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Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine‐crystallized fraction (70%) that was developed to combine the rapid‐acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP‐bi‐asp and Novo‐bi‐asp, and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure. This was a phase 1, randomized, double‐blind, 2‐sequence, 2‐period crossover study. Thirty‐four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP‐bi‐asp or Novo‐bi‐asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs. The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins–T) parameters of Gp‐bi‐asp and Novo‐bi‐asp were close to 100% and within the 80%‐125% limits for establishing bioequivalence. The safety profiles of both drugs were also comparable. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether mesna—sodium‐2‐mercaptoethane sulfonate) can reduce diet‐induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. Methods: C3H/HeH mice were shifted to a high‐fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24‐hour urine. Results: Compared with controls, mesna‐treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall =.002), but similar lean mass gain. In men with overweight, mesna doses of 400‐1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post‐dosing). With increasing mesna dose, tCys AUC0‐12h decreased (Ptrend <.001), and urine tCys excretion increased (Ptrend =.004). Conclusions: Mesna reduces diet‐induced fat gain in mice. In men with overweight, single oral doses of mesna (800‐1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys‐lowering by repeated mesna administration on weight loss in humans deserves investigation. [ABSTRACT FROM AUTHOR]

Introduction: Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). Methods: Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML‐LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo‐identical (n = 3) or matched unrelated donors (n = 2). Results: The median cell dose infused was 9 × 106 CD34/kg (range 4.8–12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14–17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non‐relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2–48), two patients have relapsed. Overall survival at 2 years is 80% while the disease‐free survival is 75%. Conclusions: The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML‐LBC. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety/tolerability, efficacy and pharmacokinetics of once‐daily, 600‐μg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher. Materials and Methods: This phase I, randomized, double‐blind, placebo‐controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment‐emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight. Results: Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m2, respectively. Through the follow‐up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal‐related events were the most common TEAEs. Cotadutide‐treated patients achieved significantly improved 7‐day mean glucose measured by continuous glucose monitoring; the 7‐day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were −1.13% (0.64%) and −0.17% (0.65%); and mean percentage changes in body weight were −6.93% (3.44%) and −1.23% (1.20%). Conclusions: Cotadutide was well tolerated at doses up to 600 μg; efficacy versus placebo for weight loss and glycaemic control was shown. [ABSTRACT FROM AUTHOR]

Background: This phase I study aimed to assess the safety, dose‐limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary effect of nanoparticle albumin‐bound (nab)‐paclitaxel in combination with concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced ESCC who were ineligible or refused surgery were enrolled. Nab‐paclitaxel (60 mg/m2, 75 mg/m2, and 90 mg/m2) and cisplatin (25 mg/m2) were administered intravenously weekly on days 1, 8, 15, 22, and 29 on the basis of the 3 + 3 dose escalation method. The total dose of radiation was 50–64 Gy. The primary endpoint was the safety of chemotherapy. Results: The study enrolled 12 patients across three dose levels. No treatment‐related deaths occurred. One patient in the 60 mg/m2 dose level occurred dose‐limiting Grade 3 febrile neutropenia. No DLT was found in the 90 mg/m2 dose level thus the MTD was not reached. The phase II study's recommended dose was 75 mg/m2 based on the available preclinical and clinical data including pharmacokinetics, pharmacodynamics, efficacy, and toxicity. The frequent hematologic toxicities were leukocytopenia (Grade 1–2 of 66.7% and Grade 3–4 of 33.3%), neutropenia (Grade 1–2 of 91.7% and Grade 3–4 of 8.3%). Nonhematologic toxicities were mild and manageable. Overall response rate (ORR) of all patients achieved 100%. Conclusions: Weekly schedule of cisplatin and nab‐paclitaxel in combination with concurrent radiotherapy showed manageable toxicities and promising antitumor activity in patients with locally advanced ESCC. The recommended dose of nab‐paclitaxel for further studies is 75 mg/m2. [ABSTRACT FROM AUTHOR]

Aim: Pyrotinib (an irreversible pan‐ErbB small‐molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)‐positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2‐positive GC. Methods: This multicenter, phase I study followed a standard "3 + 3" design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1‐21, q3W) combined with docetaxel (60 mg/m2, d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel. Results: A total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment‐related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t1/2 was approximately 20 h. Pyrotinib exposure was dose‐dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively. Conclusions: Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2‐positive GC. Trial Registration: This study was registered with ClinicalTrials.gov, NCT02378389. [ABSTRACT FROM AUTHOR]

Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3‐h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients. Twenty‐two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose‐limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/m2, BTZ 1.3 mg/m2, DXM 40.0 mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea/vomiting refractory to antiemetic therapy). Grade ≥ 3 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality. At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%–47.6%), including one stringent complete response, one very good partial response, and two partial responses in r/r patients to BTZ and/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4–93.6%). No major pharmacokinetic drug–drug interaction was found. In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM. [ABSTRACT FROM AUTHOR]

Recently, model‐assisted designs, including the Bayesian optimal interval (BOIN) design with optimal thresholds to determine the dose for the next cohort, have been proposed for cancer phase I studies. Model‐assisted designs are useful because of their good performance as model‐based designs in addition to their algorithm‐based simplicity. In BOIN, escalation and de‐escalation based on boundaries can be understood as a type of change point detection based on a sequential test procedure. Notably, the sequential test procedure is used in a wide range of fields and is known for its application to control charts, statistical monitoring methods used for detecting abnormalities in manufacturing processes. In control charts, abnormalities are detected if the control chart statistics are observed to be outside of the optimal boundaries. The cumulative sum (CUSUM) statistic, which is developed for control chart applications, derives higher power under the same erroneous judgment rate. Hence, it is expected that a more efficient model‐assisted design can be achieved by the application of CUSUM statistics. In this study, a model‐assisted design based on the CUSUM statistic is proposed. In the proposed design, the dose for the next cohort is decided by CUSUM statistics calculated from the counts of the dose‐limiting toxicity and pre‐defined boundaries, based on the CUSUM control chart scheme. Intensive simulation shows that our proposed method performs better than BOIN, and other representative model‐assisted designs, including modified toxicity probability interval (mTPI) and Keyboard, in terms of controlling over‐dosing rates while maintaining similar performance in the determination of maximum tolerated dose. [ABSTRACT FROM AUTHOR]

In this survey, 4 such cases were identified; for 3 drugs (oral to intravenous, oral to intramuscular, and oral to ocular injection) J-PhI study waivers were accepted, but for 1 drug (subcutaneous to intravenous) the waiver was not accepted. For small-molecule drugs, 5 drugs were successfully waived (dosing route: inhalation, ocular instillation, intramuscular, intravenous or subcutaneous injection) due to at least 1 reason in Table 1. Keywords: ethnic sensitivity/difference; dosage regimen; drug dose; Japanese; phase I study; regulatory science EN ethnic sensitivity/difference dosage regimen drug dose Japanese phase I study regulatory science 1410 1418 9 12/13/21 20211201 NES 211201 The pharmacokinetic (PK) and the pharmacodynamic (PD) properties of a drug and correlations of PK and PD with clinical efficacy and safety are important to assess the sensitivity of a drug to potential differences between ethnic groups. [Extracted from the article]

TAS0313, a novel cancer vaccine cocktail, was developed to overcome the disadvantages of previously developed short and long peptide vaccines; it comprises several long peptides targeting multiple cancer antigens. We evaluated TAS0313 monotherapy in Japanese patients with advanced solid tumors for which no other therapies were available. In the dose‐finding cohort, patients received TAS0313 (9 or 27 mg) on days 1, 8, and 15 of cycles 1 and 2, and then on day 1 of each subsequent 21‐day cycle. The primary objective was the evaluation of safety and tolerability. Secondary objectives were evaluation of efficacy, tumor responses, and immune activation (CTL, IgG, and tumor‐infiltrating lymphocyte [TIL] levels). The full analysis set contained 10 patients in the 9‐mg group and seven in the 27‐mg group. No dose‐limiting toxicities were reported in cycle 1. All adverse drug reactions (ADRs) were grade 1 or 2; the most common ADRs were injection site‐related events. The best response was stable disease in four of 17 patients. The median progression‐free survival (PFS) duration was 2.2 (95% confidence interval, 1.0‐2.3) months overall; patients with baseline low lymphocyte counts (≤750/μL) had shorter PFS. Compared with baseline, TILs were increased in five patients. Although CTLs, IgG, and TILs were induced, no correlative pattern with clinical outcomes was observed. The safety, tolerability, and induction of immune responses in patients with advanced solid tumors receiving TAS0313 were confirmed. Further evaluation of TAS0313's efficacy as monotherapy or in combination with pembrolizumab is underway. The study is registered at www.clinicaltrials.jp (JapicCTI‐183824). [ABSTRACT FROM AUTHOR]

Background: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin‐type lymphoma (B‐NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28‐day/cycle manner. Tazemetostat dose‐limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. Results: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B‐cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59‐85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment‐related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment‐related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. Conclusions: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B‐NHL. [ABSTRACT FROM AUTHOR]

Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor‐specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC‐1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose‐escalation was applied (every other week dosing). Twenty‐three patients were treated with ADC‐1013 intratumorally (dosing from 22.5 μg/kg up to 400 μg/kg) or intravenously (dosing at 75 μg/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC‐1013 and cytokine release (MCP‐1, TNFα and IL‐6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC‐1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen‐presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC‐1013 treatment in this mouse model acted synergistically with a PD‐1 inhibitor. The results from the first‐in‐human study of ADC‐1013 indicate that intratumoral administration of ADC‐1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses. What's new? To date, the main mode of delivery of agonistic CD40 antibodies in clinical trials has been through the intravenous route. However, intratumoral administration has the potential to both improve anti‐tumor efficacy and reduce adverse events. Here, the authors conducted a first‐in‐human study of agonistic anti‐CD40 antibody ADC‐1013 in patients with advanced solid tumors. The therapeutic ratio was more favorable for injections into superficial than deep metastases. The study demonstrates dose levels that are safe and provides pharmacokinetic and pharmacodymamic information for clinical studies of other intratumorally delivered antibodies. Moreover, mouse data support future studies combining ADC‐1013 with a PD‐1 inhibitor. [ABSTRACT FROM AUTHOR]

Objectives: Domatinostat (4SC‐202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1‐14 with 7 days off or continuously days 1‐21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty‐four patients were treated with domatinostat. Results: No formal maximum tolerated dose (MTD) was determined. One dose‐limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment‐related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety/tolerability, efficacy and pharmacokinetics of once-daily, 600-μg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m 2 or higher., Materials and Methods: This phase I, randomized, double-blind, placebo-controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight., Results: Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m 2 , respectively. Through the follow-up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal-related events were the most common TEAEs. Cotadutide-treated patients achieved significantly improved 7-day mean glucose measured by continuous glucose monitoring; the 7-day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were -1.13% (0.64%) and -0.17% (0.65%); and mean percentage changes in body weight were -6.93% (3.44%) and -1.23% (1.20%)., Conclusions: Cotadutide was well tolerated at doses up to 600 μg; efficacy versus placebo for weight loss and glycaemic control was shown., (© 2023 AstraZeneca and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

E7777, a recombinant cytotoxic fusion protein comprising diphtheria toxin fragments A and B and human interleukin‐2, shares an amino acid sequence with denileukin diftitox but has improved purity and an increased percentage of active protein monomer species. A phase I study was carried out to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T‐cell lymphoma. E7777 (6, 12, and expanded 9 μg/kg/day) was given to 13 patients by i.v. infusion on five consecutive days per 21‐day cycle. Dose‐limiting toxicities, including increased alanine aminotransferase, hyponatremia (n = 2), hypokalemia, lymphopenia, fatigue, hypoalbuminemia, rash, and increased lipase (n = 1), were observed in all three patients in the 12 μg/kg/day cohort, whereas two of six patients in the 9 μg/kg/day cohort showed decreased appetite or fatigue. The maximum tolerated and recommended dose of E7777 was 9 μg/kg/day for five consecutive days per 21‐day cycle. The objective response rate was 38% (5/13) and did not appear to depend on tumor expression of CD25. E7777 was well tolerated, assuming careful management of adverse events during treatment, and preliminary but clinically meaningful antitumor activity was observed. Subsequent studies of E7777 for T‐cell lymphomas are warranted. This study was registered with www.ClinicalTrials.gov (NCT1401530). [ABSTRACT FROM AUTHOR]

Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity ( DLT) and the recommended dose ( RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with : NCT01208831.) [ABSTRACT FROM AUTHOR]

We carried out a multicenter dose-escalation phase I study of oral OPB-51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory hematological malignancies to evaluate the safety, maximum tolerated dose ( MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB-51602 at doses of 1, 2, 3, 4, and 6 mg in the '3 + 3' dose escalation design. The most common treatment-related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug-related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose-limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1-2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB-51602 was rapidly absorbed, and exposure tended to increase in a dose-dependent manner. Accumulation of OPB-51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB-51602 was 6 mg. OPB-51602 was safe and well tolerated in a dose range of 1-4 mg. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB-51602 for hematological malignancies with a daily dosing schedule was terminated. [ABSTRACT FROM AUTHOR]

We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m2) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m2 nab-paclitaxel on days 1, 8, and 15 with 80 mg/m2 S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy. [ABSTRACT FROM AUTHOR]

A c-Met inhibitor tivantinib is a candidate anticancer agent for patients with hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for tivantinib. Previous Japanese phase I studies in patients with solid tumors (except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this study, Japanese patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID, dose-limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6) and 7 PM (capsule: 4, tablet: 3) during the DLT-observation period (for 29 days after first dosing). At this dose, the pharmacokinetic profiles of tivantinib (AUC0-12 and Cmax) did not remarkably differ between EM and PM. When treated with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed neutropenia-related DLT accompanying plasma tivantinib concentration higher than expected from the previous studies. Consequently, PM did not receive 240 mg BID. In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype. [ABSTRACT FROM AUTHOR]

Background Immune globulin intravenous ( IGIV), 10% is a donor-derived polyclonal human immunoglobulin G antibody mixture that has potent immune modulatory properties and contains conformation selective anti-amyloid antibodies. We evaluated the safety and tolerability of multiple doses of IGIV, 10% in Japanese patients with mild to moderate Alzheimer's disease. Methods Among the 16 subjects, 12 subjects were assigned to the IGIV group and 4 subjects to the placebo group. Subjects received a total of six infusions of either IGIV at a dose of 0.2 or 0.4 g/kg, or placebo every 2 weeks. Results A total of 33 treatment-emergent adverse events ( TEAE) occurred in 14 subjects: 13 TEAE in five subjects in both the IGIV 0.2 and 0.4 g/kg groups, and 7 TEAE in four subjects in the placebo group. The most common TEAE in the IGIV subjects were nasopharyngitis, injection-site swelling, and erythema. All 26 TEAE in the IGIV group were considered to be mild. Only one mild TEAE (rash) was considered to be possibly related to the study drug. There were no significant differences in incidence of TEAE between the treatment groups. Four serious TEAE were reported, and all of these were considered to be unrelated to the study treatment. Other assessments related to safety revealed neither clinically significant abnormal values nor findings in the study. Conclusion IGIV is generally safe and well tolerated with multiple intravenous infusions at doses of 0.2 g/kg and 0.4 g/kg in Japanese patients with mild to moderate Alzheimer's disease. [ABSTRACT FROM AUTHOR]

GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose-limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C-reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose-proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long-term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. Twenty healthy participants received roflumilast, 500 µg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 19. The safety and tolerability of all treatments were also assessed. In 19 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with roflumilast alone. For roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance. [ABSTRACT FROM PUBLISHER]

This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N-oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of roflumilast and roflumilast N-oxide by about 47%. The maximum plasma concentration (Cmax) of roflumilast increased by about 46%, with no effect on Cmax of roflumilast N-oxide. The increase in tPDE4i of roflumilast and roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine. [ABSTRACT FROM PUBLISHER]

Background This study was established to determine the maximum tolerated dose of intra-arterial cisplatin (IAC) concurrent with accelerated fractionation radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). Methods We conducted a phase I study. Treatment consisted of 70 Gy/35 fractions/5.8 weeks and 2 weekly IAC infusions during the last 2 weeks. Results Ten patients were recruited. Two patients had stage III, 1 had stage IVa, and 7 had stage IVb disease. Three patients received IAC at 100 mg/m2, 3 at 125 mg/m2, and 4 at 150 mg/m2. Nine patients received both planned infusions. Dose-limiting toxicity occurred at 150 mg/m2 as transient grade 4 leukopenia and prolonged grade 3 acute skin reactions. The maximum tolerated dose was 125 mg/m2. Six patients survived disease-free at 39 to 67 months. Conclusions It was feasible to give IAC concurrent with accelerated fractionation radiotherapy for locally advanced HNSCC. The maximum tolerated dose of cisplatin was 125 mg/m2. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [ABSTRACT FROM AUTHOR]

Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m2) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3–4 neutropenia was reported in 12 patients, and grade 3–4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study. [ABSTRACT FROM AUTHOR]

The study compared maximum drug concentration (Cmax) and area under the time-concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for Cmax and AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal-human ratios of Cmax were different among animals in both normalizations. Surface area-normalized AUC ratios were not different, whereas weight-normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose-normalized Cmax and AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human Cmax and AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability. [ABSTRACT FROM PUBLISHER]

Interleukin 12 (IL-12) has potential efficacy in malignant, infectious and allergic diseases. Its side-effects include activation of coagulation and fibrinolysis, as documented in chimpanzees. We assessed the coagulative and fibrinolytic response in 18 patients with renal cell carcinoma after subcutaneous injection of 0·5 μg/kg recombinant human IL-12. IL-12 induced a fibrinolytic response in 17 patients (94%): plasmin-α2–anti-plasmin complexes (PAPc) increased from 11·8 ± 6·6 nmol/l (mean ± SD) to a maximum of 18·8 ± 7·4 nmol/l at 72 h. Baseline levels of tissue plasminogen activator (tPA) and plasminogen-activator inhibitor-I (PAI) were elevated in eight and 14 patients respectively. tPA increased from 12·6 ± 5·2 ng/ml to a maximum of 19·0 ± 6·7 ng/ml at 72 h. PAI decreased from 111 ± 69 ng/ml to a minimum of 65 ± 53 ng/ml at 8 h, thereafter remaining below baseline. Elevation of PAPc correlated with elevation of tPA and reduction of PAI. A coagulative response occurred in nine patients (50%): thrombin–anti-thrombin III complexes increased from 29 ± 53 ng/ml to a maximum of 460 ± 322 ng/ml at 12 h. Patients with and without a coagulative response had similar levels of recombinant human IL-12, interferon-γ or tumour necrosis factor-α. We conclude that IL-12 can activate both fibrinolysis and coagulation in a significant proportion of patients with cancer. The time-frame and sequence of these activation processes differ from those known for other cytokines. [ABSTRACT FROM AUTHOR]

Aims The objective of this study was to evaluate the tolerability of a novel dual ACE-NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK). Methods In this randomized, placebo-controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double-blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once. Results Single oral doses of Z13752A, as high as 800 mg, were well tolerated. Only six mild-to-moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses ≥ 100–200 mg. NEP inhibition was indicated by elevation of ANP and cGMP plasma concentrations in almost all subjects. In the 200–800 mg dose range, Z13752A produced a 50–100% increase of plasma cGMP levels and a 50–80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half-life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared to be dose-independent. Conclusions Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in humans. The relatively slow clearance indicates that a once-a-day dose regimen could be considered for Z13752A. [ABSTRACT FROM AUTHOR]

Background Chemoradiotherapy is the standard treatment for locally advanced non-small cell lung cancer ( NSCLC); however, it is disputed whether this treatment is suitable for patients aged ≥75. This study was conducted to determine the maximum tolerated dose ( MTD) of pemetrexed for use in concurrent radiotherapy for elderly patients with locally advanced non-squamous NSCLC. Methods The eligibility criteria were as follows: aged ≥75 with inoperable stage IIIA or IIIB non-squamous NSCLC, no history of chemotherapy or radiotherapy, a performance status of 0 or 1, and adequate organ function. The patients were scheduled to receive pemetrexed on days 1, 22, 43, and 64 with concurrent once daily thoracic radiotherapy (60 Gy). The initial pemetrexed dose was 400 (level 1), and it was planned to increase the dose to 500 mg/m2 (level 2). Results Two patients were enrolled in this trial. In the first case, the patient suffered prolonged leukocytopenia, and treatment was discontinued on day 35. In the second case, febrile neutropenia occurred on day 32, and the patient developed drug-induced pneumonitis and acute respiratory distress syndrome. Both patients experienced dose-limiting toxicities; therefore, the level 1 dose was considered to be the MTD. Conclusions During combined treatment with pemetrexed and concurrent radiotherapy, a pemetrexed dose of 400 mg/m2 was the MTD; we did not set up a phase II study. Concurrent chemoradiotherapy might be too toxic for elderly patients aged ≥75 with locally advanced NSCLC. [ABSTRACT FROM AUTHOR]