Tae-Min Kim

Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors

Purpose OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. Results Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression. Conclusion This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.

Expression of Class III Beta-Tubulin Correlates with Unfavorable Survival Outcome in Patients with Resected Non-small Cell Lung Cancer

Background: We analyzed the significance of class III beta-tubulin (TUBB3) expression in curatively resected non-small cell lung cancer as a prognostic marker along with previously reported excision repair cross complementation group 1 (ERCC1). Methods: One hundred and thirty-six consecutive patients were included in this retrospective study. Patients who received adjuvant chemotherapy were excluded. We used immunohistochemistry to evaluate TUBB3 and ERCC1 expression on tissue microarray in duplicate. Semiquantitative H score was used for the scoring of tumor staining. Results: Sixty percent of patients had stage I disease, 17% stage II, 18% stage IIIA, and 5% stage IIIB. TUBB3 H score showed bimodal distribution with the minimum at the value of 4, which was used as a cutoff value for determination of TUBB3 positivity. TUBB3 was expressed in 60 patients (44%). Patients with a positive TUBB3 expression survived shorter than did the patients with a negative expression (5-year overall survival [OS] rate was 40% versus 61%; p = 0.005/5-year disease-free survival rate was 34% versus 55%; p = 0.024). ERCC1 expression showed tendency for prolonged OS without reaching statistical significance. A multivariate analysis that incorporated covariates including TUBB3 expression, age, stage, EGFR mutation status, histology, and ERCC1 expression showed that TUBB3 was an independent unfavorable prognostic factor for OS (hazard ratio 2.083; p = 0.008) and relapse free survival (hazard ratio 1.978; p = 0.020). Conclusions: TUBB3 expression is an independent unfavorable prognostic marker in patients with curatively resected non-small cell lung cancer who did not receive adjuvant chemotherapy.

D‐dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer

The occurrence of stroke in cancer patients is caused by conventional vascular risk factors and cancer‐specific mechanisms. However, cryptogenic stroke in patients with cancer was considered to be more related to cancer‐specific hypercoagulability. In this study, we investigated the potential of the D‐dimer level to serve as a predictor of early neurologic deterioration (END) in cryptogenic stroke patients with active cancer.

Prolonged sleep increases the risk of intracerebral haemorrhage: a nationwide case−control study

Although abnormal sleep duration is positively associated with increased risk for cardiovascular disease and mortality, the specific impact on intracerebral haemorrhage (ICH) risk remains unclear. The relationship between sleep duration and the risk of ICH was investigated in our study.

Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors.

Purpose CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. Results Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). Conclusion This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks.

Novel echocardiographic indicator for potential cardioembolic stroke.

In many cardioembolic strokes (CSs), the specific embolic source is uncertain. Despite the high mortality of CS, not enough attention is paid to its potential source. Although atrial fibrillation (AF) is the most common source of embolism, more complex and dynamic multiplicities may influence CS. The aim of this study was to evaluate novel indicators of transthoracic echocardiography (TTE) that have additional value for detecting CS.

Phase II Study of Irinotecan and Cisplatin Combination Chemotherapy in Metastatic, Unresectable Esophageal Cancer

Purpose The objective of this multicenter phase II study was to evaluate the efficacy and safety of irinotecan and cisplatin combination chemotherapy in metastatic, unresectable esophageal cancer. Materials and Methods Patients were treated with irinotecan 65 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 of each 21-day treatment cycle. The primary endpoint was response rate, and secondary endpoints were survival, duration of response, initial metabolic response rate, and toxicity. Results A total of 27 patients with squamous cell histology were enrolled in the study. The median age of the patients was 61 years. The objective response rate of the 20 patients in the perprotocol group was 30.0% (90% confidence interval [CI], 13.2 to 46.9). The median follow-up duration was 10.0 months, and the median progression-free survival and overall survival were 4.5 months (95% CI, 1.6 to 6.2) and 8.8 months (95% CI, 4.7 to 10.5), respectively. Four of 13 patients (30.8%) evaluated showed initial metabolic response. The median duration of response for partial responders was 5.0 months (range, 3.4 to 8.0 months). The following grade 3/4 treatment-related hematologic toxicities were reported: neutropenia (40.7%), anaemia (22.2%), and thrombocytopenia (7.4%). Two patients experienced febrile neutropenia. The most common grade 3/4 non-hematologic toxicities were asthenia (14.8%) and diarrhoea (11.1%). Conclusion Irinotecan and cisplatin combination chemotherapy showed modest anti-tumour activity and manageable toxicity for patients with metastatic, unresectable esophageal cancer.

Clopidogrel may decrease the risk of post-stroke infection after ischaemic stroke

The P2Y12 receptor, a well‐known factor in the platelet activation pathway, plays a role in thrombosis as well as systemic inflammation. Clopidogrel, a prototype P2Y12 receptor antagonist, reportedly decreases inflammation and systemic infection. The aim of this study was to evaluate whether clopidogrel use decreases the risk of post‐stroke infection following ischaemic stroke.

Response to the comment ‘Long sleep duration: an epiphenomenon or a risk for stroke?’

We thank Dr Nagai and colleagues for their interest in our study and for comments on the correlation between long sleep duration and intracerebral hemorrhage (ICH). They suggested that arterial stiffness and blood pressure variability could be pivotal moderators for the relationship between long sleep duration and ICH risk. Their comments give us an opportunity to consider the relationship between long sleep duration and the risk of ICH from a different point of view. We would reply to their comments as follows. Arterial stiffness associated with long sleep duration might be a possible mechanism to increase risk of ICH. Previous studies suggested that increased sympathetic activity related to sleep fragmentation might lead to arterial stiffening in long sleep duration patients [1,2]. However, sleep fragmentation was not associated with long sleep duration in our study. Therefore, we find no clues that arterial stiffness related to increased activity of the sympathetic nervous system might contribute to the increased risk of ICH [3]. Blood pressure variability could be a moderator for the correlation between long sleep duration and increased risk of ICH [4,5]. Unfortunately we do not have data regarding blood pressure variability in our study subjects to discuss the issue. Future studies would be required to clarify the suggested relationship. Disclosure of conflicts of interest

Abstract 4553: Multiplexed, digital gene expression and fusion transcript analysis to screen for EML4-ALK positive lung cancer

Purpose: EML4-ALK fusions occur in approximately 5% of non-small cell lung carcinoma and define a subpopulation of lung cancer patients highly responsive to ALK kinase inhibitors. Current methodologies for detecting presence of ALK rearrangements are labor-intensive, costly, and not ideally suited for screening large number of patient samples. To allow for a sensitive, facile, and inexpensive methodology to detect EML4-ALK fusions, we developed a direct transcript profiling to detect common variants of EML4-ALK fusions. Experimental Design: Using a single multiplex assay, we simultaneously interrogated presence of EML4-ALK transcripts and ALK 3′ over-expression in 8 ALK-positive and 22 ALK-negative NSCLC samples previously tested by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). For controls, we also tested ALK-positive cancer cells lines NCI-H3122 and NCI-H2228, and an ALK-negative cell line A549. Purified RNA from formalin-fixed paraffin-embedded (FFPE) tissue sections was hybridized in duplicates to a biotinylated capture probe and a color-coded reporter probe designed to hybridize to sequences spanning EML4-ALK junction. In addition, multiple probes were created to hybridize within 5′ and 3′ regions of ALK transcript to detect discordant levels between the breakpoint, indicative of fusion event. Purified hybridization complexes are immobilized and aligned on a cartridge where a microscope CCD camera images and counts the molecular color-coded tags attached to reporter probes. The number of reporter counts corresponds to the number of transcripts being interrogated. Results: With this assay, we obtained 100% concordance in EML4-ALK fusion calls to results generated by FISH and IHC analyses. Similar findings were obtained for control cancer cell lines. The assay is highly reproducible and sensitive, detecting ALK-fusion transcripts even in samples with low tumor content. Using the combined strategy of fusion detection and ALK 5′ and 3′ transcript quantification, we were able to validate the status of one patient negative for ALK rearrangement by FISH but positive for ALK protein expression by IHC. Conclusions: We have developed a novel and sensitive methodology to screen for common EML4-ALK fusions in NSCLC. The assay is inexpensive, easy to perform, high-throughput and compatible with FFPE tissue samples. This is a promising technology highly suitable for screening large numbers of tumor samples without the need for cDNA synthesis and PCR amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4553. doi:1538-7445.AM2012-4553