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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Princess Margaret Hospital; 2 Bayer, Inc., Toronto, Ontario, Canada; 3 Jules Bordet Institute, Brussels, Belgium; 4 University of Texas Health Science Center, San Antonio, Texas; and 5 Bayer Pharmaceuticals Corporation, West Haven, Connecticut
Requests for reprints: Lillian L. Siu, Department of Medical Oncology and Hematology Princess Margaret Hospital, University Health Network, Suite 5-210, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2911; Fax: 416-946-6546; E-mail: lillian.siu{at}uhn.on.ca.
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Abstract |
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Experimental Design: An initial dose-escalation part of the study enrolled patients with advanced solid tumors, followed by an expanded cohort at the recommended dose for patients with advanced unresectable or metastatic pancreatic cancer. Sorafenib is administered continuously, whereas gemcitabine is given at 1,000 mg/m2 weekly x 7 followed by 1 rest week, then weekly x 3 every 4 weeks.
Results: Forty-two patients have been enrolled overall, including 19 in the dose-escalation part and 23 in the extended pancreatic cancer cohort. Demographics were as follows: male-to-female ratio = 26:16; median age = 61 years (range 39-83 years); Eastern Cooperative Oncology Group performance status 0:1:2 ratio = 16:21:5. The recommended dose of this combination is sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2. The most frequent grade 3 or 4 adverse events of all causalities were thrombocytopenia (28.6%), lymphopenia (21.4%), lipase elevation (19%), neutropenia (16.7%), and fatigue (14.3%). Antitumor activity was observed in both groups, with 2 (10.5%) confirmed partial responses in ovarian cancer and 12 patients (63.2%) with disease stabilization in the dose-escalation part; 13 patients (56.5%) achieved disease stabilization in the pancreatic cohort. There was no consistent pharmacokinetic drug-to-drug interaction between sorafenib and gemcitabine.
Conclusions: Sorafenib and gemcitabine are well tolerated in combination; further evaluations in pancreatic and ovarian cancers are warranted.
Preclinical studies of sorafenib have shown significant dose-dependent antitumor activity in xenograft models with Ras and B-Raf mutations, as well as in those where Ras is activated through overexpression of growth factor receptors (3–5). Tumor growth inhibition by sorafenib was associated with its downstream mechanistic effects in three xenograft models, including Ht-29 colon (B-Raf mutated), Colo-205 colon (B-Raf mutated), and MDA-MB-231 breast (B-Raf and K-Ras mutated) models (3). Immunohistchemistry and Western blot analysis showed down-regulation of phosphorylated extracellular signal-regulated kinase (pERK) in two of three xenograft models examined, consistent with inhibition of the Raf/MEK/ERK pathway in some models. Analysis of microvessel density and microvessel area showed significant inhibition of neovascularization in all three of the xenograft models. In phase I trials of sorafenib administered as a single agent on a continuous or interrupted schedule, a recommended dose of 400 mg twice daily (bid) was determined to be tolerable (6–8). Dose-limiting toxicities were diarrhea, dyspnea, and fatigue at 800 mg bid (6, 8) and skin toxicity including rash, hand-foot syndrome, and gastrointestinal symptoms at 600 mg bid (6–8). Antitumor activity was observed, including partial responses in hepatocellular and renal cell carcinomas, and disease stabilization in colorectal, renal, hepatocellular, non–small-cell lung, and ovarian cancers (6–8).
Gemcitabine (2',2',-difluoro-2',-deoxycytidine) is a nucleoside analogue of deoxycytidine that interferes with DNA synthesis through inhibition of ribonucleotide reductase and competition with dCTP for incorporation into DNA. It has broad applications as a cytotoxic chemotherapeutic agent in multiple solid tumor types including non–small cell lung, breast, pancreatic, bladder, and ovarian cancers. In a human pancreatic cancer (Mia-PaCa-2) xenograft model, sorafenib did not abrogate the efficacy of gemcitabine and the combination was well tolerated (9). Given their combinability in preclinical models and nonoverlapping toxicities in the clinical setting, a phase I dose-escalation trial of sorafenib and gemcitabine was done in patients with advanced solid tumors. The primary objective was to evaluate the safety profile and maximum tolerated dose (MTD) of this combination; the secondary objectives were to assess their pharmacokinetics and preliminary efficacy. Due to the prevalence of Ras mutations in pancreatic cancers (10) and the use of gemcitabine as standard first-line chemotherapy, an expanded cohort of patients with advanced pancreatic cancer was enrolled at the recommended phase II dose (RPTD) to determine the tolerability and preliminary efficacy of this combination in this tumor type.
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Patients and Methods |
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Other eligibility criteria included the following: (a) age 18 years or older; (b) Eastern Cooperative Oncology Group performance status 0 to 2; (c) evaluable disease; (d) adequate hematopoietic (absolute neutrophil count 
1.5 x 109/L; platelet count 100 x 109/L; and hemoglobin 9 g/dL), hepatic (bilirubin <1.5 x the upper limit of normal; aspartate aminotransferase and alanine aminotransferase <2.5 x upper limit of normal or <5.0 x upper limit of normal for subjects with hepatic metastases; prothrombin time and activated partial thromboplastin time <1.5 x upper limit of normal unless on therapeutic anticoagulants), and renal (serum creatinine 
1.5 x upper limit of normal) functions; (e) no pregnant or lactating females; (f) no clinically evident severe cardiovascular disorders (e.g., congestive heart failure, serious cardiac arrhythmias, active coronary artery disease, or ischemia); (g) no history of HIV infection or any active clinically serious infections requiring systemic therapy; (h) no metastatic brain or meningeal tumors, unless the subject was >6 months from definitive therapy and had a negative imaging study within 4 weeks of study entry; and (i) no previous malignancy except cervical carcinoma in situ, adequately treated basal cell carcinoma, superficial bladder tumors, or other malignancies curatively treated >3 years before study entry. All patients gave written informed consent in accordance with the federal and institutional guidelines before study treatment.
Study design. This was a multicenter, open-label, nonplacebo-controlled study with two parts: a dose-escalation phase I part for patients with advanced solid tumors and a fixed-dose expanded cohort for patients with pancreatic cancer. Sorafenib was given at escalating doses orally and continuously on a bid schedule, starting on day 2 of cycle 1. Gemcitabine was administered weekly at a fixed dose of 1,000 mg/m2 in a 30-minute i.v. infusion for the first 7 consecutive weeks, followed by a 1-week break. Thereafter, gemcitabine was given weekly for 3 consecutive weeks, followed by a 1-week break. Each cycle was defined as 28 days, with dose escalation decisions made based on safety data in each cohort from the first cycle of sorafenib and gemcitabine concomitant administration.
In the dose-escalation phase I part of the study, four dose levels were planned. Gemcitabine dose was fixed at 1,000 mg/m2 with escalating doses of sorafenib: dose level 1, sorafenib 100 mg bid; dose level 2, sorafenib 200 mg bid; dose level 3, sorafenib 400 mg bid (using 50 mg tablets); and dose level 4, sorafenib 400 mg bid (using 200 mg tablets). In the expanded cohort, patients with advanced pancreatic cancer were treated at the RPTD derived from the dose-escalation phase I part (dose level 5). Sorafenib was supplied in the first three dose levels and in the expanded cohort for patients with pancreatic cancer as 50 mg tablets. In the fourth dose level of the phase I part of the study, sorafenib tablets were supplied as 200 mg tablets. Dose escalations beyond sorafenib 400 mg bid with gemcitabine 1,000 mg/m2 were not planned because at this dose level, both drugs would be administered at their RPTD as single agents.
During the phase I part of the study, three patients were initially enrolled in each dose level. In the absence of a dose-limiting toxicity at the end of a 4-week treatment cycle, three patients were enrolled into the next dose level. If any patient experienced a dose-limiting toxicity, three additional patients were enrolled at that dose level. If in any dose level, three or more patients develop dose-limiting toxicity, then the MTD will be considered exceeded and the dose level immediately preceding that would be considered the RPTD. If the frequency of dose-limiting toxicity encountered at the highest dose level did not fulfill the MTD definition, then sorafenib 400 mg bid with gemcitabine 1,000 mg/m2 will be accepted as the RPTD.
Adverse events on this protocol are graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Dose-limiting toxicity is defined as follows: grade 4 neutropenia, febrile neutropenia, platelet count < 25 x 109/L or thrombocytopenic bleeding, aspartate aminotransferase or alanine aminotransferase grade 3 for > 7 days, grade 3 nonhematologic toxicity (except alopecia and unpremedicated nausea and vomiting), and inability to administer cycle 2 day 1 dose of both study drugs within 2 weeks of the planned end of the previous cycle.
Patient evaluation. Pretreatment evaluations were done within 7 days before the start of study therapy; these included history and physical examination, Eastern Cooperative Oncology Group performance status, hematology, biochemistry, urinalysis, and pregnancy test for women of childbearing potential. Baseline radiological investigations, such as scans or X-rays for disease documentation and electrocardiogram, were done within 28 days of the start of study treatment.
History, physical examination, and urinalysis were repeated on day 1 of each treatment cycle. Hematologic and biochemical laboratory evaluations were measured weekly for cycles 1 and 2 and then on days 1, 8, and 15 for all subsequent cycles. Radiological investigations were repeated every 8 weeks and tumor response was assessed based on the Response Evaluation Criteria in Solid Tumors (11). Complete or partial responses required a confirmatory scan at least 4 weeks after initial documentation.
Dose modifications. Patients must meet the following criteria to receive full doses of gemcitabine on day 1 of a treatment cycle: absolute neutrophil count 1.5 x 109/L, platelet count 100 x 109/L, and nonhematologic toxicity of grades 0 to 2. Patients may continue on sorafenib on day 1 of a treatment cycle regardless of their day 1 blood counts but must have nonhematologic toxicity of grades 0 to 2. If a dose-limiting toxicity occurred in the first cycle, treatment was withheld until toxicity resolved to grade 2 or less. At the investigator's discretion, the patient upon recovery could be rechallenged with both study drugs at reduced doses. If the toxicity failed to resolve to grade 2 or less with 14 days off treatment, or if the toxicity was a grade 4 nonhematologic adverse event, the patient must discontinue study therapy.
Duration of therapy. Patients for whom it was medically appropriate to discontinue gemcitabine (because of intolerance following achievement of complete response or completion of six cycles of chemotherapy with stable or partially responding disease) could continue to receive sorafenib alone.
Pharmacokinetics. Plasma samples for analysis of gemcitabine and its metabolite 2'-deoxy-2',2'-difluorouridine (dFdU) were collected on day 1 of cycle 1; at time points 0 hour (pretreatment), 0.5 (end of infusion), 1, 2, 4, 8, 10 to 12, and 24 hours, in the absence of sorafenib; and on day 15 of cycle 1, in the presence of steady-state concentrations of sorafenib. Plasma samples for sorafenib analysis were collected on day 14 of cycle 1 at time points 0 hour (pretreatment) and 0.5, 1, 2, 4, 8, 10 to 12, and 24 hours; in the absence of gemcitabine and dFdU; and on day 15 of cycle 1 in the presence of gemcitabine and dFdU. The gemcitabine and dFdU samples were analyzed at Emprexe Analytical, LCC (Buffalo, NY). Plasma samples were analyzed for sorafenib at Bayer HealthCare Pharmaceuticals (West Haven, CT). Concentrations of sorafenib, gemcitabine, and dFdU in plasma samples were determined using validated liquid chromatography/tandem mass spectrometry or liquid chromatography/UV methods. Lower limits of quantification were 0.1, 0.05, and 0.25 mg/L for sorafenib, gemcitabine, and dFdU, respectively.
Plasma pharmacokinetic variables, including area under the curve (AUC), maximum concentration (Cmax), time to maximum concentration (tmax), and elimination half-life (t1/2) were calculated by noncompartmental methods using the KINCALC program developed by Bayer HealthCare. This program uses a log-linear trapezoid method for determining the AUC values. Pharmacokinetic variables were analyzed with descriptive statistics. Plasma concentration-time courses of sorafenib (calculated if two thirds or more of the individual values were greater than the LOC) are presented as geometric mean values.
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Results |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Eighteen patients (43%) had at least one dose interruption of sorafenib, whereas 17 patients (41%) had at least one dose interruption of gemcitabine. Twelve patients (29%) had at least one dose reduction of sorafenib and 22 patients (52%) had at least one dose reduction of gemcitabine.
Safety. Selected adverse events that are considered most clinically relevant, based on known toxicity profiles of both study agents, are described. The incidences of adverse events of all grades from all causalities are listed in Table 2, and the incidences of grade 3 and 4 adverse events from all causalities are listed in Table 3. The most frequent adverse events in all patients were constitutional and gastrointestinal symptoms, followed by dermatologic and bone marrow toxicities. Although fatigue was commonly encountered among 78.6% of patients, it was of grade 3 or 4 intensity in only 14.3% of patients. Gastrointestinal symptoms, such as anorexia, nausea, vomiting, diarrhea, stomatitis, and pharyngitis, occurred in about one third to two thirds of patients, but were primarily of grade 1 or 2 severity. Grade 3 or 4 elevations in hepatic transaminases and bilirubin were reported in 
5% to 10% of patients, whereas grade 3 or 4 elevations in pancreatic enzymes, such as amylase and lipase, occurred in 4.8% and 19% of patients, respectively. There were two cases (4.8%) of pancreatitis that did not seem to be dose dependent: one in the dose-escalation cohort; the other in the pancreatic cancer cohort. There were five patients (21.7%) in the pancreatic cancer cohort who had biliary stents placed before study entry. In three of these patients, the existing stents were replaced during the course of the study. On one occasion, the stent change was prompted by cholangitis deemed to be possibly related to both study drugs; the other stent changes were due to elevations in bilirubin from disease and these were not considered as related to study treatment.
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Six patients died during the study, five of the six deaths occurred in the pancreatic cancer cohort. Three of these patients died from disease progression. The causes of deaths for the remaining three patients were as follows: hemolytic uremic syndrome felt to be likely gemcitabine related, cerebrovascular ischemic event felt to be possibly related to both study drugs, and aspiration pneumonia felt to be possibly related to both study drugs.
Pharmacokinetics. Twenty-seven patients are included in the subgroup of subjects for pharmacokinetic analysis, because pharmacokinetic sampling was not mandatory for all patients in the pancreatic cancer cohort. These patients were divided into five groups for analysis based on the dose of sorafenib: 100 mg bid (n = 2), 200 mg bid (n = 4), 400 mg bid as 50 mg tablets (n = 7), 400 mg bid as 200 mg tablets (n = 4), and pancreatic cancer patients who received 400 mg bid as 50 mg tablets (n = 10). Patients receiving the 400 mg bid dose were grouped into the indicated categories because they were administered 50 or 200 mg tablets, and the unique physiologic status of the pancreatic cancer patients.
The pharmacokinetic results showed no evidence that sorafenib was influenced by gemcitabine or by the presence of pancreatic cancer (Table 4). Also, at the 400 mg bid dose levels, AUC and Cmax in this limited patient population were apparently independent of whether the dose was given as 50 or 200 mg tablets. Consistent with data from previous phase I trials, there was a considerable variability in sorafenib exposure as reflected by the percent coefficient of variation expressed in Table 4. The mean AUC for sorafenib in pancreatic cancer patients was somewhat decreased upon coadministration of gemcitabine (ratio 0.59), but these differences were not statistically significant and there was no apparent change in Cmax. Therefore, there is no direct evidence that sorafenib pyruvate kinase is altered in pancreatic cancer patients receiving gemcitabine.
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Discussion |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Interestingly, the mean AUC values of sorafenib, Cmax values of gemcitabine, and AUC values of dFdU were slightly reduced among patients in the pancreatic cancer cohort but the interaction was not statistically significant. The degradation of gemcitabine, similar to other cytidine analogues, is primarily via deamination by cytidine deaminase; whereas sorafenib is subject of two biotransformation processes, including glucuronidation and oxidation (14).
Sorafenib, with its molecular targeting against the vital pathways of Ras/Raf/MEK/ERK and angiogenesis, has been shown to have antitumor activity against multiple tumor types in phase I and II trials (6–8, 15–17). A recent, randomized-controlled phase III trial in patients with advanced renal cell carcinoma showed that sorafenib significantly prolonged progression-free survival compared with placebo, and further follow-up continues for the analysis of overall survival (18). The combinability of sorafenib with cytotoxic agents will enable its development beyond monotherapy, such that promising combinations can be compared against existent standard cytotoxic therapies in an attempt to establish new paradigms. For example, the results of the current study of sorafenib and gemcitabine have led to phase II evaluations of this combination in advanced pancreatic and ovarian cancers.
Preliminary efficacy evaluations from this current study have yielded encouraging results. Two of six ovarian patients in the dose-escalation cohort achieved partial responses despite being heavily pretreated and refractory to taxanes, platinums, and anthracyclines. Whereas gemcitabine as a single-agent has produced response rates of 14% to 22% in patients with recurrent and refractory ovarian cancers (19), the results from our study support further development of the sorafenib and gemcitabine combination in this tumor type. Furthermore, two nonovarian cancer patients in the dose-escalation cohort remained stable on study drugs for over 1 year: one with advanced rectal cancer who have had prior radiotherapy, 5-fluorouracil, irinotecan, and oxaliplatin; the other with recurrent nasopharyngeal carcinoma who have had prior radiotherapy, bleomycin, etoposide, cisplatin, and gemcitabine. Given that in these two cases, one patient had a tumor type not typically sensitive to gemcitabine, and the other had disease minimally responsive to prior gemcitabine and cisplatin, it is interesting to hypothesize that the prolonged stabilization observed on this study is potentially attributable to the effects of sorafenib or its ability to reverse gemcitabine resistance.
In summary, the combination of sorafenib and gemcitabine was generally well tolerated and did not show a pharmacokinetic interaction. Full therapeutic doses of both agents can be administered without reaching MTD. Further disease-specific evaluations of this combination are warranted to determine its efficacy in tumor types such as pancreatic and ovarian cancers.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Presented in part at the 40th Annual American Society of Clinical Oncology Meeting at New Orleans, Louisiana, June 5 to 8, 2004.
Received 7/21/05; revised 9/25/05; accepted 10/20/05.
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