Efficacy Of Sorafenib In Combination Research Articles

Pterostilbene enhances sorafenib's anticancer effects on gastric adenocarcinoma.

Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down‐regulation of cyclin D1, Cdk‐2, Cdk‐4, Cdk‐6 and p62 and the up‐regulation of LC3II, caspase‐9, caspase‐3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki‐67‐ and PCNA‐positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials.

Sorafenib with concurrent multiple-line therapies improves overall survival in advanced stage hepatocellular carcinoma.

The efficacy of sorafenib in combination with transarterial chemoembolization (TACE) or multiple-line therapies in patients with advanced hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the overall survival (OS) of patients with advanced HCC in response to different combination therapies.We analyzed the treatment and OS of 401 patients with Barcelona clinic liver cancer stage C HCC between 2012 and 2017. Mortality was analyzed using multivariate Cox regression, and OS was analyzed by the Kaplan–Meier method.The mean age was 59 years and males were predominant. During a median follow-up time of 8.6 months (range, 1–80 months), 346 (86.2%) patients died. In the multivariate Cox regression analysis, primary tumor size ≥5 cm, serum alpha-fetoprotein ≥200, and serum albumin ≥3.5 were significantly associated with mortality. In addition, compared with sorafenib alone, multiple-line treatments with sorafenib and multiple-line treatments without sorafenib yielded significantly decreased mortality. In the Kaplan–Meier analysis, sorafenib with TACE, multiple-line treatments with sorafenib, third-line treatments with sorafenib, and multiple-line treatments without sorafenib yielded a significantly better median OS than sorafenib alone.Sorafenib with concurrent multiple-line therapies significantly improved OS. These combination therapies will provide important information for immunotherapy combination with locoregional therapies in advanced HCC.

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.

Abstract CT407: Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma

Abstract Background: Preoperative treatment with fluoropyrimidine-based chemoradiotherapy is considered standard therapy for locally advanced rectal cancer( T3, T4 or N1). Sorafenib is an inhibitor of ras/raf, PDFGR and VEGFR with synergistic activity with radiation. The phase I trial evaluated the safety and efficacy of sorafenib in combination with infusional 5-FU and radiation Methods: Patients with stage II or III patients confirmed by EUS and CT scan were recruited in cohorts of 3 patients per dose level (DL). A 3+3 dose escalation design was used. On all dose levels RT was given in 25 fractions at 1.8Gy (45Gy) day 1- 5. Surgery was done 6-10 weeks after the completion of neoadjuvant treatment. Results: At Moffitt Cancer we enrolled 12 patients in 4 cohorts. 8 females(67%) and 4 males(33%); Median age is 55(range: 40-72). After observing toxicity in first cohort ( 2 pts with with G2 and G3 skin toxicity and 1 pt with G2 mucositis) which required dose interruptions, amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily. After the amendment, hypertension was the only grade III toxicity observed. 2 patients had G3 hypertension at 200mg adjusted dose(day1-5); 1 patient had G3 hypertension at 400 mg PO BID dose level and no grade IV toxicities were seen. No perioperative complications related to the study drugs were seen. 2 patients never went to surgery due to patient refusal. KRAS testing information was available on 10 patients. pCR rate was 30 % and downstaging was observed in 80% of the patients. pCR was 50% in patients with Kras mutant tumors ( 2/4 pts) Conclusion: After changing the schedule of the chemotherapy, the regimen was very well tolerated. pCR and downstaging rate of the tumor seems to be encouraging. Plan is to open up an expansion cohort at DL3 to gather more safety and efficacy data. Schedule of sorafenib dose escalationDose level ( 3 patients each)Sorafenib5-FU infusion Rate (mg/m2/24hrsDL 1 before amendment200mg PO QD225 on day 1-7 for 5½ weeksDL 1 after amendment200mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 2 after amendment400mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 3 after amendment400mg PO BID( Day1-5)225 on day 1-5 for 5½ weeks Citation Format: Richard Kim, Kun Jiang, Xiuhua Zhao, Dung-Tsa Chen, Tiffany Campos, Sara Hoffe, Ravi Shridhar, David Shibata. Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT407. doi:10.1158/1538-7445.AM2014-CT407

A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer

Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP. Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1-35), S-1 (40 mg/m(2) bid, days 1-21), and CDDP (60 mg/m(2), day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1. Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP. The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.

Sorafenib in combination with transarterial chemoembolization improves the survival of patients with unresectable hepatocellular carcinoma: A propensity score matching study

This prospective non-randomized controlled trial aimed to compare the efficacy of sorafenib in combination with transarterial chemoembolization (TACE) vs TACE alone for the treatment of patients with unresectable intermediate or advanced hepatocellular carcinoma. A total of 304 patients were enrolled, in which 82 received concurrent sorafenib (400 mg orally twice daily, initiated within 14 days after TACE), and these patients were matched with 164 patients who received TACE alone at a 1:2 ratio using propensity score matching to minimize selection bias. The response to treatment, time-to-progression (TTP), overall survival (OS) as well as adverse events were compared between the two groups. During a median follow-up period of 21.4 weeks (range 0.5-103 weeks), the addition of sorafenib prolonged TTP (6.3 vs 4.3 months; hazard ratio [HR] 0.60, 95% CI 0.422-0.853, P = 0.004) and median survival (7.5 vs 5.1 months; HR 0.61, 95% CI 0.423-0.884, P = 0.009) compared with TACE alone. Significant prognostic factors for OS by multivariate analysis included the use of sorafenib, Barcelona Clinic Liver Cancer stage, metastasis/vascular invasion and Child-Pugh score. The combined use of sorafenib and TACE was generally well tolerated and significantly improved OS and TTP compared with TACE alone in patients with intermediate or advanced HCC. Further studies are warranted to confirm the safety and efficacy of this combination therapy.

Phase II Trial of Sorafenib in Combination with Carboplatin and Paclitaxel in Patients with Metastatic Uveal Melanoma: SWOG S0512

BackgroundSorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma.MethodsTwenty-five patients with stage IV uveal melanoma who had received 0–1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m2) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS).ResultsNo confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0–14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1–6 months] and the 6-month PFS was 29% [95% CI: 13%–48%]. The median OS was 11 months [95% CI: 7–14 months].ConclusionIn this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.Trial Registration ClinicalTrials.gov NCT00329641

Therapeutic effects of sorafenib combined with transcatheter arterial chemoembolization and microwave ablation on postsurgical recurrent hepatocellular carcinoma

To evaluate the therapeutic efficacy of sorafenib in combination with microwave coagulation therapy (MCT) and trans-arterial chemoembolization (TACE) in patients with recurrent liver cancer. From January 2006 to January 2010, 90 patients with recurrent hepatocellular carcinoma (HCC) were treated with MCT and TACE in our hospital. The treatment group received sorafenib + MCT + TACE, and the control group received MCT + TACE. RR of the treatment group was 66.7%, which of the control group was 52.0% (P > 0.05). DCR was 83.3% in the treatment group and 64.5% in the control group (P < 0.05). Through a comparison of survival curves along with the extension of time, the survival rates of the two groups were decreased, but the treatment group (group 1) had a significantly higher one than the control group (group 2), with a statistically significant difference (P < 0.05). Sorafenib combined with MCT and TACE can improve the disease control rate and prolong the survival in patients with recurrent HCC.

High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation

Treatment options of recurrent hepatocellular carcinoma (HCC) after liver transplantation are limited and data on systemic compounds for advanced tumor stages in transplant recipients are sparse. We retrospectively analyzed the toxicity, tolerability, and efficacy of sorafenib in combination with mTOR inhibitors (mTORi), or calcineurin inhibitors (CNI) in transplant recipients with recurrent HCC. In total, 20 of 92 patients transplanted for HCC within a 10-year time period, experienced tumor recurrence. In case of ineligibility for other treatment options, patients received sorafenib (n = 13). In addition, CNI were stopped and switched to mTORi in nine patients, whereas CNI were continued in four patients. Grade 3-4 adverse events were observed in 92% of all patients necessitating sorafenib discontinuation in 77%. The most common severe adverse events were acute hepatitis, diarrhea, hand-foot - skin reaction and bone marrow suppression. In patients receiving sorafenib/mTORi one patient achieved partial response, and four achieved stable disease. In this cohort of liver transplant recipients side effects prevented full dosing of sorafenib and necessitated discontinuation of sorafenib in the majority of patients, yet antitumor efficacy seemed promising in combination with mTORi.

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors

Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin. Patients with advanced solid tumors were treated with 75mg/m(2) cisplatin on day 1 and 1,250mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400mg twice daily was started and continued throughout the complete treatment cycles without interruption. Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug-drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC(0-72) and C (max) of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C (max) of gemcitabine by 12 and 21%. Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.

Phase I study of sorafenib and cisplatin/pemetrexed regimen in untreated malignant pleural mesothelioma (MPM) patients: Italian SoMe Study.

7087 Background: This phase I study investigated the safety and efficacy of sorafenib in combination with cisplatin and pemetrexed in untreated MPM patients (pts). Methods: Pts with an histological diagnosis of MPM received cisplatin 75 mg/m2 iv and pemetrexed 500 mg/m2 iv on day 1 of a 3-week cycle for a maximum of 6 cycles, and oral sorafenib was administered continuously from day 1 of cycle, at 200 mg twice daily (Level 1) or 400 mg twice daily (Level 2). Maintenance sorafenib treatment was performed at the same level dose in pts with CR/PR/SD. All pts received folic acid and vitamin B12 from 7 to 14 days before the start of treatment until 21 days after the last pemetrexed dose. Tumor response according to RECIST criteria was evaluated by CT-scan every two cycles of chemotherapy. 18F-FDG-PET was performed before the start of treatment and after three weeks. Results: Twelve patients were enrolled (6 pts in each dose level): 11 males, 1 female; median age 61 years (range 43-71); KPS 100 in 2 pts, 90 in 5, 80 in 3, 70 in 2; IMIG stage III in 8 pts, IV in 4; epithelial subtype in 10 pts, sarcomatous in 2; all pts had symptomatic pleural effusion. DLTs were at dose level 1 neutropenia (2 pts G3), thrombocytopenia (1 pt G3), skin toxicity (1 pt G3), and at dose level 2 neutropenia (3 pts G3 and 1 G4), thrombocytopenia (1 pt G3 and 1 G4), skin toxicity (2 pts G3). At the dose level 2 five pts received a dose reduction to 200 mg bid due to toxicity. At least one dose reduction after the 1st cycle of cisplatin/pemetrexed was performed in 1 pt of level 1 and 3 pts of level 2. PRs were observed in 5 (42%) pts (2 pts in level 1, 3 in level 2) and SD in 3 (25%) pts (all pts in level 1); the median TTP was 6 months (range 1-16) and the median OS was 12 months (range 4-23). One pt with PR was submitted to pleuro-pneumonectomy and post-surgery radiotherapy. A marked SUV reduction (>35%) in early PET evaluation after 3 weeks of treatment was observed in all 5 pts with PR. Conclusions: Continuous oral sorafenib 400 mg bid was not tolerated in combination with cisplatin/pemetrexed chemotherapy. Our results in MPM pts suggest a drug interaction that amplifies toxicity with no evidence of tumor control improvement.

Efficacy of sorafenib in combination with gemcitabine and fluorouracil in metastatic renal-cell carcinoma: Preliminary result of a multicenter phase II study.

e15042 Background: To investigate the efficacy in terms of the overall response rate and progression-free survival (PFS) time of the combination of gemcitabine, fluorouracil, and sorafenib for meta...

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

The response of pancreatic cancer to treatments remains unsatisfactory, highlighting the need for more effective therapeutic regimens. Sorafenib, an orally available multikinase inhibitor, is active against different tumors, including pancreatic cancer. We studied the antitumor efficacy of sorafenib in combination with different antitumor drugs currently used in clinical practice in in vitro and in vivo experimental models of human pancreatic cancer. The cytotoxic effect of sorafenib and conventional antitumor drug combinations was evaluated in vitro in human pancreatic cancer cell lines and the efficacy of the most active combination was tested on tumor-bearing mice. Flow cytometric, Western blot and immunohistochemistry analyses were performed to investigate the mechanisms involved in the activity of single drugs and in their interaction when used in combination. Sorafenib showed a strong sequence-dependent synergistic interaction in vitro with docetaxel, which was highly dependent on the drug sequence employed. In vivo, human pancreatic cancer-xenografted mice treated with docetaxel followed by sorafenib reduced and delayed tumor growth, with complete tumor regression observed in half of the mice. This marked antitumor effect resulted in an overall increase in mouse survival of about 70% and in a complete cure in 3 of the 8 treated mice. The strong activity was also accompanied by marked apoptosis induction, inhibition of tumor angiogenesis and downregulation of ERK signalling. Our results show that the docetaxel and sorafenib combination exerts high therapeutic efficacy in experimental models of human pancreatic cancer, indicating a promising antitumor strategy for clinical use.

Abstract A260: A phase 1 study of sorafenib (BAY 43-9006) in combination with S-1 plus cisplatin in patients with advanced gastric cancer

Abstract Background: Sorafenib (BAY 43-9006) is a multi-kinase inhibitor, targeting Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-. S-1, an oral fluoropyrimidine, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase 1 study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP in patients (pts) with AGC. Methods: Pts with histologically confirmed previously untreated AGC were enrolled in the study. Treatment of pts in 3 cohorts was planned. Cohort 1: sorafenib (400 mg bid, day 1–35), S-1 (40 mg/m2 bid, day 1–21) and CDDP (60 mg/m2, day 8); cohort 2: sorafenib (400 mg bid, day 1–28), S-1 (25 mg/m2 bid, day 1–21), and CDDP (75 mg/m2, day 1); cohort 3: sorafenib (400 mg bid, day 1–28), S-1 (40 mg/m2 bid, day 1–21), and CDDP (75 mg/m2, day 1). Treatment schedule and dosages for cohort 1 were set based on the SPIRITS study (Koizumi, et al. Lancet Oncol. 9, 2008), and for cohorts 2 and 3 on the FLAGS study (Ajani, et al. ASCO, 2009). Treatment was continued until disease progression or unacceptable toxicity occurred. Results: Between May/2008 and Jan/2009, 13 Japanese pts were enrolled in cohort 1 and received at least one dose of the study treatment. Cohorts 2 and 3 were canceled because of negative results of the FLAGS study reported during our study of cohort 1. Pt characteristics were: 10 male and 3 female, median age 61 years (range 41–72), ECOG PS 0 in 9 pts and 1 in 4 pts. At the data cut off (30/Jun/2009), 12 of 13 pts had discontinued the study treatment (7 due to adverse events (AEs) and 5 due to disease progression) and 1 remained under treatment. The most common AEs occurring in ≥10 pts were neutropenia (92%), thrombocytopenia (92%), rash/desquamation (100%), anorexia (100%), hand-foot skin reaction (85%), nausea (85%), fatigue (77%), and lipase increase (77%). The grade 3/4 AEs occurring in ≥3 pts were neutropenia (54%), anemia (23%), lipase increase (62%), hand-foot skin reaction (23%), fatigue (23%), and amylase increase (23%). AEs resulted in treatment discontinuation included neutropenia (Gr 3) and anemia (Gr 2) that persisted for more than 4 weeks, AST/ALT increase (Gr 4), diarrhea (Gr 3), gastric perforation (Gr 3), hand-foot skin reaction (Gr 3), and auditory disturbance (Gr 1) attributed to CDDP. A total of ≥5 cycles of the study treatment was delivered in 6 pts. Two pts did not complete the 1st cycle due to Gr 1 auditory disturbance and Gr 4 AST/ALT increase, respectively. No treatment-related death was observed. Five pts had partial response and 7 had stable disease as the best response. Conclusions: Hematological, skin-related, and gastrointestinal events were the main toxicities of sorafenib plus S-1 and CDDP combination. The regimen demonstrated antitumor activity in untreated AGC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A260.

Results of a Phase I Trial of Sorafenib (BAY 43-9006) in Combination with Oxaliplatin in Patients with Refractory Solid Tumors, Including Colorectal Cancer

Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin. Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3). Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >or=10 weeks. Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.