Annals of Oncology Advance Access originally published online on February 24, 2006
Annals of Oncology 2006 17(5):866-873; doi:10.1093/annonc/mdl017
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© 2006 European Society for Medical Oncology
Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors
1 West German Cancer Center, University of Essen; 2 Department of Gastroenterology and Internal Medicine, Marienhospital Herne, University of Bochum; 3 Bayer HealthCare AG, Clinical Pharmacology, Wuppertal; 4 Bayer Pharmaceuticals Corporation, West Haven, CT, USA; 5 M.A.R.C.O. Institute for Clinical Research and Statistics – Dr. Wargenau, Düsseldorf; 6 Department of Hematology and Medical Oncology, Marienhospital Herne, University of Bochum, Germany
* Correspondence to: PD Dr. D. Strumberg, Department of Hematology and Medical Oncology, Marienhospital Herne, University of Bochum, Hölkeskampring 40, 44621 Herne, Germany. Email: dirk.strumberg{at}marienhospital-herne.de
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Background: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin.
Patients and methods: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m2 on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid.
Results: Common drug-related adverse events were neutropenia (56%), hand–foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for 
12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected.
Conclusion: Sorafenib 400 mg bid plus doxorubicin 60 mg/m2 was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.
Key words: BAY 43-9006, doxorubicin, Phase I, Raf kinase, sorafenib
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introduction |
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Sorafenib (BAY 43-9006) is a novel, oral multi-kinase inhibitor that blocks serine/threonine and receptor tyrosine kinases in both the tumor and the vasculature. Single-agent activity and acceptable tolerability were initially demonstrated with sorafenib in Phase I studies in patients with a variety of advanced, refractory solid tumors, including renal cell carcinoma (RCC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC) [1
–4]. Dose-limiting toxicities (DLTs) included diarrhea, fatigue and skin toxicity, but not bone marrow suppression. Phase II studies have also demonstrated activity of sorafenib in advanced RCC and HCC, and evidence of significantly prolonged progression-free survival over placebo in a Phase III trial in RCC was recently presented [5–7]. Good tolerability with manageable side-effects was confirmed in this Phase III trial in approximately 900 patients [6].
In preclinical studies, sorafenib was shown to target the Ras/Raf/MEK/ERK signaling pathway at the level of the serine/threonine kinase Raf [8]. This pathway plays a pivotal role in controlling tumor cell growth by relaying signals from the cell surface to the nucleus. Accumulating evidence also suggests that Raf has important pro-survival activities, independent of Ras/Raf/MEK/ERK signaling, via interaction with both anti- and pro-apoptotic molecules [9–12]. It is for these reasons that Raf represents an important target for pharmacologic intervention against solid tumors. Sorafenib has also been shown to potently inhibit the receptor tyrosine kinases vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) in vitro [8], the ligands of which—VEGF and PDGF—are important pro-angiogenic factors, essential for tumor growth and metastasis [13].
Preclinical data suggest that combining sorafenib with a variety of chemotherapeutic agents results in additive anti-tumor activity [14]. One chemotherapeutic agent tested, doxorubicin, is routinely used as a single drug or in combination with other cytostatic agents for the treatment of different malignant tumors, including small-cell lung cancer (SCLC), ovarian cancer, breast cancer, sarcoma, HCC, and gastric cancer [15]. However, the emergence of drug resistance to cytotoxic agents such as doxorubicin is a common clinical problem. Single-agent clinical studies suggest that sorafenib exhibits a toxicity profile that is different from doxorubicin, making it an appropriate agent, in terms of safety, for combination. In addition, potential effects of Raf on influencing the sensitivity of cells to doxorubicin-induced cell death and in regulation of the multi-drug-resistance-1 (mdr-1) gene suggest that doxorubicin resistance may be overcome by combination with an agent that targets Raf [16–23].
The aim of this Phase I study was to evaluate the safety and pharmacokinetics of sorafenib in combination with doxorubicin in patients with advanced refractory solid tumors.
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patient selection
Patients with advanced, histologically confirmed solid tumors refractory to standard therapy, and for whom treatment with doxorubicin was considered medically reasonable, were eligible for inclusion in this study. Patients were aged
18 years, had a life expectancy of 
12 weeks, and an Eastern Cooperative Oncology Group (ECOG) performance status 2. Adequate bone marrow, liver, and renal function were required (hemoglobin >90 g/L; absolute neutrophil count 1.5 x 109/L; platelets 100 x 109/L; total bilirubin <1.5 x upper limit of normal [ULN]; alanine aminotransferase [ALT]/aspartate aminotransferase [AST] 2.5 x ULN or 5.0 x ULN in the presence of hepatic tumor involvement; creatinine <1.5 x ULN). In addition, eligible patients had a partial thromboplastin time (PTT) within the normal range (<1.5 x ULN). Patients were excluded if they had evidence of the following medical conditions: congestive heart failure; serious cardiac arrhythmia; active coronary artery disease; myocardial infarction; ischemia; HIV infection; serious infection; history of seizures; major surgery within 3 weeks of treatment initiation; metastatic brain/meningeal tumors; organ allograft; or known liver function abnormalities. Pregnant or breast-feeding women were also excluded, and adequate birth control was required for the duration of the trial. Patients were excluded if they had received anticancer chemotherapy, radiotherapy, or immunotherapy within 4 weeks of study entry. Previous exposure to a Ras pathway inhibitor or doxorubicin within 3 months of enrollment also led to exclusion. Exclusion due to previous exposure to doxorubicin or any other anthracycline was limited to the maximum lifetime cumulative doxorubicin dose of 450 mg/m2 or the corresponding maximum lifetime cumulative dose of other anthracyclines.
All patients provided written, informed consent in accordance with federal and institutional guidelines. Documented approval from appropriate Ethics Committees and Institutional Review Boards was obtained, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
study design
Doxorubicin was administered on day 1 of each 3-week cycle at a dose of 60 mg/m2. Starting on day 4 of cycle 1, sorafenib was administered continuously without interruption throughout all further cycles. A sorafenib-free interval starting 48 h before the second doxorubicin administration (day 20 of cycle 1), and lasting until 24 h after the second doxorubicin administration (day 1 of cycle 2), was enforced. Doxorubicin was administered for a maximum of six consecutive cycles, or for the corresponding number of cycles to not exceed lifetime cumulative anthracycline dose (450 mg/m2). At the end of the doxorubicin therapy, single-agent sorafenib was continued in patients who had not progressed. Three different dosing levels of sorafenib were tested: cohort 1, 100 mg (50 mg tablets) bid; cohort 2, 200 mg (50 mg tablets) bid; cohort 3, 400 mg bid. To improve patients' compliance, a 200 mg tablet was introduced, and in order to compare the pharmacokinetics of both tablets, the 400 mg bid dose level was analyzed separately using 50 mg tablets (cohort 3A) and 200 mg tablets (cohort 3B). Six patients were enrolled in cohorts 1 and 2, 12 patients in cohort 3A, and 10 patients in cohort 3B. If, in any cohort, 3/6 patients experienced a DLT, the maximum tolerated dose (MTD) was determined to have been exceeded.
DLTs were defined as: grade 4 neutropenia and thrombocytopenia 7 days (absolute granulocyte count [AGC] <0.5 x 109/L); febrile neutropenia grade 3 (AGC <1 x 109/L and fever >38.5 °C, platelet count <25 000/µL, thrombocytopenic bleeding); ALT or AST grade 3 for >7 days; grade 3 non-hematologic toxicity (excluding alopecia, and non-premedicated nausea/vomiting). If the toxicity failed to resolve to grade 2 with 14 days off treatment, the patient was removed from the study. In the case of doxorubicin-related DLTs leading to discontinuation of doxorubicin, sorafenib was continued if possible.
study outcomes
The primary objective of this study was to determine the safety profile for sorafenib in combination with doxorubicin. The secondary objectives were to evaluate pharmacokinetics, and tumor response.
safety.
All patients who had at least one dose of sorafenib and who had post-treatment data available were evaluated for safety. The incidences of adverse events, DLTs and abnormal laboratory values were recorded for each cohort. The severity of adverse events was assessed according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0, and the relationship of each adverse event to study drug was assessed by the investigator. Cardiotoxic effects were assessed by multigate (radionuclide) angiogram (MUGA) scans: evaluable patients needed a MUGA scan at baseline and after the last doxorubicin infusion.
pharmacokinetics.
Blood samples for the determination of the plasma concentration–time profiles of sorafenib were collected after multiple dosing with sorafenib alone on day 21 of cycle 1, prior to dosing, and at 0.5, 1, 2, 4, 8, 10, and 12 h thereafter. On day 1 of cycle 2 (day 22), the collection of blood samples was repeated at the same times after the administration of sorafenib together with an intravenous infusion of 60 mg/m2 doxorubicin. Plasma concentration–time courses of doxorubicin and its metabolite doxorubicinol were determined on day 1 of cycle 1 (administration of doxorubicin alone), and on day 1 of cycle 2 (administration of doxorubicin together with sorafenib). Blood samples were collected prior to the infusion of doxorubicin, and at 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 h after start of infusion. The determination of plasma concentrations of sorafenib was performed using a fully validated specific LC/MS-MS assay method with a lower limit of quantification (LOQ) of 0.01 mg/L for sorafenib. Doxorubicin and doxorubicinol were quantified in plasma samples, applying a fully validated HPLC assay method with UV detection. The LOQ for both doxorubicin and doxorubicinol was 0.2 µg/L. Pharmacokinetic parameters assessed were maximum drug concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC), and apparent terminal half-life (t
). These parameters were calculated by non-compartmental methods using the program Kincalc (Bayer HealthCare AG).
efficacy.
All patients who completed at least one cycle of treatment and who had their disease re-evaluated were assessed for tumor response and duration of response. Tumor response measurements based on WHO criteria were performed at baseline and after two cycles during the treatment period. Thereafter, for patients with stable disease or an objective response, survival assessment follow-up was performed every 3 months (for a maximum of 2 years) until documented progressive disease or death.
statistical analyses
This was primarily a descriptive safety and tolerability trial; therefore, no formal sample size estimation was performed. No formal sample size estimation was performed for evaluating the effect of sorafenib co-administration on doxorubicin pharmacokinetics. This study was considered an observational evaluation of the effect of sorafenib on doxorubicin pharmacokinetics.
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patients' demographics
A total of 34 patients were enrolled in this dose-escalation study: six in cohort 1, six in cohort 2, 12 in cohort 3A, and 10 in cohort 3B. The baseline demographics for all patients are shown in Table 1, and were similar across the cohorts. All patients had an ECOG performance status of 0 or 1, with the exception of one patient in cohort 3A, who had an ECOG performance status of 2. All patients had progressive disease at study entry, apart from one patient in cohort 3B whose disease was classified as stable. A total of 97% of patients had undergone prior surgery or diagnostic tests, and 79% of patients had received prior systemic anticancer therapy.
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Five patients are still receiving treatment. Of the 29 patients who discontinued, 24 did so as a result of disease progression, three were due to adverse events, and two were due to non-compliance. The actual delivered dose of sorafenib per cycle was virtually identical to the planned dose (i.e. 200, 400, or 800 mg per day)—the majority of patients (85%) received
90% of the planned sorafenib dose for 6–500 days. The mean duration of treatment with sorafenib across all cohorts was 138 days, and was lower in cohorts 1 and 4 (50 and 91 days, respectively) compared with cohorts 2 and 3 (192 and 194 days, respectively). Patients received a mean of 3.2 cycles of doxorubicin. The extent of exposure to doxorubicin (mean number of cycles) was slightly lower in cohorts 1 and 3B (2.3 and 2.7 cycles, respectively) compared with cohorts 2 and 3A (4.0 and 3.8 cycles, respectively).
safety
All 34 enrolled patients were evaluable for safety analyses. The most frequent treatment-emergent adverse events were gastrointestinal (33/34 patients [97%]), constitutional symptoms (30/34 patients [88%]), blood/bone marrow toxicities (26/34 patients [76%]), and skin toxicity (25/24 patients [74%]). There were no obvious differences in incidence of adverse events between cohorts 1 and 2, and cohorts 3A and B.
Serious adverse events, regardless of relationship to study drug, were reported in 23/34 (68%) patients, predominantly classified as blood/bone marrow (14/34 patients [41%]), constitutional (9/34 [26%]), gastrointestinal (6/34 patients [18%]), and hepatic (5/34 patients [15%]) events.
drug-related adverse events.
The most frequent drug-related adverse events of any NCI-CTC grade are summarized in Table 2. Hand–foot skin reaction (HFS) was reported more frequently in the high sorafenib dose cohorts (cohorts 3A and 3B) than in the low-dose cohorts (cohorts 1 and 2).
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Drug-related adverse events with NCI-CTC
grade 3 are summarized in Table 3. No relationship was evident between dose of sorafenib and frequency of myelotoxicities. All cases of grade 3 HFS related to sorafenib were observed at the 400 mg bid dose in cohort 3A. Thirteen (38%) patients experienced drug-related serious adverse events, with some patients experiencing more than one event. These events were reduced neutrophils/granulocytes (11 patients), reduced platelets (two patients), reduced hemoglobin (one patient), febrile neutropenia (three patients), cardiac insufficiency (one patient) and HFS (one patient). Of these 13 patients, four were in cohort 1, one in cohort 2, five in cohort 3A and three in cohort 3B. All of these serious adverse events were attributed to doxorubicin rather than sorafenib, apart from one case of HFS in a patient in cohort 3A, which resolved following dose interruption. Three patients discontinued study drug permanently because of adverse events that were not related to either sorafenib or doxorubicin. There were no deaths during the study.
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hematologic and biochemical toxicities
Hematologic and biochemical toxicities were assessed across all cohorts. Although elevations in alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase were relatively common at all doses, this was attributed to the underlying liver metastases that were present in 59% of the patients at baseline. Increases in serum amylase and in serum lipase (both in 5 of 34 [15%] patients) were possibly related to sorafenib, and increases in amylase and lipase were reported in association with sorafenib in previous studies [1].
cardiotoxicity.
Cardiotoxic effects in association with doxorubicin treatment were assessed by MUGA scans in 14 evaluable patients. In cohort 1, one out of four evaluable patients had a left ventricular ejection fraction (LVEF) decrease of 10.7%, compared with baseline without clinical symptoms. In cohort 2, LVEF was reduced in three out of four evaluable patients by 8.3%, 34.8% and 4.7%. In cohort 3A, all five evaluable patients showed LVEF -reductions during the course of the study. Four of these were <10% without clinical symptoms; however, one patient in this cohort had a decrease in LVEF of 27.6%, resulting in cardiac dysfunction, which resolved after discontinuation of doxorubicin but continuation of sorafenib. In cohort 3B, only one evaluable patient did not show a detectable LVEF change while on-study.
dose-limiting toxicities.
Three (25%) patients in cohort 3A and two (20%) patients in cohort 3B experienced DLTs. All were HFS (one patient with grade 1 and four patients with grade 3) and considered related to sorafenib. All cases improved or resolved following action. The MTD was not reached in this study.
pharmacokinetics
Pharmacokinetic parameters were assessed in 23 patients. Comparison of Cmax and AUC(0–8) values from day 21 of cycle 1 (sorafenib in the absence of doxorubicin), and day 1 of cycle 2 (sorafenib plus doxorubicin) showed that doxorubicin administration partly increased either Cmax or AUC(0–8) compared with sorafenib alone, but had no relevant effect on steady-state sorafenib pharmacokinetics (Table 4). Mean Cmax and AUC values of doxorubicin were not significantly altered when doxorubicin was administered with 100 mg or 200 mg bid sorafenib (day 1 of cycle 2) compared with dosing of doxorubicin alone (day 1 of cycle 1) (Table 5). However, when 400 mg bid sorafenib was co-administered in cohort 3A (50 mg tablets), mean Cmax of doxorubicin was increased by 103%, and mean AUC by 47%. In contrast to this finding, a slight reduction in mean Cmax and no effect on mean AUC was observed following co-administration of 400 mg bid sorafenib in cohort 3B. No relevant effect on the pharmacokinetics of doxorubicinol was detected (Table 5).
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In order to evaluate the clinical impact of the observed increase in doxorubicin exposure when co-administered with sorafenib at a dose of 400 mg bid, a statistical analysis was performed comparing the magnitude of myelosuppression (decrease of neutrophils) in cycle 1 and cycle 2 with the change in doxorubicin exposure in cycle 1 and cycle 2. A correlation between the change in myelosuppression (after co-administration of doxorubicin and sorafenib versus administration of doxorubicin alone) and the corresponding changes in doxorubicin exposures could not be verified (data not shown). Therefore, the observed increase in doxorubicin exposure when co-administered with sorafenib, particularly at a dose of 400 mg bid, was not associated with enhanced clinical toxicity in this study with a small number of patients.
efficacy
A total of 31 out of 34 patients were valid for efficacy analysis. One patient from cohort 3A with progressive pleural mesothelioma achieved a confirmed partial response and remained on therapy for 39.7 weeks. Another patient, with progressive pancreatic cancer (cohort 3B), had a reduction in target lesions of 43% in the first restaging on day 43, followed by a further reduction of 56% on day 77. However, during further follow-up, this reduction could not be confirmed, resulting in an overall assessment of a stable disease as best response.
Fifteen patients (48%) experienced stable disease as best response (Table 6). The primary tumor types in these patients were HCC (n = 4), pancreatic cancer (n = 3), renal cell carcinoma (n = 2), breast cancer (n = 1), lung cancer (n = 1), colon cancer (n = 1), and other tumor types (n = 3). The geometric mean duration of sorafenib therapy for patients with stable disease was 23.9 weeks for cohort 2, 30 weeks for cohort 3A, and 58 weeks for cohort 3B.
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The combination of sorafenib and doxorubicin in this study was well tolerated across all dose levels, with adverse events similar to those expected for each drug alone.
The safety profile of sorafenib plus doxorubicin was dominated by the well-known myelotoxicities of single-agent doxorubicin and the dermatologic toxicities of single-agent sorafenib [1–4, 6, 7, 24]. In this study, HFS of NCI-CTC grade 3 occurred only in cohort 3A. This suggests a relationship with increased sorafenib exposure, as patients in cohort 3A had the highest exposure for sorafenib across all cohorts. The observed increase in doxorubicin exposure when co-administered with sorafenib, particularly at a dose of 400 mg bid as 50 mg tablets, was not reflected by a statistically significant enhancement of the clinical toxicity in this study with a small number of patients. Further investigations with a higher number of patients would be needed to address this issue. It should be noted that the 50 mg sorafenib tablet used in this cohort is no longer being studied. Because of the potential risk of increased doxorubicin exposure when co-administered with sorafenib, patients should be monitored thoroughly for adverse events.
The increased doxorubicin exposure seen in this study did not translate into increased myelotoxicities, and there was no relationship between sorafenib dose and the appearance of myelotoxicities. Doxorubicin monotherapy is also associated with cardiotoxicity. The combination of doxorubicin with sorafenib 100–400 mg bid did not increase cardiotoxicities over those expected with single-agent doxorubicin.
Concomitant administration of doxorubicin 60 mg/m2 and sorafenib revealed no relevant effect on the pharmacokinetics of sorafenib, independent of the dose of sorafenib. Similarly, the combination of this dose of doxorubicin with 100 mg or 200 mg bid sorafenib had no impact on the pharmacokinetics of doxorubicin. However, when 400 mg bid sorafenib was co-administered as 50 mg tablets, a moderate increase in AUC of doxorubicin by an average of 47% was observed, while mean Cmax increased by 103%. In contrast to this result, no change in AUC, and even a slight decrease in Cmax, was found when the same dose of sorafenib was given as 200 mg tablets. Therefore, the use of 50 mg tablets in cohort 3A may have resulted in a higher exposure than seen with the use of 200 mg tablets in cohort 3B. However, the increase in Cmax of doxorubicin observed in cohort 3A should be interpreted with caution. Cmax was identical to the plasma concentration at the end of the doxorubicin infusion. As the plasma concentrations decreased very rapidly after cessation of the doxorubicin infusion, the doxorubicin concentration in the first sample after the end of the infusion (and thus the accuracy of Cmax) strongly depends on how close to the actual end of infusion the sample was collected. Therefore, the Cmax data may be considered slightly less reliable compared with the AUC data. This is supported by the fact that the pharmacokinetics of doxorubicinol were not significantly affected in cohort 3A (as in all other cohorts), which means that the effect on Cmax of doxorubicin in cohort 3A may be overestimated. An analysis of the ratios of Cmax and AUC of doxorubicin in the combined administration versus doxorubicin alone as a function of AUC(0–8) or dose of sorafenib, showed a trend but not a significant correlation. Higher patient numbers would be needed to obtain significant correlations.
A strong rationale for combining sorafenib with doxorubicin has emerged from numerous reports that suggest that cellular signal transduction pathways may be involved in the regulation of several aspects of drug resistance [18, 25–27]. For instance, the Raf/MEK/ERK pathway has been shown to regulate the activity of the Mdr-1 gene promoter [17, 19]. Moreover, a correlation between high Raf-1 activity and resistance to doxorubicin has been suggested in several reports [22, 23]. The Raf/MEK/ERK pathway has also been shown to synergize with Bcl-2 overexpression in hematopoietic cells [28, 29]. The finding that Bcl-2 mRNA levels are increased in cells expressing activated Raf-1 suggests that the Raf/MEK/ERK pathway may regulate Bcl-2 expression, perhaps by ERK-mediated phosphorylation of p90RSK isoforms that in turn, activate cyclic AMP-responsive element binding protein (CREB). Activated CREB has been proposed to induce Bcl-2 transcription by binding to the human bcl-2 promoter [30–33]. This synergism may also result in part from enhancement of Bcl-2 antiapoptotic function attributable to phosphorylation of serine 70 by ERK-1 and ERK-2 [34]. In a breast cancer cell line, overexpression of Raf-1 activity increased resistance to doxorubicin, and this increase was greater in cells that also overexpressed Bcl-2 resistance [35]. Furthermore, Raf-1 activation in these cells, but not Bcl-2 activation, led to increases in mRNA levels of P-glycoprotein, of which doxorubicin is a known substrate. These data suggest that both Raf-1 and Bcl-2 overexpression contribute to drug resistance, Raf-1 can induce additional signaling pathways over Bcl-2 to cause drug resistance [35].
Together, these data provide a rationale for a combination approach of doxorubicin and sorafenib, which has demonstrated potent activity against Raf kinase, along with other receptor tyrosine kinases. Preclinical studies with other inhibitors of Raf-1 in combination with doxorubicin are also underway. A recently developed cationic liposome-entrapped ends-modified Raf-1 antisense oligonucleotide – LErafAON (NeoPharm) [36] – was shown to enhance the therapeutic effects of doxorubicin and paclitaxel in various human tumor models [37].
In this trial, particular activity of sorafenib plus doxorubicin combination was apparent in patients with advanced HCC; all four enrolled patients achieved stable disease and remained on treatment for more than 1 year. Single-agent doxorubicin has been shown to induce response rates in advanced HCC of 10.9%, and stable disease was achieved in a further 42.7% of patients [38]. Promising results with sorafenib monotherapy have also been reported in a Phase II study in patients with advanced HCC with a 9% PR rate and stable disease in 43% of the 137 patients treated [5]. Both VEGFR and the Raf/MEK/ERK signaling pathway have been associated with the development of liver cancer, supporting the rationale for the use of sorafenib for the treatment of advanced HCC [39–41].
Sorafenib has been shown to be safely combined with other chemotherapeutic agents, including gemcitabine, oxaliplatin, docetaxel and carboplatin/paclitaxel combination, in a variety of tumor types [14, 42–44]. Adverse events were mainly mild to moderate in severity and manageable; DLTs included HFS, diarrhea, mucositis, and febrile neutropenia. The most striking results in terms of efficacy were obtained in metastatic melanoma, in which a conventional dose and schedule of paclitaxel/carboplatin, which normally has limited efficacy in this setting [45, 46], led to partial responses in 40% of patients, which lasted at least 6 months [43].
In conclusion, sorafenib in combination with doxorubicin was generally well tolerated, with a moderate pharmacokinetic interaction, and the toxicity profile was not markedly worse compared with that expected with either compound administered individually. A phase II extension study in patients with advanced HCC is ongoing.
Received for publication August 25, 2005. Revision received January 6, 2006. Accepted for publication January 10, 2006.
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