IC50. We hypothesized that for both long term tolerability and delaying of HCC development, lower doses maybe ideal. Viral titers of WHV DNA were serially assessed, PK exposure of sorafenib and serial ultrasound (USG) was done q2 weeks to assess HCC development. Six WHV+ animals of similar age per arm were randomized to Placebo (P), low or high dose sorafenib. Time to tumor development (TTD) was measured from start of therapy to first occurrence of at least one 2 cm HCC was confirmed on 2 serial USGs. Tumor volume of all tumors seen was assessed as tumor burden. Results: Median TTD was 393 days, 490 and 498 days in the P, low and high dose sorafenib groups respectively. No toxicity was seen and PK results showed exposures as predicted in the two sorafenib groups. The tumor burden adjusted for the duration of therapy was significantly lower in the low dose group than the high dose and P groups. We evaluated three possible mechansims for this delay in HCC. WHV titers decreased as tumor burden increased as viral replication halts when malignant transformation occurs. The delay in TTD was not secondary to an antiviral effect that is known in this model and in humans to delay HCC occurrence. Anti-angiogenic effect was measured on H/E following necropsy as tumor necrosis and involved 7% of the total tumor volume in low dose and 13% of total tumor volume in high dose animals and 0% in P animals. High dose sorafenib inhibited the ex-vivo mixed lymphocyte reaction of woodchuck PBMC whereas low dose sorafenib did not which mechanistically may explain the difference seen in tumor burden with low compared to high dose sorafenib. Conclusions: The delay in HCC by 100 days seen in woodchucks would translate into a 3-9 years delay in HCC occurrence in humans. The tolerability at low dose for over 2 years, lower tumor burden and differential immune effects seen at low dose vs higher dose have great translational significance in the light of the recently completed STORM trial. Support: Sorafenib: Bayer. Funding: ACS- MSRG 08-096-01-CCE Citation Format: Renuka V. Iyer, Sandra Sexton, Leslie Curtin, Gerald Fetterly, Orla Maguire, Hans Minderman, Ilia Toshkov, Bud Tennant, Alan Hutson, Donald L. Trump, Candace Johnson. Low dose sorafenib delays hepatocellular cancer (HCC) development in the woodchuck model of hepatitis B related HCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5144. doi:10.1158/1538-7445.AM2015-5144

2-Deoxy-d-Glucose Can Complement Doxorubicin and Sorafenib to Suppress the Growth of Papillary Thyroid Carcinoma Cells.

Tumor cells display a shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. A subset of papillary thyroid carcinoma (PTC) is refractory to surgery and radioactive iodine ablation. Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects. In this study, we assessed the anti-cancer activity of 2-deoxy-d-glucose (2-DG) alone and in combination with doxorubicin or sorafenib in PTC cell lines with (BCPAP) and without (CG3) the BRAFV600E mutation. BCPAP cells were more glycolytic than CG3 cells, as evidenced by their higher extracellular l-lactate production, lower intracellular ATP level, lower oxygen consumption rate (OCR), and lower ratio of OCR/extracellular acidification rate. However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment. Regression analysis showed that cell growth in both cell lines was dependent on ATP generation. 2-DG increased the chemosensitivity of BCPAP and CG3 cell lines to doxorubicin and sorafenib. These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.

Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma.

Acquired evasive resistance is a major limitation of hepatocellular carcinoma (HCC) treatment with the tyrosine kinase inhibitor (TKI) sorafenib. Recent findings suggest that resistance to sorafenib may have a reversible phenotype. In addition, loss of responsiveness has been proposed to be due to a gradual decrease in sorafenib plasma levels in patients. Here, the possible mechanisms underlying reversible sorafenib resistance were investigated using a Hep3B-hCG orthotopic human xenograft model of locally advanced HCC. Tissue and plasma sorafenib and metabolite levels, downstream antitumor targets, and toxicity were assessed during standard and dose-escalated sorafenib treatment. Drug levels were found to decline significantly over time in mice treated with 30 mg/kg sorafenib, coinciding with the onset of resistance but a greater magnitude of change was observed in tissues compared with plasma. Skin rash also correlated with drug levels and tended to decrease in severity over time. Drug level changes appeared to be partially tumor dependent involving induction of tumoral CYP3A4 metabolism, with host pretreatment alone unable to generate resistance. Escalation from 30 to 60 mg/kg sorafenib improved antitumor efficacy but worsened survival due to excessive body weight loss. Microvessel density was inhibited by sorafenib treatment but remained suppressed over time and dose increase. In conclusion, tumor CYP3A4 induction by sorafenib is a novel mechanism to account for variability in systemic drug levels; however, declining systemic sorafenib levels may only be a minor resistance mechanism. Escalating the dose may be an effective treatment strategy, provided toxicity can be controlled.

P-111 Final results of the GIDEON (Global Investigational of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) study according to patient etiology: The Italian experience

Introduction: Sorafenib is the only targeted agent indicated for the treatment of hepatocellular carcinoma (HCC). The global, prospective, non-interventional GIDEON study enrolled over 3200 patients (pts) with unresectable HCC (uHCC) treated with sorafenib in real-life clinical practice conditions. The primary objective of the study was to evaluate the safety of sorafenib in HCC patients in clinical practice. Secondary objective was efficacy. We report the final analysis of the Italian subgroup of patients according to etiology. Methods: Patients with uHCC for whom the decision to administer sorafenib was taken were eligible for enrollment. Disease and patient characteristics were assessed at baseline. Sorafenib dose, adverse events (AEs) and disease assessments were reported at follow-up. Results: Of 278 pts enrolled in Italy, 274 were evaluable for efficacy and 271 for safety analysis. The median age was 70 years (range: 44-90), 227 pts (83%) were male, 266 pts (97%) Caucasian and disease stage was BCLC-B in 87(32%) and BCLC-C in 142(52%) pts. The etiology of the underlying liver disease was recorded as hepatitis B (hep-B) in 58(21%) pts, hep B only in 39(14%) pts, hepatitis C (hep-C) in 157(57%), hep-C only in 119(43%) pts, alcohol use in 112(41%) pts and nonalcoholic steatohepatitis (NASH) in 7(2.6%) pts. Overall adverse events were slightly more frequent in pts with hep-B (88%) than those with hep-C (75%) or alcohol use (75%). The type and incidence of AEs were consistent among all subgroups, the most frequent being gastrointestinal (diarrhea/ascites), dermatologic (hand-foot skin reaction/rash) and fatigue. There were no new unexpected AEs. Median OS in days (months) in pts with hep-B, hep-C, alcohol use, NASH, hep-B only and hep-C only were 351(11.5), 617(20.5), 402(13.1), 211(6.9), 351(11.5) and 633(20.7) respectively. Conclusion: The most frequent etiology was hep-C followed by alcohol use and hep-B. Safety was consistent with the known profile of sorafenib. Overall survival was longer in the subgroup of hep-C pts than in the other etiology subgroups. This has also been reported in previous analyses. Table: P-111

Safety of sorafenib (SOR) dose in United States (US) patients (pts) with advanced hepatocellular carcinoma (HCC) with varying liver dysfunction: Lessons from a Hispanic-rich South Texas institution.

e15150 Background: HCC pts often present with Child Pugh (CP) B liver dysfunction but are poorly represented in trials. GIDEON showed median dose (duration) was 742 mg (17.6 weeks) in CP A vs 677 m...

A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma

This study is a rare example of effective doses of both targeted agents being both administered and tolerated.This combination should not be used in melanoma. Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented. Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m(2) weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. The combination of sorafenib and bortezomib is safe but not active in patients with melanoma.

Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer.

BackgroundDespite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus.MethodsConditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays.ResultsPharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30–60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naïve and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3β and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers.ConclusionsIn summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0509-x) contains supplementary material, which is available to authorized users.

Skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma treated with sorafenib.

The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the L3 skeletal muscle index (L3 SMI) was obtained. The factors contributing to overall survival, sorafenib dose reduction, and discontinuation of sorafenib were analyzed using the Cox proportional hazards model. L3 SMI (p = 0.020) and log (α-fetoprotein (AFP)) (p = 0.010) were identified as independent prognostic factors in HCC patients treated with sorafenib. The initial dose of sorafenib (p = 0.008) was an independent risk factor for sorafenib dose reduction, and log (AFP) (p = 0.008) was the only significant risk factor for the discontinuation of this drug. L3 SMI was not a risk factor for either dose reduction (p = 0.423) or the discontinuation (p = 0.132) of sorafenib. A multiple linear regression analysis determined the following relationship between skeletal muscle mass (assessed as L3 SMI) and the explanatory factors: L3 SMI = −0.1896 × (Age) − 10.3441 × (Child-Pugh score) − 9.3922 × (log (AFP)) + 1.6139 × (log (AFP)) × (Child-Pugh score) + 112.9166. Skeletal muscle depletion is inversely associated with age, Child-Pugh score, and log (AFP). Moreover, it is an independent prognostic factor for HCC patients treated with sorafenib.

Metronomic vinorelbine (oral) in combination with sorafenib in advanced non-small cell lung cancer.

To date, biomarkers to predict benefit from anti-angiogenic therapy are still lacking. Sorafenib and metronomic oral vinorelbine combination was studied and changes in blood and DCE-MRI parameters were investigated as biomarkers for benefit. Patients with advanced NSCLC were recruited to 3 successive cohorts. Each cohort was given a fixed metronomic (3 times a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, or 120 mg/week respectively. Within each cohort, patients received a starting dose of sorafenib at 200mg bid for 4 weeks. In the absence of dose-limiting toxicities, each patient's dose of sorafenib was escalated to 400mg bid for 4 weeks, 600 mg bid for 4 weeks and finally 800 mg bid. Biomarkers measured include DCE-MRI parameters, circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and plasma thrombospondin (TSP-1). 48 evaluable patients were analyzed. There were 4 (8.9%) patients with partial response (PR) and 7 (15.2%) with cavitary response (CaR). Two subpopulations of CECs (CEC(hi), CEC(lo)) were identified that trended in opposite directions during treatment, with CEC(hi) demonstrating an upward trend in contrast to CEC(lo). Higher baseline CEC(hi) and lower baseline blood flow (F) and fractional intravascular blood volume (V1) predicted for response. Multivariate analysis revealed a lower baseline V1, and dynamic changes of CEC during treatment (CEC increase, sum of CEC(hi) and CEC(lo)) predicted for improved survival. Sorafenib and metronomic oral vinorelbine is active in advanced NSCLC. Baseline levels and changes in DCE parameters and CEC may be useful predictive biomarkers.

Pancreatic Atrophy in Hepatocellular Carcinoma Patients Receiving Long-Term Treatment with Sorafenib

Objective: To date, sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). Pancreatic atrophy has recently been reported in 2 patients as a novel side effect after long-term sorafenib treatment. Methods: We retrospectively analyzed clinical and radiological data of patients with advanced HCC with long-term treatment of sorafenib (median 279 days, range 153-826 days). Pancreata were semi-manually segmented section by section to calculate the pancreas volumes before and under sorafenib treatment. Results: Sorafenib reduced pancreatic volume in 18/19 (95%) HCC patients with a mean pancreatic volume loss of 25% (p = 0.002). Pancreatic volume loss depended on the dose (r = 0.36) and exposure time of sorafenib (r = 0.35) and was detectable as early as after 3 months of sorafenib treatment and already after a cumulative sorafenib dose of <100 g. Median overall survival was 13.2 months (range 7.8-31.3 months) but did not correlate with sorafenib-induced pancreatic volume reduction (hazard ratio 1.002, 95% confidence interval 0.981-1.060, p = 0.24). Conclusion: We could confirm pancreatic atrophy as a novel adverse event of sorafenib therapy in HCC patients, correlating with sorafenib dose and exposure time.

Comparative dosing and efficacy of sorafenib in hepatocellular cancer patients with varying liver dysfunction.

Sorafenib is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, dose reductions are often required, although there are limited efficacy data related to dose modifications. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib therapy in relation to dose and Child Pugh (CP) score. A retrospective analysis was done of advanced HCC patients, starting sorafenib at 400 mg twice daily, or at physician discretion at 400 mg daily, with the goal of titrating to twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed. Among 107 patients, median OS (mOS) was 10.2 months; median PFS (mPFS) was 5.2 months. mOS for sorafenib 400 mg/day was 6.6 vs. 800 mg/day was 12.8 months [hazard ratio (HR), 0.59; P=0.04]; mPFS was 3.5 vs. 5.9 months, respectively (HR, 0.66; P=0.07). For Child Pugh A class (CP-A) patients, mOS was 15.8 months for 400 mg/day vs. 12.8 months for 800 mg/day (HR, 1.48; P=0.35); mPFS was 9.0 vs. 5.9 months, respectively (HR, 1.23; P=0.56). For Child Pugh B class (CP-B) patients, mOS was 5.0 months for 400 mg/day vs. 11.2 months for 800 mg/day (HR, 0.33; P=0.002); mPFS was 2.1 vs. 5.6 months, respectively (HR, 0.41; P=0.006). No differences in adverse events (AEs) were observed in CP-A vs. CP-B. Patients with CP-A or CP-B advanced HCC should be offered sorafenib at 400 mg twice daily with optimal management of AEs in order to improve survival.

Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells.

Molecular-targeted therapy has shown promise as a treatment for advanced osteosarcoma (OS). Sorafenib (SOR), a multikinase inhibitor, is the approved systemic drug of choice for OS, but has demonstrated limited benefits due to its toxicity and other adverse effects. Therapy strategies for reducing toxicity include using lower doses of SOR in combination with other complementary agents. Cisplatin (CDDP) has been shown to be a promising anticancer drug against various types of cancer including OS. In the present study, SOR was combined with CDDP to determine whether this combinatorial treatment suppressed tumor growth thereby simultaneously reducing doses of the two drugs for the treatment of OS. Human Saos-2 OS cells were treated with SOR and CDDP, alone and in combination, and the effect of these treatments on cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion, and involvement in receptor signaling, as well as tumor growth ability in nude mice was determined. It was found that the combination of low concentrations of SOR and CDDP significantly suppressed the cell proliferation, colony formation, migration and invasion, and induced cell apoptosis and cell cycle arrest in the G0/G1 stage, and suppressed tumor growth in a nude mouse model compared to the actions of either agent alone. The results also showed that SOR in combination with CDDP significantly suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), which may contribute to the inhibition of tumor growth. These results suggested that SOR in combination with CDDP acts synergistically in the treatment of OS.

Randomized Controlled Trial of the Prophylactic Effect of Urea-Based Cream on Sorafenib-Associated Hand-Foot Skin Reactions in Patients With Advanced Hepatocellular Carcinoma

To assess whether urea-based cream (UBC) has prophylactic benefits on sorafenib-induced hand-foot skin reaction (HFSR) in patients with advanced hepatocellular carcinoma (HCC). In this randomized, open-label trial, 871 patients with advanced HCC throughout China were treated with 10% UBC three times per day plus best supportive care (BSC; n = 439) or BSC alone excluding all creams (n = 432), starting on day 1 of sorafenib treatment, for up to 12 weeks. HFSR was assessed every 2 weeks and at 14 weeks for patients completing the study. Once HFSR occurred, patients were allowed any cream, including a UBC. The 12-week incidence of any grade HFSR was significantly lower in the UBC group versus the BSC-alone group (56.0% v 73.6%, respectively; odds ratio [OR], 0.457; 95% CI, 0.344 to 0.608; P < .001), as was the incidence of grade ≥ 2 HFSR (20.7% v 29.2%, respectively; OR, 0.635; 95% CI, 0.466 to 0.866; P = .004). Median time to first occurrence of HFSR was significantly longer in the UBC group than the BSC-alone group (84 v 34 days, respectively; hazard ratio, 0.658; 95% CI, 0.541 to 0.799; P < .001). Elevated AST was associated with increased risk of HFSR but did not alter the treatment effect of UBC. UBC plus BSC, compared with BSC alone, did not affect the sorafenib dose reduction or interruption rate (9.1% v 11.8%, respectively; P = .1937), response rate (11.1% v 10.1%, respectively; P = .6674), or disease control rate (98.8% v 98.2%, respectively; P = .5350) at week 12. UBC prophylaxis in patients with advanced HCC starting sorafenib reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with BSC. Blinded, randomized, placebo-controlled trials to determine the role of UBC on the incidence and severity of HFSR are warranted.

Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia.

FLT3/ITD is associated with poor outcomes in adult and pediatric acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) can improve cure rates, however relapse is still common. Recent studies demonstrate the activity of FLT3 inhibitors, including sorafenib, in targeting the underlying mutation. We conducted a retrospective study of 15 pediatric patients with FLT3/ITD+ AML treated with sorafenib within 18 months after receiving HSCT. Sorafenib was administered either as prophylaxis in patients considered at very high risk for relapse (n = 6) or at the time of disease recurrence (n = 9). Sorafenib was initiated at a median of 100 days post HSCT. Overall, 11/15 (73%) of patients experienced medically significant toxicities. Among patients who experienced toxicity, 6/11 (55%) received treatment at doses above what was later determined to be the maximum tolerated dose of sorafenib for pediatric leukemia. Importantly, sorafenib did not appear to exacerbate graft versus host disease. Our findings suggest that sorafenib may be of particular efficacy in patients with minimal residual disease (MRD); all patients who received sorafenib for MRD immediately prior to transplant or with emergence post-HSCT are alive and remain in complete remission at a median of 48 months post HSCT. Our case series suggests that sorafenib administration is feasible and tolerable in pediatric FLT3/ITD+ AML patients early post HSCT. Ongoing prospective controlled studies are needed to further define the dosing of sorafenib in the post-HSCT period and to determine the optimal context for this treatment approach.

Phase I/II study of sorafenib in combination with intermittent hepatic arterial infusion chemotherapy using cisplatin for unresectable advanced hepatocellular carcinoma with portal vein tumor thrombus.

441 Background: Our purpose in the study was to ascertain the feasibility of a combination therapy with sorafenib and hepatic arterial infusion therapy (HAIC) using cisplatin (CDDP) for unresectable advanced HCC included portal vein tumor thrombus. Methods: Phase I study: Soraenib was administered continuously, whereas CDDP was given on day1, 8, and 15. The dose of sorafenib was escalated in two steps from 400 to 800 mg/body, whereas the dose of CDDP was escalated in three steps from 20 to 25 and 30 mg/m2. We estimate the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of this therapy, to determine the recommended dose (RD). Phase II study: Thirty-five patients with unresectable HCC received this therapy under RD, and the efficacy and safety were assessed. Results: Phase I study: 15 patients (11 male/4 female, median age: 73.1 years) with unresectable advanced HCC have been enrolled. None of the patients treated with sorafenib 400mg and cisplatin 20 mg/m2 experienced DLT. Three of three patients treatd with sorafenib 800mg and cisplatin 20 mg/m2 experienced DLTs (two serum bilirubin elevation and one hepatic encephalopathy). None of the patients treated with sorafenib 400mg and cisplatin 25 mg/m2 experienced DLT. One of six patients treated with sorafenib 400mg and cisplatin 30 mg/m2 experienced dose-limiting thrombocytopenia, and One of them experienced dose-limiting serum aspartate aminotransferase elevation. Phase II study: 35 patients (27 male / 8 female, median age : 69.2 years) with unresectable advanced HCC have been enrolled. The clinical response were rated as 9 partial response (PR), 18 stable disease (SD), and 8 progressive disease (PD). Conclusions: In this study, RD of this therapy was sorafenib 400mg/body and CDDP 30 mg/m2. Sorafenib in combination with intermittent HAIC using CDDP for unresectable advanced HCC was expected to be safe and effective treatment. Clinical trial information: 000008571.

Micro- and macroarteriolar blockade of hepatocellular carcinoma (HCC): Ramping up the dose of sorafenib over two weeks before hepatic arterial chemoembolization (HACE) for liver cancer.

472 Background: Multiple sessions of hepatic artery chemo-embolization (HACE) are usually necessary to achieve partial or complete ablation of a hepatoma (HCC). Blocking the pro-angiogeneic environment and re-establishment of tumor microvasculature with the tyrosine kinase inhibitor sorafenib administered prior to HACE may enhance tumor necrosis and possibly patient survival. Methods: Twenty patients with inoperable HCC were subject to 2 weeks of sorafenib, followed by HACE using Adriamycin and mitomycin C. The first 10 patients were treated with a sorafenib 400 mg twice a day. The second 10 patients had their dose of sorafenib ramped up from 200 mg twice a day to 400 mg twice a day over 1-2 weeks according to tolerability. Patients were continued on sorafenib during as many HACE procedures needed to achieve no evidence of enhancement on multi-phase imaging. Results: The mean length of treatment for the ramped up group was significantly longer that the non-ramped up group as shown in table 2. (3.90 vs 3.05, N &lt; 0.05). There was no significant difference in survival, nor adverse events between groups. Three patients (5, 12, 13) ultimately went on to receive a liver transplant. Conclusions: Use of sorafenib prior to HACE is feasible and safe. Ramping up the dose over 2 weeks allows more patient to stay on treatment longer. Further studies are needed to determine how best to combine sorafenib with HACE in order to increase survival and eligibility of patients to be listed for liver transplant. Clinical trial information: NCT00949182.