Dose Of Sorafenib Research Articles

Sorafenib in the Treatment of Early Breast Cancer: Results of the Neoadjuvant Phase II Study - SOFIA*

Background: Sorafenib was tested for neoadjuvant treatment with an anthracycline/taxane-based chemotherapy in the open-label, multicentre, single-arm phase II study, ‘SOFIA'. Patients and Methods: Inclusion criteria were: HER2 negative, cT3, cT4 or cT2 cN+, M0 primary breast cancer. Patients received 4 × epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) intravenously (i.v.) in 3-weekly cycles followed or preceded by 12 weeks of paclitaxel (Pw) 80 mg/m². In cohort 1, sorafenib started at 800 mg daily with chemotherapy. An initial daily sorafenib dose of 200 mg was escalated, based on individual toxicities, every 3 weeks in cohort 2 (starting with EC) and every 2 weeks in cohort 3 (starting with Pw). The primary objective was to identify the most feasible regimen; secondary objectives were safety, pathological complete response (pCR) at surgery and pharmacokinetics. Results: Of the 36 recruited patients, 7/12 patients completed the study in cohort 1 and 24/24 patients in cohorts 2 and 3. The median cumulative sorafenib dose per patient was 37%, 65% and 46% in cohorts 1, 2 and 3, respectively. The main grade 3-4 toxicities were neutropenia and hand-foot syndrome. The pCR (ypT0/is) rate was 27.7%. No pharmacokinetic interaction was observed between sorafenib and epirubicin. Conclusion: Sorafenib EC-Pw is feasible if the starting dose is 200 mg, escalated every 3 weeks based on the patients' individual toxicities.

Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: A propensity score analysis.

Patients with hepatocellular carcinoma (HCC) who receive an initial full dose of sorafenib (800 mg/day) often require a decreased dose (400 mg/day) or discontinuation of therapy because of severe adverse events. We conducted a retrospective analysis of patients with HCC to compare the safety and efficacy of full- to half-dose sorafenib. We reviewed the medical records of 218 consecutive patients with intermediate or advanced stage HCC who received half (n = 73) or full-dose sorafenib (n = 145) between 2009 and 2012 at four institutions. A propensity score-matching analysis was used to adjust for potential bias. Multivariate logistic regression analysis showed that increased age was an independent factor for the selection of initial half-dose sorafenib (odds ratio, 1.10; 95% confidence interval, 1.05-1.15; P < 0.001). Fifty-eight patients each in the half-dose and full-dose groups were selected for propensity score matching. The incidence of grade 3-4 severe adverse effects was lower in the half-dose group (47.4% vs 66.7%, P = 0.037). In contrast, the median progression-free survival (PFS) and overall survival (OS) rates were not significantly different (half-dose group, 3.8 and 10.2 months; full-dose group, 2.5 and 8.8 months; P = 0.143 and 0.911, respectively). Propensity score-matched analyses indicate that initial half-dose sorafenib treatment led to fewer severe adverse effects and a comparable survival benefit compared with a full dose in select patients with HCC, particularly for those of advanced age.

The emerging questionable benefit of sorafenib as a neo-adjuvant in HCC patients treated with Y-90 radioembolization pending liver transplantation

The emerging questionable benefit of sorafenib as a neo-adjuvant in HCC patients treated with Y-90 radioembolization pending liver transplantation

Mo1055 Clinical Features Associated With Radiological Response to Sorafenib Therapy for Unresectable Hepatocellular Carcinoma; A Multicenter Study in Japan

Background and Aim: There has been no established biomarker to predict clinical response to sorafenib. The aim of this study is to investigate predictive factors associated with radiological response to sorafenib therapy for Japanese patients with unresectable hepatocellular carcinoma (HCC). Method: A total of 465 patients with unresectable HCC were treated with sorafenib in our fourteen hospitals in Japan before August 2013. Among them, 316 patients with sufficient available clinical data were included in this study.We analyzed the relationship between radiological response and clinicopathological factors including age, sex, performance status, liver function, tumor status such as portal invasion and serum AFP decrease during the first one month, and examined the predictive factors for the favorable responder to sorafenib therapy. Furthermore, we performed tumor biopsy prior to sorafenib therapy in 62 patients, and investigated the relationship between tumor differentiation degree and radiological response. Results: Study population consisted of 259 males and 57 females with a median age of 70 years (range, 37-90 years). Of these, 191 patients (60.4%) were classified with BCLC stage C, and 271 patients (85.8%) had liver function of Child-Pugh A. Median overall survival and progression free survival were 289 and 98 days. Regarding the best tumor response evaluated by modified RECIST, number of CR/ PR/ SD/ PD were 4/ 51/ 136/ 125, respectively. In a multivariate analysis, female (p = 0.001, odds ratio = 3.018, 95% confidence interval (CI); 1.540-5.915) and AFP decrease (p = 0.014, odds ratio = 2.146, 95% CI; 1.170-3.922) were the independent predictors linked to objective tumor response (CR or PR). Regarding the background of female patients, females were elder (p = 0.007) with lower body weight (p < 0.001) than males and tended to be given reduced initial dose of sorafenib (p = 0.081). Their mean initial dosage of sorafenib per kg was less than males (7.2 vs. 8.5 mg/kg, p = 0.013). As for any adverse events and administration period of sorafenib, no difference in genders was found. In 62 patients with tumor biopsy samples, disease control rate (DCR) of patients with well differentiated HCC was significantly higher than the others (80% vs. 45.9%, p = 0.009). Conclusion: Serum AFP decrease in the first one month was associated with radiological response as previously reported. In addition, our results suggested that female would be one of the independent predictors for favorable response to sorafenib. In histological examination, well differentiated HCC was associated with favorable disease control. Further investigations with regard to biomarkers predicting the clinical response to sorafenib in HCC patients are warranted.

Mo1056 Risk Factors of Incidental Hepatocellular Carcinoma Occurrence: Single-Center Experience

Background and Aim: There has been no established biomarker to predict clinical response to sorafenib. The aim of this study is to investigate predictive factors associated with radiological response to sorafenib therapy for Japanese patients with unresectable hepatocellular carcinoma (HCC). Method: A total of 465 patients with unresectable HCC were treated with sorafenib in our fourteen hospitals in Japan before August 2013. Among them, 316 patients with sufficient available clinical data were included in this study.We analyzed the relationship between radiological response and clinicopathological factors including age, sex, performance status, liver function, tumor status such as portal invasion and serum AFP decrease during the first one month, and examined the predictive factors for the favorable responder to sorafenib therapy. Furthermore, we performed tumor biopsy prior to sorafenib therapy in 62 patients, and investigated the relationship between tumor differentiation degree and radiological response. Results: Study population consisted of 259 males and 57 females with a median age of 70 years (range, 37-90 years). Of these, 191 patients (60.4%) were classified with BCLC stage C, and 271 patients (85.8%) had liver function of Child-Pugh A. Median overall survival and progression free survival were 289 and 98 days. Regarding the best tumor response evaluated by modified RECIST, number of CR/ PR/ SD/ PD were 4/ 51/ 136/ 125, respectively. In a multivariate analysis, female (p = 0.001, odds ratio = 3.018, 95% confidence interval (CI); 1.540-5.915) and AFP decrease (p = 0.014, odds ratio = 2.146, 95% CI; 1.170-3.922) were the independent predictors linked to objective tumor response (CR or PR). Regarding the background of female patients, females were elder (p = 0.007) with lower body weight (p < 0.001) than males and tended to be given reduced initial dose of sorafenib (p = 0.081). Their mean initial dosage of sorafenib per kg was less than males (7.2 vs. 8.5 mg/kg, p = 0.013). As for any adverse events and administration period of sorafenib, no difference in genders was found. In 62 patients with tumor biopsy samples, disease control rate (DCR) of patients with well differentiated HCC was significantly higher than the others (80% vs. 45.9%, p = 0.009). Conclusion: Serum AFP decrease in the first one month was associated with radiological response as previously reported. In addition, our results suggested that female would be one of the independent predictors for favorable response to sorafenib. In histological examination, well differentiated HCC was associated with favorable disease control. Further investigations with regard to biomarkers predicting the clinical response to sorafenib in HCC patients are warranted.

Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies

FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy. Acquired point mutations of FLT3-ITD gene were screened using cDNA-based sequencing approach in vitro sorafenib-resistant cells, which were developed by long-term exposure of Ba/F3-ITD to increasing doses of sorafenib, and in FLT3-ITD mutated AML patients, who developed relapse following sorafenib therapy. Drug effects (e.g., proliferation inhibition, apoptosis induction, and changes in signal transduction protein expression) were assessed in AML cells harboring the point mutations in vitro and in FLT3-ITD-mutated AML patient samples. We identified several acquired point mutations in the tyrosine kinase domains (TKD) of the FLT3 gene in sorafenib-resistant murine leukemia cell line carrying human FLT3-ITD mutations, which were also detected in two of four sorafenib-resistant patient samples. Engineering these point mutations into Ba/F3-ITD cells generated sublines that demonstrated varying degrees of sorafenib [a type II tyrosine kinase inhibitor (TKI)] resistance. A similar pattern of resistance could be observed by exposing these sublines to the other type II TKIs AC220 and MLN518. However, these sublines retained sensitivity to the type I TKIs PKC412 or crenolanib. The combination of crenolanib with sorafenib demonstrated marked cytotoxic effects in all of the sorafenib-resistant sublines. These combination strategies could be clinically important in reversing acquired resistance to FLT3 inhibition in AML.

Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer.

Sorafenib has proven efficacy in advanced differentiated thyroid cancer (DTC), but many patients must reduce the dose or discontinue treatment because of toxicity. The tolerability and efficacy of lower starting doses of sorafenib for DTC remain largely unstudied. Methods. We retrospectively examined overall survival, time to treatment failure, time to progression, discontinuation rates, and dose-reduction and interruption rates in patients with metastatic DTC treated with first-line sorafenib outside of a clinical trial. Two patient groups were compared; group 1 received the standard starting dose of 800 mg/day, and group 2 received any dose lower than 800 mg/day. Results. We included 75 adult patients, with 51 in group 1 and 24 in group 2. Mean age at diagnosis was 54 years, and 56% were male. The most common histologies included 43% papillary thyroid cancer of the conventional type, 15% papillary thyroid cancer of the follicular variant, and 15% Hürthle cell carcinoma. Time to treatment failure was 10 months (95% confidence interval [CI]: 5.6-14.3) in group 1 and 8 months (95% CI: 3.4-12.5) in group 2 (p = .56). Median overall survival was 56 months (95% CI: 30.6-81.3) in group 1 and 30 months (95% CI: 16.1-43.8) in group 2 (p = .08). Rates of discontinuation due to disease progression were 79% in group 1 and 91% in group 2, and 21% in group 1 and 9% in group 2 (p = .304) stopped treatment because of toxicity. Dose-reduction rates were 59% and 43% (p = .29), and interruption rates were 65% and 67% (p = .908) in group 1 and group 2, respectively. Conclusion. Efficacy and tolerability of sorafenib in treatment-naïve DTC patients does not appear to be negatively influenced by lower starting daily doses.

Sorafenib Cardiotoxicity Increases Mortality After Myocardial Infarction

Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism. Determining the mechanism of sorafenib-mediated cardiotoxicity. Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2'-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated. Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality.

MP35-14 THE CONTRIBUTION OF METABOLIC REMODELING TO THERAPY RESISTANCE IN RENAL CANCER

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2014MP35-14 THE CONTRIBUTION OF METABOLIC REMODELING TO THERAPY RESISTANCE IN RENAL CANCER Sunil Sudarshan, Dustin Gayheart, Tanner Hughes, Akash Kapadia, and Dan Benson Sunil SudarshanSunil Sudarshan More articles by this author , Dustin GayheartDustin Gayheart More articles by this author , Tanner HughesTanner Hughes More articles by this author , Akash KapadiaAkash Kapadia More articles by this author , and Dan BensonDan Benson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1057AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Therapy resistance is a significant obstacle in the treatment of patients with advanced renal cell carcinoma (RCC). One of the proposed mechanisms underlying therapy resistance is the propensity of RCC to utilize glycolysis in lieu of the tricarboxylic acid (TCA) cycle/oxidative phosphorylation for rapid energy production, a phenomenon known as the Warburg effect. In this study, we interrogated the biologic basis of the Warburg effect in RCC as well as its contribution to therapy resistance. METHODS Comparative gene expression analysis by mRNA microarray demonstrates a marked increase in the expression of Pyruvate Dehydrogenase Kinase-1 (PDK-1) in metastatic RCC compared with both normal tissue and primary RCC. PDK-1 promotes glycolytic metabolism by blocking the entry of pyruvate into the TCA cycle thereby inhibiting oxidative phosphorylation. Based on these data, we investigated the contribution of PDK-1 overexpression to therapy resistance utilizing two pharmacologic inhibitors of PDK-1, dichloroacetate (DCA) and phenylbutyrate (PB). RCC cell lines A498 and 786-O were exposed to Sorafenib only and PDK-1 inhibitors (DCA or PB) alone in order to determine the drug-response relationship. Minimally inhibitory doses of PDK-1 inhibitors were then used in combination with increasing doses of Sorafenib. MTS assays were performed in each experimental design in order to determine cell proliferation and viability. In tandem, Annexin V staining was utilized to determine the contribution of apoptosis to cell death following treatments. RESULTS PDK-1 inhibition with either DCA or PB sensitized 786-O RCC cells to the cytotoxic effect of sorafenib. These data reached statistical significance (p<0.05). Similarly, PB sensitized A498 cells to sorafenib (p<0.05). Furthermore, the differences in cell viability between control groups (no treatment) and PDK-1 inhibitor (DCA or PB) alone were not statistically significant. Annexin V staining revealed significantly increased apoptosis with sorafenib/PB cotreatment when compared to Sorafenib alone. CONCLUSIONS Activation of the TCA cycle via inhibition of PDK-1 potentiates the anti-tumor activity of Sorafenib. Although further characterization of the role of PDK-1 inhibitors in tumor growth suppression is required, our preliminary data suggests an important role of the Warburg effect demonstrated by RCC in the development of treatment resistance. Furthermore, unlocking metabolic pathways associated with this phenomenon may be the key to a novel therapeutic approach in the treatment of RCC. Rising Star Award-Urology Care Foundation © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e375-e376 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Sunil Sudarshan More articles by this author Dustin Gayheart More articles by this author Tanner Hughes More articles by this author Akash Kapadia More articles by this author Dan Benson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Activity of anti-cancer protein kinase inhibitors against Leishmania spp.

There is an urgent need to develop new and effective treatments for poverty-related neglected diseases. In light of the time required to bring a new drug to market and the cost involved (10-15 years, >1 billion US$), one approach to identifying new treatments for diseases like leishmaniasis is to evaluate drugs that are already registered for the treatment of other diseases. This paper describes the anti-leishmanial activities of 10 FDA-approved protein kinase inhibitors already available for the treatment of human cancers. In vitro and in vivo models of Leishmania infection were used to evaluate the potency of selected protein kinase inhibitors. Sunitinib, sorafenib and lapatinib were identified as active against Leishmania donovani amastigotes in cultured murine macrophages with IC(50) values of 1.1, 3.7 and 2.5 μM, respectively, a level of potency similar to that of miltefosine (IC(50) = 1.0 μM), and were not toxic to mammalian cells. In addition, some of the protein kinase inhibitors were active against L. donovani in the BALB/c mouse model of infection; dosing on days 7-11 with a 50 mg/kg oral dose of sunitinib, lapatinib or sorafenib reduced liver amastigote burdens by 41%, 36% and 30%, respectively, compared with untreated control mice. Although less efficacious, sorafenib was also active in vitro against intracellular amastigotes of the cutaneous disease-causing species Leishmania amazonensis, Leishmania major and Leishmania mexicana. This study demonstrates in vivo anti-leishmanial activity of clinically used protein kinase inhibitors and provides further evidence of the potential of drug repurposing.

Sorafenib Dose Escalation Is Not Uniformly Associated With Blood Pressure Elevations in Normotensive Patients With Advanced Malignancies

Hypertension with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased doses of sorafenib cause incremental increases in blood pressure (BP) we measured 12-hour ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose escalation study. After 7 days’ sorafenib (400mg BID) mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400mg TID) had marginally significant further increase in 12-hour mean DBP (p=0.053) but group B (600mg BID) did not achieve statistically significant increases (p=0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to the BP elevating effects of sorafenib.

A Phase I Study of High-Dose Interleukin-2 With Sorafenib in Patients With Metastatic Renal Cell Carcinoma and Melanoma

This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h×8–12 doses) was administered on days 1–5 and 15–19, followed by sorafenib on days 29–82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.

Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial

Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) axitinib-treated patients (N = 359) and 103 (29.0 %) sorafenib-treated patients (N = 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to axitinib dose interruptions (n = 46; 12.8 %), dose reductions (n = 16; 4.5 %), or discontinuations (n = 1; 0.3 %). Approximately 50 % of axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of axitinib-treated patients. Hypertension was more frequently observed during treatment with axitinib than sorafenib in patients with RCC, but axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during axitinib therapy are presented.

Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent. For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %). Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).

Characteristics of 18 patients with hepatocellular carcinoma who obtained a complete response after treatment with sorafenib

Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line systemic treatment for advanced hepatocellular carcinoma (HCC). However, possible predictors of the efficacy of sorafenib treatment in HCC patients remain unclear. We conducted a nationwide survey to examine the situation of patients with HCC treated with sorafenib who obtained a complete response (CR) according to the modified response evaluation criteria in solid tumors (mRECIST). The investigation was intended to collect clinical information regarding CR patients and to compare this data with an interim report examining all-patient surveillance for sorafenib use in Japan, which was released in May 2012. Among the 3047 patients who were treated at institutions belonging to the Liver Cancer Study Group of Japan, 18 patients (0.6%) obtained a CR. Significant factors in the CR group were a female sex, a low bodyweight (<59 kg), an early clinical stage and a small initial dose of sorafenib (P < 0.05). Furthermore, specific adverse events (palmar-plantar erythrodysesthesia syndrome, hypertension, diarrhea, alopecia, fatigue, nausea and anorexia) were frequently observed in the CR group (P < 0.05). This study identified the characteristics of CR patients during sorafenib treatment. The evaluation of patients receiving sorafenib, including the investigation of biomarkers, warrants further exploration in future clinical studies to identify a population in which sorafenib treatment is remarkably effective.

Is intra-patient sorafenib dose re-escalation safe and tolerable in patients with advanced hepatocellular carcinoma?

Although sorafenib improves survival in patients with hepatocellular carcinoma (HCC), doses have to be reduced in quite a few patients because of adverse events. We investigated whether intra-patient sorafenib dose re-escalations were safe and tolerable in patients with advanced HCC. Of the 73 advanced HCC patients treated with sorafenib, 42 achieved a tolerable dose with a dose reduction. We evaluated safety and tolerability in patients who attempted intra-patient dose re-escalations from the reduced dose. Thirteen of 42 patients increased the sorafenib dose from the reduced dose. Ten patients had a tolerable dose of 400 mg on alternate days, and 3 patients had a tolerable dose of 400 mg daily. Dose-limiting toxicity (DLT), defined as toxicity resulting in a dose reduction, was observed in 8 of 13 patients as a hand-foot skin reaction (HFSR), and DLT was noted in 2 of 13 patients as an increase in alanine aminotransferase/aspartate aminotransferase levels. Seven of 13 patients did not exhibit DLT after dose re-escalations. Although 6 patients exhibited DLT, the cause of the adverse event was HFSR in all cases. The median escalation dose ratio, which was calculated as the ratio of the real cumulative dose to the cumulative dose when continued at the tolerable dose after dose re-escalation, was 1.84. The results of the present study indicated that intra-patient sorafenib dose re-escalations were safe and tolerable. Further prospective analyses are needed to determine in more detail the safety and efficacy of intra-patient sorafenib dose re-escalations.

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study.

BackgroundDespite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor.MethodsIn this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated.ResultsIn phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib.ConclusionIL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC.Trial registrationClinicalTrials.gov Identifier: NCT00389285

Potential factors influencing initial sorafenib dose selection in hepatocellular carcinoma (HCC): U.S. regional analysis of GIDEON.

304 Background: GIDEON is a global, prospective, noninterventional study to evaluate sorafenib (SOR) safety under real-life practice conditions. Here we examine potential factors that may have had an impact on initial SOR dose (ID) selection in the U.S. cohort of GIDEON. Methods: Patients (pts) with unresectable HCC who were candidates for systemic therapy and for whom a decision was made to treat with SOR were eligible for inclusion. ID choice was at physician discretion. Baseline characteristics were analyzed for their potential impact on the choice of ID. Adverse events (AEs) were evaluated by ID. All results are descriptive. Results: 563 pts were valid for safety. 54% of pts received the recommended ID of 800 mg/d, 35% received 400 mg/d, and 11% other (includes 100, 200, 600 mg/d. dose). Among pts who had an ID &lt;800 mg/d, 37% underwent a dose increase to 800 mg/d. ID did not appear to differ by baseline Child-Pugh or its components, BCLC stage, etiology, or body mass index. By ECOG performance status (PS), IDs of 800/&lt;800 mg/day were given as follows: PS ≤1: 55%/45%; PS ≥2: 44%/56%. By age, corresponding values were 57%/42% for &lt;75 yr; 33%/67% for ≥75 yr. The incidence of AEs was similar across dose levels (Table). Conclusions: Baseline liver function, tumor stage, and etiology did not seem to have an influence on ID selection. We observed a trend toward lower ID in pts with age ≥75 yr and PS ≥2. Despite differences in average daily dose and time on drug, the safety profile for each ID was similar and dose adjustments may have contributed. Additional analyses are being evaluated to assess these and other contributing factors. Clinical trial information: NCT00812175. [Table: see text]

Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.

551 Background: Sorafenib inhibits various pro-angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3-7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m2 d1, 5-FU infusion 2400 mg/m2d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1-37). Three pts with CRC had disease control &gt; 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083. Clinical trial information: NCT01383343.

Management of Common Adverse Events in Patients Treated With Sorafenib: Nurse and Pharmacist Perspective

Sorafenib, a tyrosine kinase inhibitor, is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). Sorafenib is currently being evaluated in phase II and III trials in various malignancies as a single agent (locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer [DTC]), as part of multimodality care (HCC), and in combination with chemotherapies (metastatic breast cancer). Grade 1 and 2 adverse events (AEs) that commonly occur during treatment (ie, dermatologic manifestations, diarrhea, fatigue, and hypertension) should be proactively managed. The goal is to allow patients to remain on their full dose of sorafenib for as long as their treatment is indicated. A combination of early recognition of and intervention for AEs, patient education, and an open dialogue between patients and their multidisciplinary healthcare team, with timely reporting of AEs, will allow for effective management of AEs and minimize the need for sorafenib dose reduction or discontinuation.