1-week Off Research Articles

Phase I study to evaluate the safety and to assess the food effect of HM781-36B, a novel pan-HER inhibitor continuously given in patients with advanced solid tumors.

2565 Background: HM781-36B, a novel pan-HER tyrosine kinase inhibitor, showed potent in vitro and in vivo antitumor activities for EGFR mutant models including T790M mutation. In the previous 2-weeks on, 1-week off phase I study, the maximum tolerated dose (MTD) was determined as 24 mg/day. Phase I study with a continuous daily dosing schedule was conducted to determine the recommended dose (RD), and to assess the effect of food on pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation study, and additional 8 patients were enrolled to test food effects. Results: 20 pts (median age: 55 years [range32-77], M:F=13:7, ECOG PS 0/1/2/3 8/12/0/0) were enrolled (5 NSCLC, 4 colon cancer, 3 stomach cancer, 2 breast cancer, 2 rectal cancer, 2 common bile duct cancer, 1 pancreatic cancer and 1 esophageal cancer); 12 in the dose escalation and 8 in the food effect study cohort. Twelve pts were heavily pretreated(≥4 regimens). Dose limiting toxicities (DLTs) were G3 anorexia in 1 pt at 18mg/day, G3 diarrhea and anorexia in 1 pt, and drug compliance <80% due to G2 adverse events in 1 pt at 24mg/day. The MTD was determined as 18 mg/day, and RD was determined as 16 mg/day. The most common drug-related adverse events were diarrhea, stomatitis, skin rash, paronychia, pruritus and anorexia. Among 16 evaluable pts, 4 achieved partial responses (PR)[1 NSCLC, 2 breast cancer, 1 common bile duct cancer], and the duration of response were 32, 40+, 21, and 8 weeks, respectively. Five pts had stable disease (SD). The median duration of treatment in pts with PR or SD was 33.5 weeks (range, 15-82). Under both fasted and fed condition, there were no significant differences of AUClast values, whereas Cmax values were lower in fed condition than in fasted condition. Conclusions: Continuous daily dosing schedule of HM781-36B is safe and well tolerated in advanced solid tumors. It exerts anticancer activity, without being influenced by food. Updated data will be presented at the meeting. Clinical trial information: NCT01455584.

Association of drug exposure with clinical response and toxicities in metastatic renal cell carcinoma patients (mRCC) receiving an alternative dosing (AD) regimen of sunitinib.

e13582 Background: An AD regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for mRCC. This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients starting on sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and graded according to CTCAE and plasma AUCss was quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Statistical tests such as Mann-Whitney U were used to compare the levels between groups. Results: 24 patients with a mean age of 58.8 ± 11.2 years were recruited. Majority were males (75%) and Chinese (87.5%). Among the 17 and 14 analyzable cases for cycle 1 and 2, median total AUCsswere 2.2 and 2.1 µg•h/ml respectively. Fourteen patients completed 2 treatment cycles; 7 (50%) partial response, 4 (28.6%)stable disease and 3 (21.4%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical responseand among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]

Management of Antiangiogenic Therapy-Induced Hypertension

Angiogenesis, or the formation of new blood vessels, is essential for solid tumor growth and metastasis, and it is regulated by proangiogenic soluble mediators, including the vascular endothelial growth factor (VEGF).1 Antiangiogenic drugs that block the VEGF signaling pathway prolong progression-free survival (PFS) in several cancers2–4 and are now in broad clinical use to treat advanced-stage solid tumors. Hypertension is among the most common toxicities of this therapeutic class, with recent meta-analyses reporting the incidence of hypertension induced by a single antiangiogenic agent to be ≈20%,5–7 and single studies have reported incidence as high as 87%.8 Thus, the appropriate diagnosis and management of antiangiogenic therapy-induced hypertension are now common clinical problems. In this report, we present a patient who developed antiangiogenic therapy-induced hypertension and review the mechanisms, management, and emerging questions in this evolving field. ### Case The patient is a 56-year–old man with a history of hypertension, coronary artery disease, and tobacco use. Medications included atenolol, hydrochlorothiazide, and aspirin. He developed weight loss with microscopic hematuria and was found to have a large exophytic mass of 8 cm in the left kidney, with small liver and pulmonary nodules suspicious for metastases. He underwent radical nephrectomy, and pathology revealed Fuhrman grade 3 clear cell renal cell carcinoma. He was started on single-agent sunitinib therapy administered in a 4-week–on, 2-week–off regimen. Before starting sunitinib, his metabolic workup, including serum electrolytes, fasting blood glucose, and lipid profile, was unremarkable. His serum creatinine after nephrectomy was 1.3 mg/dL, and a 24-hour protein excretion was 270 mg/24 hours. An echocardiogram showed mild left ventricular hypertrophy, unchanged over the last 2 years. Over the last year, his office blood pressure (BP) measurements have been in the 120s/80s mm Hg range. Two weeks after starting sunitinib, his office BP was …

P1-17-05: Preliminary Results of a Randomized Phase 2 Study of PD 0332991, a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole for First-Line Treatment of Patients (pts) with Post-Menopausal, ER+, HER2−Negative (HER2–) Advanced Breast Cancer.

Abstract Background: PD 0332991 is an orally bioavailable selective inhibitor of CDK 4/6 and prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase. Preclinical evaluations suggest that reduction in CDKN2A (p16) expression and cyclin D1 (CCND1) overexpression confer susceptibility to PD 0332991 (Finn 2009). In addition, PD 0332991 was synergistic in combination with tamoxifen in vitro in ER+ human breast cancer cell lines. Based on these observations, a phase 1/2 study in combination with letrozole as first-line therapy for advanced ER+ post-menopausal breast cancer was initiated. The phase 1 part of the study (completed) determined the recommended phase 2 dose to be PD 0332991 125 mg QD on Schedule 3/1 (3 weeks on treatment followed by 1-week off treatment) in combination with letrozole 2.5 mg QD. The combination was generally well tolerated and encouraging antitumor activity was observed. We present preliminary data from the randomized Phase 2 portion comparing letrozole alone to letrozole plus PD 0332991. Methods: The Phase 2 portion of the study is designed as a two-part study; we present data from Part 1. In both parts, eligible patients are randomized 1:1 to letrozole 2.5 mg QD alone (control) or PD 0332991 125 mg QD on schedule 3/1 and letrozole 2.5 mg QD (treatment, tx). Part 1enrolled post-menopausal women with ER+, HER2− cancer using only ER+, HER2−as a selection criteria. Part 2 is now enrolling post-menopausal women with ER+, HER2− breast cancer with CCND1 amplification and/or loss of p16 by FISH (target N=150). The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival, response rate, safety, and correlative studies. Pts are stratified for disease site and length from prior adjuvant therapy. Pts continue assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal and are followed every 2 months to assess disease status. Tumor tissue was required for participation. Results: 66 patients have been randomized in Part 1. At the time of data cut-off (April 2011) median duration of treatment is 20 (range 4–64) wks for control and 27 (2-59) wks for tx. Dose reductions occurred in 9 pts on the tx arm and none on the control arm. There are no complete responses. The number of partial responses for pts with measurable disease are similar between arms (4/22 control vs 5/24 in tx). The number of pts with stable disease> 24 weeks was higher in the tx arm (5 vs 8). The number of pts with best response of progressive disease is lower in the treatment arm (2 vs 6). PFS data are immature. Twelve pts remain on control vs. 21 on tx. As in the Phase I portion of the study, the most common treatment-related AEs were neutropenia and leucopenia without febrile neutropenia. Biomarker studies for CCND1 amplification, p16 loss, RB status, and Ki67 are ongoing. Conclusion: The combination of PD 0332991 and letrozole is well tolerated as first-line treatment of ER+, HER2− post-menopausal breast cancer. Updated efficacy data and biomarker data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-05.

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (ρ) = 0.378, p = 0.028] and vWF (ρ = 0.417, p = 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p = 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (ρ = 0.605; p = 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.

Phase I trial of metronomic oral vinorelbine in patients with advanced cancer

Antitubulin agents exhibit antiangiogenic effects in vitro and in vivo. We evaluated the safety and feasibility of administering a metronomic schedule of oral vinorelbine designed to optimize its antiangiogenic effects. Patient with advanced cancer who had progressive disease after standard therapy received oral vinorelbine 3times weekly (i.e., Monday, Wednesday, Friday) at the 6 dose levels ranging from 20mg (1week on, 1week off) to 50mg (3weeks on, 1week off) in cohorts of 3-6 patients at each dose level using a standard phase I design. Dose-limiting toxicity (DLT) during cycle 1 included: (1) neutrophil nadir<500/μL attributed to therapy, (2) platelet nadir<50,000/μL attributed to therapy, (3) grade 3-4 non-hematologic toxicity attributed to therapy, and (4) neutropenia associated with grade 2 fever (i.e., febrile neutropenia). Nineteen patients received 50cycles of therapy (range 1-11cycles) at 6 dose levels. There were no dose-limiting toxic events. There were no consistent changes in serum TIE-2 or VCAM-1 levels, or urinary VEGF. One patient with renal cell carcinoma had stable disease for 9months, and another patient with metastatic prostate cancer had a 70% decline in serum prostate-specific antigen, which lasted 4months. Oral vinorelbine may be given using a metronomic schedule, 50mg thrice weekly for three of 4weeks, with minimal toxicity in patients with advanced cancer.

Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases

Clear cell carcinoma (CCC) of the ovary is well-known to be chemotherapy resistant compared with other histologic subtypes. An inhibitor against the mammalian target of rapamycin, temsirolimus (TEM) has been reported to be effective in renal CCC. Therefore, we investigated the effects of TEM in patients with CCC of the ovary. Six patients with CCC of the ovary who had been heavily pretreated by more than 4 regimens were given TEM: the cycle consisted of weekly TEM (10mg/m(2)) for 3weeks followed by 1week off. The treatment was continued until development of either progressive disease, or unmanageable adverse effects. Response evaluation was based upon the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events version 3.0. The median cycle of weekly TEM was 3 (range 2-14). Among five cases in which responses could be evaluated, partial response was observed in one case (20%) and stabilized disease was seen in another case (20%). There were no toxicities greater than grade 3, and no case developed severe toxicity requiring discontinuation of weekly TEM. The patient who showed a partial response obtained a progression-free period of 14months. In conclusion, weekly TEM shows a potential therapeutic benefit for patients with CCC of the ovary. Further studies including a translational approach are needed to select candidates for whom TEM therapy would be beneficial.

Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors

This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted. Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa. DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses. The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.

Gastrectomy and chemotherapy with S-1 for gastric cancer in a patient with acquired immunodeficiency syndrome

Total gastrectomy and chemotherapy with S-1 after surgery were performed in a 50-year-old woman with gastric cancer associated with acquired immunodeficiency syndrome (AIDS). She was given a diagnosis of gastric cancer at the lesser curvature of the body of the stomach, and distal gastrectomy was performed in December 2004. The postoperative course was eventful, with persistent high fever of unknown origin after surgery and infiltrative shadows in the bilateral lung fields showing on CT scan. Polymerase chain reaction (PCR) for pneumocystis carinii on bronchoscopy was positive, serum HIV antibody was positive, HIV-RNA was 2.2×10(5)copies/ml, and the serum CD4 lymphocyte level was 25/mm(3) on postoperative day 28. She was given a diagnosis of pneumocystis carinii with AIDS. Pneumocystis carinii and fever improved immediately when ST mixture and highly active antiretroviral therapy (HAART) were performed. After 3months, the serum CD4 lymphocyte level was elevated to 125/mm(3), and she underwent total gastrectomy because cancer cells at the cut end of the resected stomach were positive microscopically. The postoperative course was uneventful, and she underwent adjuvant chemotherapy with S-1 because the serum CD4 lymphocyte level was 568/mm(3). S-1 therapy was continued for 2years (each course consisting of 2weeks of administration followed by 2weeks off) while performing HAART and monitoring CD4 lymphocyte levels. No side effects such as decreases in white blood cell counts or CD4 lymphocyte levels were seen during S-1 therapy. She is alive and well without recurrence of gastric cancer 5years after initial gastrectomy.

Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy

BackgroundSystemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. Patients and methodsPatients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. ResultsThirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a ≥50% prostate-specific antigen (PSA) decline and seven (21.2%) had a ≥30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score ≥2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. ConclusionSunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

A Phase I Dose-Escalation Study of SR271425, an Intravenously Dosed Thioxanthone Analog, Administered Weekly in Patients With Refractory Solid Tumors

The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with broad antitumor activity in preclinical models. The objectives of this phase I study were to determine the dose-limiting toxicities, maximum tolerated dose, recommended phase II dose, pharmacokinetic profile, and trend for efficacy in patients with advanced cancer. SR271425 was administered intravenously over 1-hour, weekly for 2 weeks, followed by 1 week rest. Because of Cmax-related corrected QT (QTc) prolongation in preclinical testing of SR271425, all patients underwent an extensive pretreatment cardiac assessment. Eighteen patients received SR271425 at 5 dose levels ranging from 64 to 675 mg/m/wk. No dose-limiting toxicities were identified. In all tested dose-levels, Grade 3 adverse events were observed in 10/18 patients (55.6%) and Grade 4 in 4/18 patients (22.2%). QTc prolongation was reported at the 3 highest dose levels but did not exceed Grade 2. Six deaths occurred during the study, 5 of them because of disease progression and 1 because of disease related bowel perforation. SR271425 exposure increased in a near dose-proportional manner. The mean terminal plasma half-life of SR271425 was 6 hours and there was no drug accumulation after repeated dosing. Stable disease was the best outcome observed (5 patients). SR271425 was administered safely at doses up to 675 mg/m/wk on a 2-week on, 1-week off schedule. No dose-limiting toxicities were observed. Grade 2 QTc prolongation was observed at the highest dose levels. Maximum tolerated dose was not reached because of early termination of the SR271425 program by the sponsor.

Sunitinib-Induced Myeloid Lineage Redistribution in Renal Cell Cancer Patients: CD1c+ Dendritic Cell Frequency Predicts Progression-Free Survival

A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients. Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data. Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1(+) MDC frequencies were predictive for tumor regression and improved progression-free survival. The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.

A phase II study of the efficacy and safety of sunitinib in treatment-naïve and pretreated Japanese patients (pts) with metastatic renal cell carcinoma (mRCC)

16108 Background: Sunitinib malate (SU) is an oral multitargeted receptor tyrosine kinase inhibitor that is approved multinationally for the treatment of advanced RCC. A multicenter phase II trial of SU in Japanese pts with mRCC has recently been completed; here we report efficacy and safety data from this trial. Methods: mRCC pts with prior nephrectomy received sunitinib 50 mg/day p.o. on a 4-week on, 2-week off schedule in 6-week cycles. Primary efficacy endpoint was objective response rate (ORR) as determined by RECIST. Secondary endpoints included progression-free survival (PFS) and time to tumor response (TTR). Responses were determined every 6 weeks (wks) by computed tomography/magnetic resonance imaging. Toxicity assessments were undertaken every 2 wks (NCI-CTCAE version 3). Results: In total, 51 Japanese pts received SU, comprising 25 treatment-naïve pts (1st-line group) and 26 pts who had received prior cytokine-based therapy (pretreated group), for a median of 4 and 5 cycles, respectively. In the intention-to-treat population, ORR was 48.0% in the 1st-line group, 46.2% in the pretreated group and 47.1% in the overall population (independent review). Median PFS was 46.0, 33.6 and 46.0 wks in the 1st-line, pretreated and overall populations, respectively. Median TTR was 10.0 wks in the overall population, and 7.1 wks and 10.7 wks in the two arms. The most commonly observed grade 3–4 Aes were fatigue (20%), hand-foot syndrome (14%), and hypertension (12%). The most common grade 3–4 laboratory abnormalities were reduced platelet (55%) and neutrophil (51%) levels, and increased lipase levels (39%). In total, 37 pts required dose reductions and 10 pts discontinued SU due to Aes. Conclusions: These data show significant efficacy and tolerability with SU in Japanese mRCC pts. Although Aes were generally manageable and reversible, there was a trend towards higher efficacy and a higher incidence of some Aes in Japanese pts compared with previously reported international phase II/III trials with mostly Western pts; this potential difference remains to be clarified. It is strongly suggested that SU is effective and tolerable for the treatment of Japanese pts in the 1st- and 2nd-line settings. No significant financial relationships to disclose.

A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.

Phase I/II study of combination chemotherapy with S-1 and cisplatin every 3 week schedule in patients with metastatic or recurrent gastric cancer

15066 Background: S-1 plus cisplatin has been reported to be highly active in advanced gastric cancer (AGC). The objectives of this study were to define the maximal-tolerated dose (MTD) of S-1, given for 2 weeks separated by 1 week rest, with a fixed dose of cisplatin, and to determine the activity and safety of this combination regimen at the recommended dose (RD) when used as the first line treatment of AGC. Methods: Cisplatin was fixed at a dose of 60 mg/m2 on D1 and the starting dose of S-1 was 30 mg/m2 bid (level I) on D1 to D14 every 3 weeks. The dose of S-1 was increased by 5 mg/m2 bid up to 50 mg/m2 bid (level V) unless MTD was achieved. At every level, a cohort of 3 patients (pts), which could be expanded to 6 pts, was studied. Dose-limiting toxicities (DLTs) were assessed for the first 2 cycles. Results: From February 2004 to January 2006, 62 eligible pts were enrolled. In phase I (N=21), DLTs occurred at level V (S-1 50 mg/m2 bid), with 2 of 3 pts developing G3 diarrhea or febrile neutropenia. The RD was determined at level IV (45 mg/m2 bid) because only 1 DLT occurred out of 6 pts at this level. After the first 20 pts (series I) were enrolled in phase II, the protocol was amended; the S-1 dose was reduced down to 40 mg/m2 bid (level III, series II, N=23) because of poor bone marrow recovery and resultant treatment delay. At the time of analysis, a total of 272 cycles of chemotherapy were administered. The median age was 52 years (28–70) and ECOG PS was 0/1 in 98% of pts. The objective response was observed in 20(47%; 95% CI, 36–66%) of 43 pts. SD was achieved in 15 (35%) pts. With a median FU of 12.1 months (range 9.8–23.3) for all survivors, median PFS was 5.3 months (95% CI, 4.6–6.0 months) with a median OS of 10.0 months (95% CI, 5.1–14.8 months). G3–4 toxicities included neutropenia (33%), anemia (31%), anorexia (24%), and asthenia (14%); however severe febrile neutropenia, abdominal pain, and stomatitis were never observed. Conclusions: The cisplatin plus S-1 regimen incorporating 2-weeks on and 1-week off is highly active against gastric adenocarcinoma with favorable toxicitiy profiles in Korean patients. No significant financial relationships to disclose.

A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period

Sunitinib, an oral multitargeted tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, FLT3, KIT, and RET, is currently approved for the treatment of imatinib-refractory GIST and advanced renal cell carcinoma at a dose of 50 mg daily for 4 weeks followed by a 2-week off period (4/2 schedule). This trial was performed to investigate the safety, tolerability, and pharmacokinetics of sunitinib 50 mg daily for 2 weeks followed by a 1-week off period (2/1 schedule). Twelve patients with advanced refractory malignancies were treated with sunitinib on the 2/1 schedule. Intensive safety monitoring included serial measurements of left ventricular ejection fraction (LVEF). Extensive pharmacokinetic sampling was performed on days 1 and 14 of course 1, and on day 14 of courses 2 and 3 to evaluate sunitinib and the SU12662 metabolite. Twelve patients received a total of 50 courses with an average (+/-SD) off-drug period of 11.5 +/- 5.7 days. Two patients experienced DLT: one patient had asymptomatic grade 4 elevations in lipase and amylase, and another patient had an asymptomatic grade 2 decline in LVEF in course 1. In total, five patients demonstrated asymptomatic grade 2 declines in LVEF. Other principal effects were similar to previous experience with sunitinib, including fatigue, myelosuppression, skin discoloration, and gastrointestinal effects. Pharmacokinetic studies revealed no significant accumulation of sunitinib or SU12662. One patient with papillary thyroid cancer developed a partial response, and was on study for 16 courses, followed by an additional 18 courses on a continuation protocol. The 2/1 schedule of sunitinib 50 mg was tolerable, and no significant drug accumulation was demonstrated. The safety profile on this schedule was consistent with the safety profile of sunitinib when administered on a 4-week on, 2-week off schedule.

Eslicarbazepine Acetate: A Double‐blind, Add‐on, Placebo‐controlled Exploratory Trial in Adult Patients with Partial‐onset Seizures

To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy. A multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18-65 years with >or=4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n=50), twice daily (BID, n=46), or placebo (PL, n=47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a >or=50% seizure reduction) was the primary end point. The percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =-infinity, -14; p=0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =-infinity, -1; p=0.12). A significantly higher proportion of responders in weeks 5-8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p=0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred. Eslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients.

Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]

Stress-induced insomnia treated with kava and valerian: singly and in combination.

Kava and valerian are herbal remedies that are claimed to have anxiolytic and sedative properties respectively, without dependence potential or any appreciable side effects. In this pilot study, 24 patients suffering from stress-induced insomnia were treated for 6 weeks with kava (LI-150), 120 mg daily. This was followed by a 2-week 'wash-out' period off treatment, and then, five patients having dropped out, 19 received valerian (LI-156), 600 mg daily, for another 6 weeks. Then there was a further 2-week period off treatment, and a final 6 weeks of treatment of these 19 patients with the two compounds combined (kava + valerian). Stress was measured in three areas: social, personal and life events; insomnia in three areas also: time to fall asleep, hours slept and waking mood. Total stress severity was significantly relieved by both compounds individually (p < 0.01), with no significant differences between them; and there was also improvement with the combination, significant in the case of insomnia (p < 0.05). On direct questioning, 16 patients (67%) reported no side effects on kava, 10 (53%) on valerian and 10 (53%) on the combination. The 'commonest' effect was vivid dreams with kava + valerian (4 cases (21%)) and with valerian alone (3 cases (16%)), followed by gastric discomfort and dizziness with kava (3 cases each (3 %)). These results are considered to be extremely promising but further studies may be required to determine the relative roles of the two compounds for such indications. Copyright 2001 John Wiley & Sons, Ltd.

Uridine allows dose escalation of 5-fluorouracil when given with N-phosphonacetyl-L-aspartate, methotrexate, and leucovorin.

In a previous trial in which methotrexate and N-phosphonacetyl-L-aspartate (PALA) were used to modulate 5-fluorouracil (5-FU), four of six patients could not tolerate treatment at the 600 mg/m2 5-FU dose level because of mucositis, diarrhea, and a decrease in performance status. The current study examines the ability of uridine rescue to prevent such toxic effects in the same regimen and, thereby, allow additional dose escalation of 5-FU. Twenty-nine patients with advanced malignant neoplasms received PALA and MTX, each at 250 mg/m2, followed 24 hours later by increasing bolus doses of 5-FU (600-750 mg/m2) with a leucovorin rescue (10 mg orally every 6 hours for eight doses) and uridine rescue (3 g/m2/hour, for a 72-hour infusion, 3 hours on, 3 hours off). Treatment was repeated weekly with either 2 weeks on, 2 weeks off, or 3 weeks on, 1 week off. Mucositis, which occurred in 4 of 12 patients treated at the 750 mg/m2 5-FU dose level, was the only significant chemotherapy-induced toxic effect. However, uridine-related central venous catheter complications (cellulitis in six patients and superior vena cava syndrome in one patient) precluded additional treatment on this protocol. In the current regimen, uridine allowed dose escalation of 5-FU to 750 mg/m2, which some patients tolerated on a 3-week on, 1-week off schedule. Because of the vascular toxic effects associated with intravenous uridine, the authors recommend additional studies with oral uridine to determine whether the increase in 5-FU dose that uridine allows is associated with improved response rates.