Clinical tolerability and pharmacokinetics of troxacitabine / 中华肿瘤杂志

Objective: To investigate the safety and efficacy of troxatabine in advanced or relapsed malignant tumors resistant to standard therapy in China. Methods: This is a phase Ⅰ prospective study. During dose escalation, patients in Cancer Hospital, Chinese Academy of Medical Sciences received a single-dose intravenous infusion of troxacitabine. The planned dosing groups were 1.8, 3.6, 4.8, 6.4 and 8.0 mg/m(2) on days 1 and 8 every 3 weeks. The data of all patients were collected for safety analyses. Safety and tolerability were evaluated by monitoring adverse events. Results: Nineteen patients were enrolled from April 2018 to May 2019. The major adverse events were fatigue (89.5%, 17/19), leukopenia (84.2%, 16/19) and neutropenia (78.9%, 15/19). The dose limiting toxicity was neutropenia. The maximum tolerated dose was 6.4 mg/m(2). The best effect was stable disease (43.8%). The half-life of elimination phase from 15.91 hours to 76.63 hours in each dose group. Conclusions: The toxicity of troxacitabine is well tolerant. We recommend that the dose for Phase Ⅱ clinical trial should be 6.4 mg/m(2).

Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The signal transducer and activator of transcription 3 (STAT3) signaling pathway might be a promising therapeutic target for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was a multicenter, open-label, non-comparative, dose escalating phase I study of OPB-111077, an oral STAT3 inhibitor, in patients with advanced HCC who failed on sorafenib. Continuous dosing (daily administration, 50 to 400 mg) and intermittent dosing (4-days on/3-days off administration: 300 to 900 mg) regimens were evaluated and the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended dose (RD) were the primary endpoints. RESULTS: A total of 33 patients (19 for continuous dosing and 14 for intermittent dosing) were enrolled. One patient experienced a DLT with grade 3 dizziness, but the MTD was identified in neither the continuous nor the intermittent dosing cohorts. The RDs were determined to be 250 mg for the continuous dosing regimen and 600 mg for the intermittent dosing regimen. There was no treatment-related death; five patients (15.2%) had grade 3-4 toxicities including thrombocytopenia (6%), fatigue (3%), and dizziness (3%). No patients achieved complete or partial responses and the median progression-free survival was 1.4 months (95% confidence interval, 0.8 to 2.8). CONCLUSION: OPB-111077 was well tolerated in patients with advanced HCC after sorafenib failure, but only showed limited preliminary efficacy outcomes. Further investigation of the role of the STAT3 signaling pathway in HCC and the development of biomarkers for STAT3 inhibitors are warranted.

Bright Light Therapy in the Morning or at Mid-Day in the Treatment of Non-Seasonal Bipolar Depressive Episodes (LuBi): Study Protocol for a Dose Research Phase I / II Trial

OBJECTIVE: This study protocol aims to determine, using a rigorous approach in patients with bipolar disorder (BD) and non-seasonal major depressive episode (MDE), the characteristics of bright light therapy (BLT) administration (duration, escalation, morning and mid-day exposures) depending on the tolerance (hypomanic symptoms). METHODS: Patients with BD I or II and treated by a mood stabilizer are eligible. After 1 week of placebo, patients are randomized between either morning or mid-day exposure for 10 weeks of active BLT with glasses using a dose escalation at 7.5, 10, 15, 30 and 45 minutes/day. A further follow-up visit is planned 6 months after inclusion. Patients will be included by cohorts of 3, with at least 3 days of delay between them, and 1 week between cohorts. If none meet a dose limiting toxicity (DLT; i.e hypomanic symptoms), the initiation dose of the next cohort will be increased. If one patient meet a DLT, an additionnal cohort will start at the same dose. If 2 or 3 patients meet a DLT, from the same cohort or from two cohorts at the same dose initiation, the maximum tolerated dose is defined. This dose escalation will also take into account DLTs observed during the intra-subject escalation on previous cohorts, with a “Target Ceiling Dose” defined if 2 DLTs occured at a dose. DISCUSSION: Using an innovative and more ergonomic device in the form of glasses, this study aims to better codify the use of BLT in BD to ensure a good initiation and tolerance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03396744.

Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. MATERIALS AND METHODS: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. RESULTS: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). CONCLUSION: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). MATERIALS AND METHODS: Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. RESULTS: Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. CONCLUSION: TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose.

Efficacy of Nasal Cellulose Powder in the Symptomatic Treatment of Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE: Nasal Cellulose Powder (NCP), which can prevent from binding an allergen to nasal mucosa, may reduce allergic rhinitis (AR) symptoms in dust mite-sensitized children. This study was conducted to assess the efficacy of NCP in improving clinical symptoms of a nasal airflow limitation and the response of nasal inflammatory cells. METHODS: Children with dust mite-sensitized AR aged 6–18 years were recruited. After a 4-week run-in period, NCP or a placebo was administered, 1 puff per nostril 3 times daily for 4 weeks. The nasal provocation test (NPT) with Dermatophagoides pteronyssinus (Der p) was performed before and after treatment. The daily symptom scores (DSS), daily medication scores (DMS), the peak nasal inspiratory flows (PNIF), nasal airway resistance (NAR), as well as the maximum tolerated dose of NPT and eosinophil counts in nasal scraping, were evaluated. RESULTS: Sixty children (30 NCP and 30 placebos) were enrolled. Before treatment, there were no significant differences in age, dust mite control measures, DSS, DMS, PNIF, NAR, the maximum tolerated dose of NPT, or nasal eosinophil scores between children receiving NCP and placebos. After treatment, there were no significant differences between the NCP and placebo groups in the median (range) of the outcomes—DSS: 2.06 (0.18–3.77) vs. 1.79 (0.08–7.79), P=0.756; DMS: 1.60 (0–5.13) vs. 0.56 (0–4.84), P=0.239; PNIF (L/min): 110 (60–160) vs. 100 (50–180), P=0.870; NAR (Pa/cm³/s): 0.40 (0.20–0.97) vs. 0.39 (0.24–1.32), P=0.690; the maximum tolerated dose of NPT and the nasal eosinophil scores: 1 (0–4) vs. 1 (0–4), P=0.861. CONCLUSIONS: NCP treatment may not be more effective than placebo treatment in dust mite-sensitized AR children.

An open-label, multicenter, phase I trial of a cremophor-free, polymeric micelle formulation of paclitaxel combined with carboplatin as a first-line treatment for advanced ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG-3016) / 부인종양

OBJECTIVE: This phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer. METHODS: This open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40–75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m², once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group. RESULTS: In this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m² or 260 mg/m², but at 300 mg/m², 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m² or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%. CONCLUSION: Genexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m² or less for a phase II study.

Establishment of one-step approach to detoxification of hypertoxic aconite based on the evaluation of alkaloids contents and quality / 中国天然药物

Aconite is a valuable drug and also a toxic material, which can be used only after detoxification processing. Although traditional processing methods can achieve detoxification effect as desired, there are some obvious drawbacks, including a significant loss of alkaloids and poor quality consistency. It is thus necessary to develop a new detoxification approach. In the present study, we designed a novel one-step detoxification approach by quickly drying fresh-cut aconite particles. In order to evaluate the technical advantages, the contents of mesaconitine, aconitine, hypaconitine, benzoylmesaconine, benzoylaconine, benzoylhypaconine, neoline, fuziline, songorine, and talatisamine were determined using HPLC and UHPLC/Q-TOF-MS. Multivariate analysis methods, such as Clustering analysis and Principle component analysis, were applied to determine the quality differences between samples. Our results showed that traditional processes could reduce toxicity as desired, but also led to more than 85.2% alkaloids loss. However, our novel one-step method was capable of achieving virtually the same detoxification effect, with only an approximately 30% alkaloids loss. Cluster analysis and Principal component analysis analyses suggested that Shengfupian and the novel products were significantly different from various traditional products. Acute toxicity testing showed that the novel products achieved a good detoxification effect, with its maximum tolerated dose being equivalent to 20 times of adult dosage. And cardiac effect testing also showed that the activity of the novel products was stronger than that of traditional products. Moreover, particles specification greatly improved the quality consistency of the novel products, which was immensely superior to the traditional products. These results would help guide the rational optimization of aconite processing technologies, providing better drugs for clinical treatment.

Impact of the beta-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between beta adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study

BACKGROUND/AIMS: We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF). METHODS: One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year. RESULTS: Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the beta-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 +/- 14.3 to 70.0 +/- 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 +/- 2.62 mg vs. 3.96 +/- 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group. CONCLUSIONS: The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring beta-blocker therapy according to genotype.

Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy. MATERIALS AND METHODS: Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. RESULTS: The initial four patients received gemcitabine 1,000 mg/m2 intravenously on days 1 and 8 and cisplatin 70 mg/m2 intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). CONCLUSION: The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.

Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination. MATERIALS AND METHODS: Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months. CONCLUSION: In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

Topical Anaesthesia for Pain Relief during High Dose Rate Brachytherapy for Carcinoma of the Cervix

Purpose: To determine the clinical efficacy of a local anaesthetic spray of 10 xylocaine in reducing pain and discomfort in patients undergoing high dose rate (HDR) brachytherapy. Patients and Method: Ninety two consenting patients diagnosed with cervical cancer and planned for HDR as part of their treatment were enrolled for the study. Each patient had three sessions of brachytherapy following the standard procedures. In the first session all the patients had brachytherapy in the usual manner with conscious Sedation with parenteral diazepam and pentazocine. For the second and third sessions; they had treatment sessions using conscious sedation and 10 xylocaine spray and a control session using conscious sedation and a placebo spray with 0.9 normal saline (NS) respectively. Visual Analogue Scale (VAS) was used in assessing pain during each of the procedure. Results: Only 80 patients completed the study. Their age ranged from 28-70 years with a median age of 54 years. The pre-treatment VAS median scores in the treatment and the control sessions were similar at 0.275 and 0.200. However; the post-procedure median VAS scores were increased to 6.3 in the control group and 3.2 in the xylocaine-treated group (P 0.0001). The haemodynamic status including the blood pressure (BP) and pulse rates (PR) were similar pre and post procedure in both groups. Conclusion: Topical xylocaine spray is efficacious in reducing pain and discomfort in HDR Brachytherapy without any appreciable adverse effect

Tolerance and toxicity of neoadjuvant docetaxel, cisplatin and 5 fluorouracil regimen in technically unresectable oral cancer in resource limited rural based tertiary cancer center.

BACKGROUND: Recent studies indicate neoadjuvant chemotherapy (NACT) can result in R0 resection in a substantial proportion of patients with technically unresectable oral cavity cancers. However, data regarding the efficacy and safety of docetaxel, cisplatin and 5 fluorouracil (TPF) NACT in our setting is lacking. The present audit was proposed to evaluate the toxicities encountered during administration of this regimen. It was hypothesized that TPF NACT would be considered feasible for routine administration if an average relative dose intensity (ARDI) of ≥0.90 or more in at least 70% of the patients. MATERIALS AND METHODS: Technically unresectable oral cancers with Eastern Cooperative Oncology Group PS 0-2, with biopsy proven squamous cell carcinoma underwent two cycles of NACT with TPF regimen. Toxicity and response rates were noted following the CTCAE 4.03 and RECIST criteria. Descriptive analysis of completion rates (completing 2 cycles of planned chemotherapy with ARDI of 0.85 or more), reason for delay, toxicity, and response are presented. RESULTS: The NACT was completed by all patients. The number of subjects who completed all planned cycles of chemotherapy are with the ARDI of the delivered chemotherapy been equal to or >0.85 was 11 (91.67%). All toxicity inclusive Grade 3-5 toxicity was seen in 11 patients (91.67%). The response rate of chemotherapy was 83.33%. There were three complete response, seven partial response, and two stable disease seen post NACT in this study. CONCLUSION: Docetaxel, cisplatin and 5 fluorouracil regimen can be routinely administered at our center with the supportive care methods and precautionary methods used in our study.

Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer.

CONTEXT: Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies. AIMS: To determine the safety, doselimiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD). SETTINGS AND DESIGN: Phase 1, open-label, dose-escalation study in men and women ≥18 years of age. MATERIALS AND METHODS: An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD). STATISTICAL ANALYSIS USED: All data summaries were descriptive. PK parameters were estimated using compartmental analysis. RESULTS: 25 patients (16 male, 9 female, 26- 66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days. CONCLUSIONS: 2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.

Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy.

OBJECTIVE: To study the safety and efficacy of weekly chemotherapy as part of induction chemotherapy, in locally advanced head and neck cancer for patients, who are unfit for upfront radical treatment. MATERIALS AND METHODS: It is a retrospective analysis of on‑use weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer, who are technically unresectable are unfit for upfront radical treatment. Induction chemotherapy given was a 2 drug combination of paclitaxel (80 mg/m2) and carboplatin AUC 2. The decision to give weekly induction chemotherapy was given on the basis of presence of 2 more following features: Poor performance status (ECOG PS 2‑3), presence of uncontrolled co morbidities, BMI below 18.5 kg/m2 and age more than 60 years. The Statistical Package for the Social Sciences software (SPSS version 16.0) was used for analysis. The response rates, toxicity (accordance with CTCAE vs. 4.02), completion rate (Cp) of radical intent treatment post neoadjuvant chemotherapy (NACT), progression‑free survival (PFS) and overall survival (OS) are reported. RESULTS: Fifteen patients were considered for such therapy. Fourteen out of fifteen patients completed NACT. The median numbers of planned weekly cycles were 6 (3-8). Response (CR + PR) was seen in 10 patients. Overall grade 3-4 toxicity was seen in 6 patients. No toxicity related mortality was noted. The calculated completion rate (Cp) of radical intent treatment post NACT was 46.7%. The median PFS and OS were 10.36 months (95% CI 6.73-14.00 months) and 16.53 months (95% CI 4.22-28.84). CONCLUSION: Use of induction chemotherapy with weekly regimen is safe and effective selected cohort of patients with locally advanced disease who are unfit for upfront radical treatment.

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. MATERIALS AND METHODS: Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2. RESULTS: A total of twenty-four patients were enrolled. Only one patient experienced a dose-limiting toxicity-a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration-time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. CONCLUSION: The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2.

Avaliacao da seguranca de diferentes doses de suplementos de acido folico em mulheres do Brasil / Evaluacion de la seguridad de uso de diferentes dosis de suplementos de acido folico en mujeres de Brasil / Evaluation of the safety of different doses of folic acid supplements in women in Brazil

OBJETIVO Avaliar a distribuição da ingestão de ácido fólico e a segurança de diferentes doses de suplementos em mulheres em idade reprodutiva. MÉTODOS Foram utilizados dados de consumo a partir de dois dias não consecutivos de registro alimentar de 6.837 mulheres em idade reprodutiva (19 a 40 anos) participantes do Inquérito Nacional de Alimentação, módulo da Pesquisa de Orçamentos Familiares 2008-2009. Médias e percentis de consumo habitual de folato natural e ácido fólico foram estimados utilizando o método do National Cancer Institute . Cinco cenários foram simulados somando-se diferentes doses diárias de fortificação (400 mcg, 500 mcg, 600 mcg, 700 mcg e 800 mcg) ao ácido fólico oriundo dos alimentos consumidos pelas mulheres. Comparou-se o total de ácido fólico (dieta + suplemento) com o nível máximo de ingestão tolerável (UL = 1.000 mcg) para definir a dose segura de suplementação. RESULTADOS Mulheres com ingestão habitual de ácido fólico acima do nível máximo de ingestão tolerável foram observadas para doses de suplemento de 800 mcg (7,0% das mulheres). Abaixo desse valor, qualquer dose de suplementação mostrou-se segura. CONCLUSÕES O uso de suplementos de até 700 mcg de ácido fólico mostrou-se seguro. .

OBJETIVO Evaluar la distribución de ingesta de ácido fólico y la seguridad de diferentes dosis de suplementos en mujeres en edad reproductiva. MÉTODOS Se utilizaron datos de consumo a partir de dos días no consecutivos de registro alimentario de 6.837 mujeres en edad reproductiva (19 a 40 años) participantes en la Investigación Nacional de Alimentación, módulo de la Investigación de Presupuestos Familiares 2008-2009. Promedios y percentiles de consumo habitual de folato natural y ácido fólico fueron estimados utilizando el método del National Cancer Institute. Cinco escenarios fueron simulados sumándose diferentes dosis diarias de fortificación (400 mcg, 500 mcg, 600 mcg, 700 mcg y 800 mcg) al ácido fólico oriundo de los alimentos consumidos por las mujeres. Se comparó el total de ácido fólico (dieta + suplemento) con el nivel máximo tolerable de ingestión (UL= 1.000 mcg) para definir la dosis segura de suplementación. RESULTADOS Mujeres con ingestión habitual de ácido fólico por encima del nivel máximo tolerable de ingestión fueron observadas para dosis de suplemento de 800 mcg (70% de las mujeres). Por debajo de ese valor, cualquier dosis de suplementación se mostró segura. CONCLUSIONES El uso de suplementos hasta 700 mcg de ácido fólico se evidenció seguro. .

OBJECTIVE To evaluate the distribution of folic acid intake and the safety of different doses of supplements in women of childbearing age. METHODS Data were used from two non-consecutive days of food records of 6,837 women of childbearing age (19-40 years old) participants of the National Food Survey, a module of the Household Budget Survey 2008-2009. Means and percentiles of usual consumption of natural folate and folic acid were estimated using the National Cancer Institute method. Five scenarios were simulated by adding different daily doses of fortification (400 mcg, 500 mcg, 600 mcg, 700 mcg and 800 mcg) to folic acid derived from food consumed by the women. To define a safe dose of the supplement, the total folate (dietary + supplement) was compared with the tolerable upper intake level (UL = 1,000 mcg). RESULTS Women with usual intake of folic acid above the tolerable upper intake levels were observed only for doses of supplement of 800 mcg (7.0% of women). Below this value, any dose of the supplement was safe. CONCLUSIONS The use of supplements of up to 700 mcg of folic acid was shown to be safe. .

A phase I/II study of bortezomib plus CHOP every 2 weeks (CHOP-14) in patients with advanced-stage diffuse large B-cell lymphomas / 대한혈액학회지

BACKGROUND: Bortezomib targets molecular dysregulation of nuclear factor-kappaB activation and cell cycle control, which are characteristic features of diffuse large B-cell lymphoma (DLBCL). We evaluated the safety and efficacy of bortezomib treatment with dose-dense cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) every 2 weeks (CHOP-14). METHODS: Untreated DLBCL patients were enrolled. A phase I dose-escalation study with 1.0, 1.3, and 1.6 mg/m2 bortezomib administration on day 1 and 4 in addition to the CHOP-14 regimen was performed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Lenograstim 5 microg/kg/d was administered on day 4-13. The bortezomib dose from the phase I study was used in the phase II study. RESULTS: Nine and 37 patients were enrolled in the phase I and phase II studies, respectively. The analysis of the phase II results (40 patients) included data of the 3 patients in the last MTD dose cohort of the phase I trial. During the phase I trial, no DLT was observed at any bortezomib dose; therefore, the recommended dose was 1.6 mg/m2. In phase II, the overall response rate was 95% (complete response: 80%; partial response: 15%). Nine out of the 40 patients showed grade 3 sensory neuropathy, and 22 required at least 1 dose reduction. Three patients could not complete the intended 6 cycles of treatment because of severe neuropathy. CONCLUSION: Bortezomib plus CHOP-14 was highly effective for the treatment of untreated DLBCL patients, but in many cases, dose or schedule modification was required to reduce neurotoxicity.

The evolution of phase I trials in cancer medicine: a critical review of the last decade / 癌症

The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.