Oral Anticancer Agent Research Articles

Assessment of adherence with oral anticancer agents in oncology clinical trials: A systematic review.

Despite recommendations for adherence reporting in clinical trials involving an oral anticancer agent, the frequency and methods of adherence reporting are inconsistent. The purpose of this systematic review is to determine the frequency and type of adherence measures used in oncology and hematology clinical trials of oral anticancer agents and their association with study characteristics including quality, cancer type, stage and treatment type. PubMed was searched of all randomized controlled clinical trials assessing self-administered pharmacological interventions in patients with cancer and published over two years, between 1 January 2011 and 31 December 2012 were evaluated. We identified 70 publications in the PubMed database, comprising 45,118 total patients. Adherence reporting was present in 14 of 70 trials (20%); quantitative reporting was present in three of 70 trials (4%). Method of adherence assessment varied and included medication count, medication diaries and patient self-report. There was no association between adherence reporting and study quality or other study characteristics, although there was a trend towards increased reporting in breast cancer studies, with 46% of the studies reporting adherence (p = 0.0621). In a preliminary analysis, hematology studies (mean Jadad score 2.19 ± 1.47) were found to have significantly lower quality when compared to non-hematology trials (mean Jadad score 3.39 ± 1.37, p = 0.0034). This systematic review demonstrates adherence reporting in clinical trials of oral anticancer agents is infrequent. When reported, adherence was not associated with overall study quality or other study characteristics. Given the potential effects of non-adherence on study power and validity, adherence reporting should be encouraged in oncology and hematology clinical trials.

Abstract 2516: SL01, an oral gemcitabine prodrug as a potent anticancer drug

Abstract SL01,dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)pyrazine-2-carboxylate, is a gemcitabine prodrug synthesized by introducing the moiety of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl at the N4-position on the cytidine ring of gemcitabine. Our goal is to investigate the efficacy and the safety of this oral prodrug as a potent oral anticancer agent, which may supplant the use of gemcitabine in clinic. The evaluation was accomplished by determining its inhibition of the growth of several tumors with gemcitabine administrated by injection as a control, and also by exploring its pharmacokinetics and its safety. In vivo, SL01 could effectively inhibit the growth of NCI-H460 human non-small cell lung cancer, MCF-7 human breast cancer, BxPC-3 human pancreatic cancer, ES-2 human bladder cancer, HepG2 human hepatocellular carcinoma cells and HCT-116 human colon adenocarcinoma cells in xenografts nude mice without loss their body weight significantly. After three weeks oral administration at the dosage of 30 umol/kg, the inhibition rates were 58.0%, 66.5%, 41.5%, 77.1%, 41.5% and 63.1%, respectively. Molecular analysis indicated that the high efficacy of SL01 was associated with its ability in inducing apoptosis, as evidenced by increase of TUNEL staining cells, activation of caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase in tumor tissues. Pharmacokinetics studies indicated that SL01 exhibited a longer mean retention time and half-life than that of gemcitabine after oral administration in rat, further analysis showed that the bioavailability of SL01 was 22.1%, which indicating that the introduction of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl moiety to gemcitabine could improve its bioavailability and reduce its first-pass metabolism. The metabolism analysis suggested that SL01 could transform into gemcitabine by hydrolyzing and then releasing into blood to keep the relatively long steady-state concentrations. Toxicity studies indicated that the LD50 was >1.4 g/kg for its acute toxicity, and the tolerated dosage was 45 mg/kg for 4 weeks evaluation in rat. Based on these results, SL01 is proposed as a potent oral anticancer agent, which may supplant the use of gemcitabine in clinic. Acknowledgment: This project was supported by the Ministry of Science and Technology of China (2010ZX09401-302-2-07and 2011ZX09102-001-03). Citation Format: Wenbao Li, Hua Yuan, Xianjun Qu. SL01, an oral gemcitabine prodrug as a potent anticancer drug. [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 2516. doi:10.1158/1538-7445.AM2014-2516

Oral anticancer agent medication adherence by outpatients.

In the present study, medication adherence and factors affecting adherence were examined in patients taking oral anticancer agents. In June 2013, 172 outpatients who had been prescribed oral anticancer agents by Ogaki Municipal Hospital (Ogaki, Gifu, Japan) completed a questionnaire survey, with answers rated on a five-point Likert scale. The factors that affect medication adherence were evaluated using a customer satisfaction (CS) analysis. For patients with good and insufficient adherence to medication, the median ages were 66 years (range, 21–85 years) and 73 years (range, 30–90 years), respectively (P=0.0004), while the median dosing time was 131 days (range, 3–3,585 days) and 219 days (24–3,465 days), respectively (P=0.0447). In 36.0% (62 out of 172) of the cases, there was insufficient medication adherence; 64.5% of those cases (40 out of 62) showed good medication compliance (4–5 point rating score). However, these patients did not fully understand the effects or side-effects of the drugs, giving a score of three points or less. The percentage of patients with good medication compliance was 87.2% (150 out of 172). Through the CS analysis, three items, the interest in the drug, the desire to consult about the drug and the condition of the patient, were extracted as items for improvement. Overall, the medication compliance of the patients taking the oral anticancer agents was good, but the medication adherence was insufficient. To improve medication adherence, a better understanding of the effectiveness and necessity of drugs and their side-effects is required. In addition, the interest of patients in their medication should be encouraged and intervention should be tailored to the condition of the patient. These steps should lead to improved medication adherence.

A case of advanced upper gingival cancer successfully treated with oral uracil-tegafur (UFT) alone

The prognosis of locoregionally advanced oral squamous cell carcinoma (OSCC) is poor. Although aggressive treatment for advanced OSCC typically includes both surgery and radiation, there are some cases in which the treatment method must be changed due to the patient's general condition, the patient's desire, or both. Oral uracil-tegafur (UFT) is an oral anticancer agent comprised of uracil and tegafur in a 4:1 molar ratio, and was associated with a survival advantage in the adjuvant setting. UFT is considered to show clinical effectiveness in head and neck cancer.

A prospective phase II trial of S-1 and cisplatin-based chemoradiotherapy for locoregionally advanced esophageal cancer

S-1 is a novel oral fluoropyrimidine anticancer agent designed to enhance clinical efficacy, reduce gastrointestinal toxicity, and enhance radiotherapy effectiveness. A phase II trial was conducted to evaluate the efficacy and safety of preoperative chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer. Eligible patients had stage IIA-IVA esophageal cancer. Patients received two cycles of S-1 (days 1-14 and days 22-35) and cisplatin (days 1 and 22) with concurrent radiotherapy (50.4 Gy total; 1.8 Gy/fraction). Esophagectomy was performed between weeks 12 and 18 as determined by the specialist multidisciplinary team. Sixty patients were enrolled in this study between March 2008 and August 2011, and 59 were eligible. The clinical stage was ≥T3 in 28 patients (47 %) and N1 in 43 patients (72 %), with squamous cell carcinoma histology in 58 patients (97 %). Fifty-four patients (90 %) completed the planned chemoradiation. After chemoradiation, the clinical tumor response rate was 64.4 %. The primary toxicities included neutropenia (24 %) and esophagitis (8.5 %). Three treatment-related deaths were noted. Twenty-five patients (42 %) underwent esophagectomy following chemoradiation, and 15 achieved complete pathologic regression. The estimated overall survival and progression-free survival rates after 2 years were 65 and 48 %, respectively. Concurrent chemoradiation with S-1 and cisplatin exhibited encouraging results with complete pathologic regression. The survival data were promising compared with the historical data of 5FU/cisplatin and should be confirmed in a randomized phase III trial. Toxicities were significant but clinically manageable.

A phase II study of S-1 in combination with sorafenib in metastatic renal cell carcinoma.

529 Background: The potential of S-1, an oral fluoropyrimidine derivative anticancer agent, for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We therefore studied the efficacy and safety profile of S-1 in combination with sorafenib in Japanese patients with mRCC. The recommended dosage of this combination therapy was based on the results of an associated phase I study, presented at the 2012 Genitourinary Cancers Symposium (Abstract #447). Methods: In this phase II study, we enrolled patients with clear-cell or papillary carcinoma who had received no previous treatment or not more than 1 regimen of cytokine therapy. S-1 was administered orally at 80-120 mg/day according to body surface area for 28 consecutive days of a 42-day cycle in combination with sorafenib (800 mg/day) until disease progression. The primary endpoint was the objective response rate (ORR), reviewed by an independent review committee. Results: A total of 21 patients aged 41-78 years were enrolled and were fully assessable for efficacy and safety. Most patients (90.5%) had clear-cell carcinoma, and 8 (38.1%) had received prior cytokine treatment. The ORR was 52.4% (90% CI, 32.8-71.4). One (4.8%) of the 21 patients had a complete response to this combination therapy, 10 (47.6%) had partial responses, and 10 (47.6%) had stable disease. The median progression-free survival was 9.8 months (95% CI, 6.5-14.3). There were no deaths. This combination therapy was well tolerated, and most adverse events were grade 2 or lower. The most common grade ≥3 drug-related adverse events were hypophosphatemia (71.4%) and elevated lipase levels (33.3%). Conclusions: Combination therapy with S-1 plus sorafenib showed promising results regarding the primary endpoint of ORR and had an acceptable toxicity profile in patients with mRCC. Clinical trial information: JapicCTI-090973.

Mechanisms of action of tasquinimod on the tumour microenvironment

Tasquinimod is a small molecule with pleiotropic effects on the tumour microenvironment. Tasquinimod inhibits the growth and metastasis of tumour cells in vitro and in vivo. It targets the tumour microenvironment, enhancing the host immune response and inhibiting the angiogenic response. Tasquinimod influences infiltrating myeloid cells in the tumour milieu shifting the balance towards a less immunosuppressive phenotype. Myeloid-derived suppressor cells and tumour-associated macrophages are major components of the immunosuppressive microenvironment and as a result promote tumour growth and favour angiogenesis and metastasis formation. Growing evidence indicates that tasquinimod targets these myeloid cells and modulates local tumour immunity by blocking the interaction between the multifunctional protein S100A9 and its ligands receptor of advanced glycation end products and Toll-like receptor 4. Its anti-angiogenic effects are achieved at least in part through these effects on regulatory myeloid cells and also potentially through inactivating histone deacetylase-4 and reducing expression of hypoxia-inducible factor 1-controlled genes. The aim is to comprehensively review the mode of action of tasquinimod as a novel oral anti-cancer agent. Based on its unique combination of effects, tasquinimod is a novel agent with clinical therapeutic potential in various solid tumours, both alone and as part of rational combination therapy.

S-1 (Teysuno®): A Review of Its Use in Advanced Gastric Cancer in Non-Asian Populations

S-1 (Teysuno(®)) is an oral anticancer agent comprising the 5-fluorouracil (5-FU) prodrug tegafur and targeted modulators, gimeracil and oteracil. S-1 in combination with cisplatin is a recommended first-line treatment for gastrointestinal cancers in Japan and has recently been approved in the EU for the treatment of advanced gastric cancer. This article reviews S-1 pharmacology from an EU perspective. In a randomized, open-label trial in 24 non-Asian countries in patients with advanced gastric cancer, there were no significant differences between S-1 plus cisplatin and 5-FU plus cisplatin groups in median overall survival (OS) [primary endpoint], progression-free survival or overall response rate. In a post hoc analysis of OS, S-1 plus cisplatin was noninferior to 5-FU plus cisplatin. There were no significant between-group differences in patient quality of life, according to the Functional Assessment of Cancer Therapy (Gastric) Trial Outcome Index, except that S-1 plus cisplatin recipients had a significantly longer time to worsening in physical well-being than 5-FU plus cisplatin recipients. Overall, S-1 plus cisplatin was better tolerated than 5-FU plus cisplatin, with significantly lower rates of haematological, some gastrointestinal tract and other adverse events, serious adverse events and deaths resulting from toxicity, along with significantly fewer haematological and renal function abnormalities. Compared with 5-FU, S-1 plus cisplatin recipients had significantly higher rates of hand-foot syndrome and hyperbilirubinaemia, although there were no between-group differences in the proportions of patients with increased liver enzymes. S-1 is a useful alternative to 5-FU for patients with advanced gastric cancer.

Randomized phase III clinical study comparing postoperative UFT/LV,UFT+LV/UFT and UFT+LV+PSK/UFT+PSK as adjuvant therapy for curatively resected stage III colorectal cancer HGCSG-CAD study.

3638 Background: Study showed that the oral anticancer agent UFT/LV is useful as postoperative adjuvant chemotherapy for stage III colorectal cancer. PSK, a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in gastric, colorectal and lung cancers. Methods: Patients aged 20-80 years with stage III colorectal cancer registered in 35 facilities were randomized to: group A (UFT/LV 28 days/5 weeks for 6 months); group B (UFT+LV 28 days/5 weeks for 6 months, then UFT for 12 months); and group C (UFT+LV+PSK 28 days/5 weeks for 6 months, then UFT+PSK for 12 months). Treatment was started within 6 months after curative resection. Outcome measures were relapse-free survival (RFS), overall survival (OS), incidence and severity of adverse events, and QOL. Results: Of 342 patients registered, 340 eligible patients were analyzed (84 in group A, 85 in group B, and 171 in group C). At baseline, variation in QOL score was observed but histopathological parameters were not different among 3 groups. Median observation period was 36 months. 3-year RFS was 73.8%, 77.6% and 73.9% in groups A, B, and C [A vs C: hazard ratio (HR) 0.960, 95% confidence interval (CI) 0.575-1.601; B vs C: HR 0.837, CI 0.488-1.433; A vs B: HR 1.151, CI 0.623-2.126]. 3-year OS was 95.2%, 91.8% and 89.9% in groups A, B, and C (A vs C: HR 0.460, CI 0.155-1.367; B vs C: HR 0.814, CI 0.338-1.963 A vs B: HR 0.570, CI 0.167-1.947). Adverse events ≥grade 3 included gastrointestinal symptoms and general status. There was no treatment-related death. Excluding high fatigue score in QOL scale that showed pretreatment variation, stratification analysis showed interaction between family score and group, and efficacy was suggested especially in group C with high score (3-yesr RFS: 66.7%, 68.2% and 88.1% in groups A, B, and C. A vs C: HR 3.289, CI 0.951-11.375, B vs C: HR 3.070, CI 0.973-9.685, A vs B: HR 1.084, CI 0.344-3.417). Conclusions: A significant difference in primary endpoint was not detected. Variation in QOL at treatment initiation probably greatly affected outcome. Clinical trial information: NCT00209742.

BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer

Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). The addition of sorafenib to gemcitabine does not improve PFS in APC patients.

O1-032 - A Prospective, Feasibility Study of S-1 and Carboplatin for Patients with Pulmonary Fibrosis (PF) and Advanced Non-Small-Cell Lung Cancer (NSCLC)

ABSTRACT Background PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil, and oteracil potassium. Although most of the anti-cancer agents have pulmonary toxicity, post marketing surveillance reported that S-1 has lower pulmonary toxicity incidence. We have conducted a feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0–2 and chemo-naive were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80 mg/m2/day) on day 1 to 14 for four to six cycles. End points were response rate, common safety profiles and effect to PF. Results From March 2009 to December 2011, 21 patients (19 males/2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3 patients, 2: 3 patients, 3: 3 patients, 4: 10 patients, 5; 1 patient, 6: 1 patients. Partial responses were observed in 7 patients (RR; 33%). The median progression-free survival duration was 4.0 months, and the median overall survival duration in 10.4 months. During the treatment, two patients experienced moderate deterioration of pulmonary fibrosis, one experienced infectious pneumonia—all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials.

O2-014 - The Feasibility Study of CDDP Plus Docetaxel Followed by TS-1 Maintenance as Post Operative Adjuvant Chemotherapy for Completely Resected Pathological Stage II to IIIA NSCLC Patient

ABSTRACT Background Maintenance chemotherapy could prolong overall and/or progression-free survival in advanced NSCLC. S-1 is an oral anticancer agent comprised of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The TORG 0809 study was conducted to evaluate the feasibility and efficacy of maintenance chemotherapy of S-1 following DOC + CDDP in patients with curatively resected stage II and IIIA NSCLC. Methods Patients received three cycles of DOC (60 mg/m2 d1) plus CDDP (80 mg/m2 d1), q3-4w, and subsequently S-1 at 40 mg/m2 twice a day for 14 consecutive days, q3w, for more than 6 months (max 1 year). The primary end point was determination of feasibility, which was defined as the proportion of patients who had completed maintenance for 8 cycles of S-1 or more. If the lower confidence interval (CI) of this proportion was 50% or more, the feasibility of the treatment was considered confirmed. The sample size was set to be 125. Results Between June 2009 and November 2010, 131 patients were enrolled, of whom 129 patients were eligible and assessable. The median age was 63 (23–74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 30, IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 patients, 109 patients (84.5%) completed three cycles of DOC + CDDP. One hundred and six patients initiated the maintenance S-1 and 66 patients (51.2%, 95% CI: 42.5–59.8) completed eight cycles or more S-1 treatment; this percentage was less than our previously defined criterion for treatment feasibility, since 32 patients terminated maintenance S-1 at three cycles or less. Grade 3/4 toxic effects during the maintenance S-1 included anemia (7.3%), neutropenia (3.7%), anorexia (3.7%), dyspnea (1.8%), infection with neutropenia of grade 0 to 2 (1.8%). Febrile neutropenia was not observed. Conclusions The toxicity level was acceptable, although the results did not meet our criterion for feasibility.

1334 - A Prospective, Feasibility Study of S-1 and Carboplatin for Patients with Advanced Non Small Cell Lung Cancer (NSCLC) Concomitant with Pulmonary Fibrosis (PF)

ABSTRACT Background PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent has pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0-2 and chemo-naive patients were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m2/day) on day 1 to 14 for four to six cycles. Endpoints were response rate, common safety profiles and effect to PF. Results From March 2009 to December 2011, 21 pts (19 males/ 2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3pts, 2: 3pts, 3: 3pts, 4: 10pts, 5; 1pts, 6: 1pts. Partial responses were observed in 7 patients (RR; 33%). The median progression free survival duration was 4.0 months and the median overall survival duration in 10.4 months. During the treatment, 2 patient experienced moderate deterioration of pulmonary fibrosis, 1 experienced infectious pneumonia, all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials. Disclosure All authors have declared no conflicts of interest.

Synthesis and Biological Evaluation of Oral Prodrugs Based on the Structure of Gemcitabine

A series of oral prodrugs based on the structure of gemcitabine (2',2'-difluorodeoxycytidine) were synthesised by introducing an amide group at the N4-position of the cytidine ring. A total of 16 compounds were obtained, and their chemical and biological characteristics were evaluated. The half-maximal inhibitory concentrations (IC(50)s) for most of these compounds were higher than that of gemcitabine in vitro. Compounds 5d and 5m, the representative compounds, were examined in terms of their physiological stabilities and pharmacokinetics. Compound 5d showed good stability in PBS and simulated intestinal fluid, and an analysis of its pharmacokinetics in mice suggested that the introduction of an amide group to gemcitabine could greatly improve its bioavailability. Further evaluation of compound 5d in vivo showed that this compound possesses higher activity than gemcitabine against the growth of HepG2 human hepatocellular carcinoma cells and HCT-116 colon adenocarcinoma cells with less toxicity to animals. These results suggest that compound 5d could be further developed as a potential oral anticancer agent for clinical applications in which gemcitabine is currently used.

Effect of a combination of S-1 and gemcitabine on cell cycle regulation in pancreatic cancer cell lines

In a previous study, we showed that a combination of an oral fluoropyrimidine anticancer agent (S-1) and gemcitabine (GEM) had synergistic effects on cell growth and cell cycle arrest in the pancreatic cancer cell line MIA PaCa-2. Therefore, we conducted further mechanistic studies using the pancreatic cancer cell lines MIA PaCa-2 and SUIT-2. The combined effect of S-1 and GEM in SUIT-2 cells was evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effects of S-1, GEM and S-1 plus GEM on cell cycle regulation were assessed using flow cytometry. We also examined the expression of several cell cycle regulatory proteins in both MIA PaCa-2 and SUIT-2 cells by western blotting. Classical isobolographic analysis of the MTT assay results showed that the combination of S-1 and GEM had a synergistic effect in SUIT-2 cells, and flow cytometric analysis of the cell cycle showed that the combination of S-1 plus GEM induced S-phase arrest to a greater degree than did either S-1 or GEM alone. Also, the combination of S-1 and GEM resulted in the downregulation of cyclin D1 expression and upregulation of cyclin A, p21 and p27 expression levels. Treatment of MIA PaCa-2 and SUIT-2 cells with a combination of both drugs also led to the increased phosphorylation of checkpoint kinase 1. Combined treatment with S-1 and GEM resulted in more prolonged S-phase arrest than with either treatment alone. This difference is shown to be potentially due to the higher levels of phosphorylated checkpoint kinase 1 in pancreatic cancer cell lines treated with the two agents.

The effect on patients with pulmonary fibrosis (PF) and advanced non small cell lung cancer (NSCLC): A prospective, feasibility study of S-1 and carboplatin.

e19583 Background: PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent have pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods: Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0-2 and chemo naive were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m2/day) on day 1 to 14 for four to six cycles. Endpoints were response rate, common safety profiles and effect to PF. Results: From March 2009 to December 2011, 21 pts (19 males/ 2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3pts, 2: 3pts, 3: 3pts, 4: 10pts, 5; 1pts, 6: 1pts. Partial responses were observed in 7 patients (RR; 33%). The median progression free survival duration was 4.0 months and the median overall survival duration in 10.4 months. During the treatment, 2 patient experienced moderate deterioration of pulmonary fibrosis, 1 experienced infectious pneumonia, all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions: This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials.

Feasibility trial of adjuvant chemotherapy with docetaxel (DOC) plus cisplatin (CDDP) followed by maintenance chemotherapy of S-1 in completely resected non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group (TORG) 0809.

7012 Background: Maintenance chemotherapy could prolong overall and/or progression-free survival in advanced NSCLC. S-1 is an oral anticancer agent comprised of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate. The TORG 0809 study was conducted to evaluate the feasibility and efficacy of maintenance chemotherapy of S-1 following DOC+CDDP in patients (pts) with curatively resected stage II and IIIA NSCLC. Methods: Pts received 3 cycles of DOC (60mg/m2 d1) plus CDDP (80mg/m2 d1), q3-4w, and subsequently S-1 at 40mg/m2 twice a day for 14 consecutive days, q3w, for more than 6 months (max 1 year). The primary endpoint was determination of feasibility, which was defined as the proportion of pts who had completed maintenance for 8 cycles of S-1 or more. If the lower confidence interval (CI) of this proportion was 50% or more, the feasibility of the treatment was considered confirmed. The sample size was set to be 125. Results: Between Jun 2009 and Nov 2010, 131 pts were enrolled, of whom 129 pts were eligible and assessable. The median age was 63 (23-74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 30, IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 pts, 109 pts (84.5%) completed 3 cycles of DOC+CDDP. 106 pts initiated the maintenance S-1 and 66 pts (51.2%, 95% CI: 42.5-59.8) completed 8 cycles or more S-1 treatment; this percentage was less than our previously defined criterion for treatment feasibility, since 32 pts terminated maintenance S-1 at 3 cycles or less. Grade 3/4 toxicities during the maintenance S-1 included anemia (7.3%), neutropenia (3.7%), anorexia (3.7%), dyspnea (1.8%), infection with neutropenia of grade 0 to 2 (1.8%). Febrile neutropenia was not observed. One pt developed interstitial pneumonia and sepsis, resulting in treatment-related death. Recurrence-free survival data will be presented. Conclusions: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule of maintenance S-1, such as a 2-week rest period rather than 1-week, might improve treatment compliance.

SL-01, an oral gemcitabine derivative, inhibited human cancer growth more potently than gemcitabine

SL-01, an oral gemcitabine derivative, was synthesized by introducing the moiety of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl at the N4-position on the cytidine ring of gemcitabine. Our goal in this study was to evaluate the efficacy of SL-01 on the growth of human cancers with gemcitabine as control. Experiments were performed on human non-small cell lung cancer NCI-H460 and colon cancer HCT-116 both in vitro and in vivo. In vitro assays, SL-01 significantly inhibited the growth of cancer cells as determined by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Further studies indicated that SL-01 induced the cancer cells to apoptosis showing chromatin condensation and externalization of phosphatidylserine. In in vivo studies, we evaluated the efficacy of SL-01 in nude mice bearing human cancer xenografts. SL-01 effectively delayed the growth of NCI-H460 and HCT-116 without significant loss of body weight. Molecular analysis indicated that the high efficacy of SL-01 was associated with its ability to induce apoptosis as evidenced by increase of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining cells, activation of caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase (PARP) in tumor tissues. SL-01 also increased Bax/Bcl-2 ratio in cancer cells. These biological activities of SL-01 were more potential than that of gemcitabine. Based on these in vitro and in vivo results, SL-01 is proposed as a potent oral anticancer agent that may supplant the use of gemcitabine in the clinic.

Structural and Physicochemical Aspects of Dasatinib Hydrate and Anhydrate Phases

Crystal structures for the commercial monohydrate form and an anhydrate form of dasatinib, an oral anti-cancer agent, are presented along with characterization by Raman spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Solubility measurements conducted in water reveal the anhydrate has dramatically improved solubility compared to the commercial hydrate form. Finally, dasatinib is a rare example of a promiscuous solvate former and the basis for this behavior can now be understood by examining the poor packing efficiency in the unsolvated form.

A phase I study of S-1 in combination with sorafenib in metastatic renal cell carcinoma (mRCC).

447 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil, with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The purpose of this study was to confirm the recommended dose (RD) and maximum tolerated dose (MTD) of S-1 in combination with sorafenib, a small molecular inhibitor of several tyrosine protein kinase, in Japanese patients with mRCC. We assessed dose-limiting toxicities (DLTs) and pharmacokinetic interactions during the first cycle of treatment. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary mRCC, measurable lesions, a history of no previous treatment or not more than 1 regimen of cytokine treatment, an ECOG performance status of 0 or 1, prior nephrectomy, and adequate organ functions. In this study, four dose levels were prepared, and the starting dose was set at Level 1B. S-1 was administered on days 1 to 28, and sorafenib was given on days 1 to 42 as one cycle. The MTD was assessed using a “3 + 3” dose escalation design and was defined as the highest dose level for which the incidence of DLTs was less than 33%. Results: Between August 2009 and March 2010, 9 patients were enrolled. Two DLTs occurred in patients assigned to level 2, which was the full therapeutic dose of each agent. Therefore, the MTD was not confirmed, but the RD was determined to be level 2. Although renal clearance affected the pharmacokinetics of S-1, there were no obvious drug interactions between S-1 and sorafenib. Details are shown in the Table. Conclusions: This combination therapy can be administered with acceptable tolerability, no overlapping toxicity, and no drug interactions. The RD for phase II studies was fixed at level 2, and a phase II study is ongoing. [Table: see text]