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Background: We investigated the clinical outcomes of involved‐field high‐dose (≥66 Gy) chemoradiotherapy (CRT) combined with respiratory motion management for esophageal squamous cell carcinoma (ESCC). Methods: Patients who underwent definitive CRT for histologically confirmed ESCC in our department between 2012 and 2018 were retrospectively analyzed. Respiratory motion management strategies included breath‐holding (63%) and mask immobilization (29%) based on individual measurements of respiratory tumor motion using radiographic fluoroscopy with endoscopically placed clip markers as landmarks. We evaluated patient characteristics, treatment efficacy, failure patterns, and toxicities. Results: We enrolled 35 patients with a prescribed dose of 66–70 Gy in 33–35 fractions. The overall response rate within 6 months post‐CRT was 94.3%; the median follow‐up period for survivors was 43 months. The 2‐year overall survival (OS), progression‐free survival, and locoregional failure‐free survival rates were 51.4%, 42.9%, and 42.9%, respectively. A significant difference in OS was observed between patients with and without esophageal fistulas after CRT (p = 0.002, log‐rank test). Disease failure occurred in 16 patients (45.7%), including one (2.9%) with out‐of‐field regional nodal failure. Major grade 3 or higher toxicities included decreased white blood cell count (48.6%), neutrophil count (34.3%), and esophageal stenosis (31.4%). No grade 3 or higher cardiopulmonary toxicities were observed. Bronchial/tracheal tumor compression and a higher radiotherapy dose (70 Gy) were significantly correlated with esophageal fistulas. Conclusion: Involved‐field high‐dose CRT with respiratory motion management may be a feasible treatment option for ESCC. However, a comprehensive assessment of esophageal fistula risk is required to identify suitable candidates. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the radiotherapy planning feasibility of dose escalation with intensity‐modulated proton therapy (IMPT) to hypoxic tumor regions identified on 18F‐Fluoromisonidazole (FMISO) positron emission tomography and computed tomography (PET‐CT) in NPC. Materials and methods: Nine patients with stages T3‐4N0‐3M0 NPC underwent 18F‐FMISO PET‐CT before and during week 3 of radiotherapy. The hypoxic volume (GTVhypo) is automatically generated by applying a subthresholding algorithm within the gross tumor volume (GTV) with a tumor to muscle standardized uptake value (SUV) ratio of 1.3 on the 18F‐FMISO PET‐CT scan. Two proton plans were generated for each patient, a standard plan to 70 Gy and dose escalation plan with upfront boost followed by standard 70GyE plan. The stereotactic boost was planned with single‐field uniform dose optimization using two fields to deliver 10 GyE in two fractions to GTVhypo. The standard plan was generated with IMPT with robust optimization to deliver 70GyE, 60GyE in 33 fractions using simultaneous integrated boost technique. A plan sum was generated for assessment. Results: Eight of nine patients showed tumor hypoxia on the baseline 18F‐FMISO PET‐CT scan. The mean hypoxic tumor volume was 3.9 cm3 (range.9–11.9cm3). The average SUVmax of the hypoxic volume was 2.2 (range 1.44–2.98). All the dose‐volume parameters met the planning objectives for target coverage. Dose escalation was not feasible in three of eight patients as the D0.03cc of temporal lobe was greater than 75GyE. Conclusions: The utility of boost to the hypoxic volume before standard course of radiotherapy with IMPT is dosimetrically feasible in selected patients. Clinical trials are warranted to determine the clinical outcomes of this approach. [ABSTRACT FROM AUTHOR]

Background: High‐dose‐rate (HDR) brachytherapy (BT) has been acknowledged as a widely utilized treatment for patients with intermediate‐ and high‐risk prostate cancer, despite its side effects such as edema, incontinence, and impotence. Nevertheless, the treatment is consistently limited by the potential danger of excessive irradiation to organs‐at‐risk (OARs) like the urethra, bladder, and rectum. Purpose: This study aims to introduce curvilinear catheter implantation in the prostate gland for HDR treatment. The objective is to improve the radiation dose distribution by offering access channels conformal to the prostate anatomy. This approach seeks to minimize toxicity to nearby OARs while utilizing a reduced number of needles, potentially leading to improved clinical outcomes. Methods: Curvilinear catheters were first pre‐planned for an anonymized patient using Oncentra treatment planning system (TPS) and hybrid inverse planning optimization (HIPO) algorithm. The trajectories of the catheters were then analyzed using MATLAB to extract their radius of curvature. Tendon‐driven active needles were then used to implant curvilinear catheters inside an anthropomorphic phantom. Results: Proposed curvilinear catheter implantation resulted in significant improvement in terms of dosimetric constraints to the OARs and coverage to the prostate. Tendon‐driven active needles were shown to be capable of realizing the required pre‐planned curvatures inside prostate. It was shown that the active needle can realize a desired radius of curvature and a desired trajectory with an average accuracy of 9.1 ± 8.6 and 1.27 ± 0.50 mm in air and inside a tissue‐mimicking phantom, respectively. Conclusion: This work demonstrates the feasibility of using tendon‐driven active curvilinear catheter implantation in prostate to improve the outcomes of HDR‐BT via improved radiation dose distribution to the prostate and reduced toxicity to the OARs. [ABSTRACT FROM AUTHOR]

Introduction: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80–0.91; p < 0.001) with longer OS versus CDR. Discussion and Conclusions: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real‐world results additionally provide an estimate of effect size of EDR for future prospective trials. [ABSTRACT FROM AUTHOR]

Patients receiving interleukin (IL)‐inhibiting biologics for moderate‐to‐severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL‐inhibiting biologic treatment and ≥1 post‐induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non‐persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL‐inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable‐adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS. [ABSTRACT FROM AUTHOR]

Background: Approximately 40% of patients with hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer (ABC) exhibit PIK3CA mutations. Aims: This study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of HS‐10352, a selective PI3Kα inhibitor, in this patient population. Materials and Methods: Conducted as a phase 1 dose‐escalation trial, HS‐10352 was administered orally once‐daily (QD) at dose levels of 2, 4, 6, and 8 mg. The primary endpoints were dose‐limiting toxicity (DLT) and the maximum tolerated dose (MTD). This study is registered at ClinicalTrials.gov (NCT04631835). Results: Between August 2020 and March 2022, a total of 18 female patients were enrolled. DLT, manifested as hyperglycemia, occurred in two patients in the 8 mg QD group, establishing an MTD of 6 mg QD. The most common treatment‐related adverse events were hyperglycemia (88.9%) and weight loss (61.3%). In the 6 mg QD group, four patients (66.7%) had a partial response (PR), and one (16.7%) had stable disease (SD). Among the four patients with PIK3CA mutated tumors in this dosage group, three (75.0%) had PR and one (25.0%) had SD. The median progression‐free survival was not reached (95% confidence interval, 11.1‐NA). Discussion and Conclusion: HS‐10352 at 6 mg QD was well‐tolerated in patients with HR‐positive, HER2‐negative ABC, and showed preliminary antitumor activity in patients with PIK3CA mutated tumors. These findings support the further clinical development of HS‐10352. [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]

We evaluated the safety and tolerability of AXA1665, a novel investigational fixed‐ratio amino acid (AA) composition, the pharmacokinetics (PK) of the constituent AAs within AXA1665, and their relative bioavailability versus standard protein supplement. This study was conducted in 2 phases; in the initial phase, healthy subjects (N = 16) were randomly assigned to 4 treatment sequences (AXA1665 4.9, 9.8, and 19.6 g or 35 g protein supplement) in an open‐label, single‐dose, 4‐way crossover study, while in the extension phase, they received single AXA1665 doses of 29.4 and 39.2 g in a sequential crossover manner. The net area under the plasma concentration–time curve (AUC) and observed time to reach maximum plasma concentration were estimated. A dose‐dependent increase in plasma AUC from time 0 to the last measurable concentration (AUClast) and maximum plasma concentration (Cmax) was observed for all AXA1665‐dosed AAs (4.9–39.2 g) except aspartic acid. AXA1665 19.6 g resulted in 1.5‐ to 9.5‐fold higher systemic exposure to all AXA1665‐dosed AAs except for aspartic acid and lysine and lower exposure to all nondosed AAs except for glutamine and alanine versus protein supplement. AXA1665 doses, up to 39.2 g, can deliver AXA1665‐dosed AAs in the systemic circulation in the linear AUC range. [ABSTRACT FROM AUTHOR]

We report the safety and pharmacokinetic properties of the HIV‐1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first‐in‐human, double‐blind, randomized, placebo‐controlled, single‐ (part 1) and multiple‐ (part 2) dose escalation study with an additional open‐label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10–800 mg) in part 1, up to 18 once‐daily 25‐ to 100‐mg or 3 once‐weekly 500‐mg doses in part 2, and single 100‐mg doses as powder‐in‐bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety‐one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug‐related AEs were gastrointestinal (14/17, 82%). The terminal phase half‐life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose‐proportional increases during part 1. Accumulation in exposure following repeat dosing was 6‐ to 7‐fold with daily dosing and ~1.7‐fold after weekly treatment, as expected due to the long half‐life. Bioavailability of GSK'937 after a meal was 1.35‐ to 1.40‐fold greater as a tablet versus powder‐in‐bottle and >2‐fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose‐limiting safety events occurred. Pharmacokinetic parameters of long half‐life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684. [ABSTRACT FROM AUTHOR]

Introduction: The study aimed to evaluate the efficacy and safety of dose‐escalated stereotactic body radiotherapy (SBRT) for primary lung cancer. Methods: Patients with peripherally located T1‐2N0M0 primary lung cancer who underwent SBRT from April 2013 to December 2019 were included. Group A received 60 Gy in five fractions with CyberKnife prescribed at 99% gross tumor volume. Group B received 48 Gy in four fractions by a gantry‐mounted linear accelerator, with isocenter prescription. Cumulative incidence of local failure (LF), progression free survival (PFS), overall survival (OS), and toxicity were retrospectively compared. Results: Groups A and B comprised 39 and 36 patients, respectively. Group A had more patients without histological confirmation (p <.001) and showed lower V20 of bilateral lungs (p =.025). The median follow‐up duration of Group A and B was 22.0 and 21.5 months, respectively, and the 2‐year cumulative incidence of LF, PFS, and OS were.0% versus 11.6% (p =.065), 66.2% versus 62.7% (p =.694), 84.1% versus 81.1% (p =.827), respectively. There was no difference in Grade ≥ 2 toxicity rate between Groups A and B (7.7% vs. 11.1%; p =.704). Conclusion: Dose‐escalated SBRT using CyberKnife showed reduced lung dose and potential benefits for improved local control with comparable toxicity. [ABSTRACT FROM AUTHOR]

Retinoic acid receptor–related orphan nuclear receptor (ROR)γt regulates the transcription of interleukin‐17 and other cytokines implicated in inflammatory and autoimmune diseases. We assessed the safety, tolerability, and pharmacokinetics (PK) of IMU‐935, an inverse agonist of RORγt, in a first‐in‐human phase 1 study. This was a double‐blind, placebo‐controlled trial that randomly assigned healthy subjects single ascending doses (25–400 mg) or multiple ascending doses (150 mg once or twice daily for 14 days) of IMU‐935 or placebo. Dose escalation was determined by the safety, tolerability, and PK. Twenty‐four and 70 subjects received placebo or IMU‐935, respectively. Of the 70 subjects who received IMU‐935, 59 received a single dose and 11 received multiple doses. Treatment‐emergent adverse events (TEAEs) occurred in 21 subjects (88%) and 58 (83%) given any dose of placebo or IMU‐935, respectively. Treatment‐related TEAEs occurred in 6 (30%) and 25 (42%) subjects given a single dose of placebo and IMU‐935, respectively. All treatment‐related TEAEs were mild except for 2 moderate TEAEs and 1 moderate TEAE in the IMU‐935 group and placebo group, respectively. No treatment‐related discontinuations or serious adverse events occurred. The PK of IMU‐935 were dose proportional with a half‐life of ≈24 hours. In conclusion, IMU‐935 was safe with no dose‐limiting toxicities and had a PK profile that supports once‐daily dosing. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to determine the impact of dosage in new users of lamotrigine (LTG) and the concomitant intake of valproic acid (VPA) on epidermal necrolysis (EN). Methods: A total of 102 EN cases with exposure to LTG were identified (1992–2018) in the German Registry of Severe Skin Reactions. All cases are validated by an independent expert committee. Six cases were excluded due to lack of exposure in the relevant time frame. Causality assessment was performed with ALDEN (Algorithm for Assessment of Drug Causality in EN) on definite/probable cases (≥12 years; n = 84). Evaluation of dosing regimen was restricted to cases with complete LTG dosing history (n = 74). Results: Demography showed a mean age of 42.4 years, female predominance (69%), and low mortality (7.3%). Epilepsy was the indication for use in 87.5%. LTG was the very probable cause in 71.4% and probable cause in 28.6%. On average, one additional antiseizure medication was taken, most frequently VPA (43/84). Combined LTG/VPA treatment showed no statistically significant difference in morbidity or mortality. Mean time latency from initiation of LTG to reaction onset was 24.2 days, varying between 21 days with high initial dose and 29.2 days with low initial dose. Low initial LTG dose (n = 9) revealed higher mortality (22.2%) and higher severity (5/9) than high initial dose (n = 35, mortality = 14.3%, 14/35 higher severity). No patient died when the starting dose was as recommended. The highest mortality (25%) was found in patients with no dose increase (n = 8), which correlated with higher age. Despite the recommended or low initial dose, 52.7% of patients developed EN, in contrast to 39.2% with a slow, recommended, or no dose escalation. Significance: Neither the initial dose, dose escalation, nor the combination with VPA seems to influence the general occurrence of EN. However, EN patients with the recommended starting dose and the recommended dose escalation had the best outcome in terms of clinical severity and mortality. [ABSTRACT FROM AUTHOR]

Dose‐finding designs for phase‐I trials aim to determine the recommended phase‐II dose (RP2D) for further phase‐II drug development. If the trial includes patients for whom several lines of standard therapy failed or if the toxicity of the investigated agent does not necessarily increase with dose, optimal dose‐finding designs should limit the frequency of treatment with suboptimal doses. We propose a two‐stage design strategy with a run‐in intra‐patient dose escalation part followed by a more traditional dose‐finding design. We conduct simulation studies to compare the 3 + 3 design, the Bayesian Optimal Interval Design (BOIN) and the Continual Reassessment Method (CRM) with and without intra‐patient dose escalation. The endpoints are accuracy, sample size, safety, and therapeutic efficiency. For scenarios where the correct RP2D is the highest dose, inclusion of an intra‐patient dose escalation stage generally increases accuracy and therapeutic efficiency. However, for scenarios where the correct RP2D is below the highest dose, intra‐patient dose escalation designs lead to increased risk of overdosing and an overestimation of RP2D. The magnitude of the change in operating characteristics after including an intra‐patient stage is largest for the 3 + 3 design, decreases for the BOIN and is smallest for the CRM. [ABSTRACT FROM AUTHOR]

This study evaluates the feasibility of the pencil beam scanning technique of carbon ion radiotherapy (CIRT) in the setting of hepatocellular carcinoma (HCC) and establishes the maximum tolerated dose (MTD) calculated by the Local Effect Model version I (LEM‐I) with a dose escalation plan. The escalated relative biological effectiveness‐weighted dose levels included 55, 60, 65, and 70 Gy in 10 fractions. Active motion management techniques were employed, and several measures were applied to mitigate the interplay effect induced by a moving target. CIRT was planned with the LEM‐I‐based treatment planning system and delivered by raster scanning. Offline PET/CT imaging was used to verify the beam range. Offline adaptive replanning was performed whenever required. Twenty‐three patients with a median tumor size of 4.3 cm (range, 1.7–8.5 cm) were enrolled in the present study. The median follow‐up time was 56.1 months (range, 5.7–74.4 months). No dose limiting toxicity was observed until 70 Gy, and MTD had not been reached. No patients experienced radiation‐induced liver disease within 6 months after the completion of CIRT. The overall survival rates at 1, 3, and 5 years were 91.3%, 81.9%, and 67.1% after CIRT, respectively. The local progression‐free survival and progression‐free survival rates at 1, 3 and 5 years were 100%, 94.4%, and 94.4% and 73.6%, 59.2%, and 37.0%, respectively. The raster scanning technique could be used to treat HCC. However, caution should be exercised to mitigate the interplay effect. CIRT up to 70 Gy in 10 fractions over 2 weeks was safe and effective for HCC. [ABSTRACT FROM AUTHOR]

The Continual Reassessment Method (CRM) was developed for Phase I trials to identify a maximum‐tolerated dose of an agent using a design in which each participant is treated with a single administration of the agent. We propose an extension of the CRM in which participants receive multiple administrations of an agent using a so‐called step‐up dosing procedure in which participants receive one or more administrations of lower doses of the agent before they receive their penultimate dose. We use methods developed for the CRM to model the probability of DLT for each administration, which leads to the use of conditional probability models to model the joint probability of DLT across multiple administrations. We compare our approach to two existing methods that use time‐to‐event modeling methods for modeling the probability of DLT. We demonstrate through simulations that our approach has operating characteristics similar to existing methods, but due to its foundations in the CRM, ours is simpler to implement than existing approaches and is therefore more likely to be adopted in practice. [ABSTRACT FROM AUTHOR]

Rivoceranib is a selective inhibitor of VEGFR‐2 being developed for the treatment of solid tumor. The objective of the study was to evaluate the effect of food on bioavailability as well as single‐ and multiple‐dose pharmacokinetics (PKs) of 81 and 201 mg doses of rivoceranib. The study was conducted as a two‐part study. In Part 1 (single ascending dose (SAD), open‐label, crossover study design), 2 oral doses of rivoceranib (81 mg or 201 mg) were given to all healthy subjects with a minimum 3‐day washout period between dosing. Part 2 was a multiple ascending dose (MAD), open‐label, crossover design where subjects were divided based on 81 and 201 mg doses. Both doses were administered with and without food in a crossover manner for the SAD and MAD parts. 24 healthy subjects completed Part 1 and 20 subjects completed Part 2. For the 81 mg dose in the SAD and MAD parts of the study, their food effect was not observed. For the 201 mg dose in both parts, food appeared to increase bioavailability by 20%–30% in Part 1, and 30%–40% in Part 2. Median tmax value was delayed when rivoceranib was administered with food at each dose level in both parts of the study. Dose proportionality was confirmed only for the AUC0‐∞ value from Part 1‐fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. In conclusion, rivoceranib when taken with food delays tmax appears to increase bioavailability at 201 mg dose. [ABSTRACT FROM AUTHOR]

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5‐fold, and solanezumab was increased 4‐fold. We evaluated to what extent mid‐trial dose increases produced a dose‐dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low‐ and high‐dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose‐dependent treatment effects (significant for gantenerumab, non‐significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose‐dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid‐trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose‐dependent treatment effect of two different amyloid‐specific immunotherapies.Dose‐dependent treatment effects were observed in some biomarkers.No dose‐dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations. [ABSTRACT FROM AUTHOR]

Background: To inform patients who are in the process of selecting prostate cancer treatment, the authors compared disease‐specific function after external‐beam radiotherapy (EBRT) alone versus EBRT plus a low‐dose‐rate (LDR) brachytherapy boost (EBRT‐LDR). Methods: For this prospective study, men who had localized prostate cancer in 2011 and 2012 were enrolled. Assessments at baseline, 0.5, 1, 3, and 5 years included the patient‐reported Expanded Prostate Index Composite, the 36‐item Medical Outcomes Study Short‐Form Health Survey, and treatment‐related regret. Regression models were adjusted for baseline function and for patient and treatment characteristics. The minimum clinically important difference in scores on the Expanded Prostate Index Composite 26‐item instrument was from 5 to 7 for urinary irritation and from 4 to 6 for bowel function. Results: Six‐hundred ninety‐five men met inclusion criteria and received either EBRT (n = 583) or EBRT‐LDR (n = 112). Patients in the EBRT‐LDR group were younger (median age, 66 years [interquartile range [IQR], 60‐71 years] vs 69 years [IQR, 64‐74 years]; P <.001), were less likely to receive pelvic radiotherapy (10% vs 18%; P =.040), and had higher baseline 36‐item Medical Outcomes Study Short‐Form Health Survey physical function scores (median score, 95 [IQR, 86‐100] vs 90 [IQR, 70‐100]; P <.001). Over a 3‐year period, compared with EBRT, EBRT‐LDR was associated with worse urinary irritative scores (adjusted mean difference at 3 years, −5.4; 95% CI, −9.3, −1.6) and bowel function scores (−4.1; 95% CI, −7.6, −0.5). The differences were no longer clinically meaningful at 5 years (difference in urinary irritative scores: −4.5; 95% CI, −8.4, −0.5; difference in bowel function scores: −2.1; 95% CI, −5.7, −1.4). However, men who received EBRT‐LDR were more likely to report moderate or big problems with urinary function bother (adjusted odds ratio, 3.5; 95% CI, 1.5‐8.2) and frequent urination (adjusted odds ratio, 2.6; 95% CI, 1.2‐5.6) through 5 years. There were no differences in survival or treatment‐related regret between treatment groups. Conclusions: Compared with EBRT alone, EBRT‐LDR was associated with clinically meaningful worse urinary irritative and bowel function over 3 years after treatment and more urinary bother at 5 years. Lay Summary: In men with prostate cancer who received external‐beam radiation therapy (EBRT) with or without a brachytherapy boost (EBRT‐LDR), EBRT‐LDR was associated with clinically worse urinary irritation and bowel function through 3 years but resolved after 5 years.Men who received EBRT‐LDR continued to report moderate‐to‐big problems with urinary function bother and frequent urination through 5 years.There was no difference in treatment‐related regret or survival between patients who received EBRT and those who received EBRT‐LDR.These intermediate‐term estimates of function may facilitate counseling for men who are selecting treatment. Among men with prostate cancer who receive external‐beam radiation therapy with or without brachytherapy boost, a clinically worse decline in urinary irritation and bowel function is observed through 3 years in the brachytherapy group. Through 5 years, these symptoms are no longer clinically meaningful; however, patients in the brachytherapy group continue to report moderate‐to‐large problems with urinary function bother and frequent urination. [ABSTRACT FROM AUTHOR]

Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1‐oleate, formed by a synthetic, alpha‐helical peptide comprising the N‐terminal 39 amino acids of alpha‐lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1‐oleate (1.7‐17 mM) on days 3 to 11. A dose‐dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1‐oleate treated group, compared to sham‐treated mice. Tumor markers Ki‐67, Cyclin D1 and VEGF were inhibited in a dose‐dependent manner, as was the expression of cancer‐related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1‐oleate‐treated, tumor‐bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose‐dependent therapeutic effect of alpha1‐oleate in a murine bladder cancer model. What's new? Tumor resection is a standard treatment for bladder cancer and often is followed by adjuvant intravesicle chemotherapy or immunotherapy. These treatments, however, frequently are accompanied by significant side effects. Here, the authors explore the effects of the peptide‐fatty acid complex alpha1‐oleate, previously reported to possess tumoricidal activity and a promising agent for the treatment of non‐muscle invasive bladder cancer. Compared to untreated mice, animals treated with alpha1‐oleate experienced a dose‐dependent reduction in tumor size, without evidence of local or systemic toxicity. The findings provide essential background for clinical trials examining the effects of alpha1‐oleate in humans. [ABSTRACT FROM AUTHOR]

Background: In this study, we aim to present the clinical outcomes of radiotherapy (RT) in clinical pelvic lymph node‐positive prostate cancer (cN1) patients. We also analyze the prognostic factors with focus on RT dose escalation to metastatic lymph nodes (LN). Methods: We retrospectively analyzed the data from cN1 patients who were treated with definitive RT and androgen deprivation therapy (ADT) between June 2004 and February 2016. All patients received localized irradiation to the prostate region and whole pelvis irradiation. Some patients received intensity‐modulated radiation therapy with RT dose escalation to metastatic LN. Univariate analyses using log‐rank test were performed to find prognostic factors between patient subgroups. Results: Fifty‐one consecutive patients were identified. The median follow‐up period for all patients was 88 (range 20‐157) months. Primary Gleason pattern and LN RT dose were statistically significant prognostic factors for relapse‐free survival (RFS) and distant metastasis‐free survival (DMFS). Especially, RT dose escalation (60 Gy or more) to metastatic LN significantly improved RFS and DMFS compared with standard dose RT (4‐year RFS 90.6% vs 82.1%, 7‐year RFS 90.6% vs 58.0%, P =.015; 4‐year DMFS 90.6% vs 82.1%, 7‐year DMFS 90.6% vs 62.8%, P =.023). The following factors were all statistically significant for biochemical relapse‐free survival (BRFS): T stage, LN RT dose, local RT dose, and ADT duration period. Any significantly different toxicity was not seen for each LN or local RT dose except for the incident rate of grade 2 or more acute urinary retention, which was significantly higher in the higher LN RT dose (60 Gy or more) group by the Chi‐square test. Conclusions: RT dose escalation to metastatic LN in cN1 patients improves BRFS, RFS, and DMFS at 4 and 7 years, without increasing severe adverse events. [ABSTRACT FROM AUTHOR]

Purpose: To introduce the definite target volume (DTV) and evaluate dosimetric consequences of boosting dose to this region of high clinical target volume (CTV)‐ and low organs at risk (OAR)‐probability. Methods: This work defines the DTV via occupancy probability and via contraction of the CTV by margin M less any planning risk volume (PRV) volumes. The equivalence to within varying occupancy probability of the two methods is established for spherical target volumes. We estimate a margin for four radiation treatment sites based on modern images guided radiation therapy‐literature utilizing repeat volumetric imaging. Based on margins and patient‐specific DTV targets, the ability to dose escalate the DTV including the effects of spatial uncertainty was evaluated. We simulate delivery assuming violation of the underlying spatial uncertainty of 130%. Results: Contracting the planning target volume (PTV) by M and excluding PRV volumes, the DTV ranged from 7.3 to 93.6 cc. In a brain treatment, DTV‐Dmax increased to 66.8 Gy (145% of prescription isodose); in advanced lung DTV‐Dmax increased to 122.2 Gy (204% of prescription isodose), in a pancreatic case DTV‐Dmax was boosted up to 87.3 Gy (173% or prescription isodose), and in retroperitoneal sarcoma to 74.6 Gy (249% of prescription isodose). The high point doses were not associated with increased dose to OARs, even when considering the effects of spatial uncertainty. Simulated delivery at 130% of assumed spatial uncertainties revealed DTV‐based planning can result in minor increases in OAR Dmean/Dmax of 2.7 ± 2.1 Gy/1.8 ± 2.2 Gy with duodenum Dmax > 110% of prescription isodose in the pancreatic case. These dose increases were consistent with simulation of clinical, homogenous PTV‐dose distributions. Conclusion: We have proposed and tested a method to deliver extremely high doses to subvolumes of target volumes in multiple treatment sites by defining a new target volume, the DTV. Based on simulated delivery, the method does not result in significant increases in dose to OARs if spatial uncertainty can be estimated. [ABSTRACT FROM AUTHOR]

Aim: To understand the potential harmful effects of dose escalation among patients with chronic, non‐cancer pain (CNCP) on chronic opioid therapy. Design Retrospective cohort study. Setting: United States Veterans Healthcare Administration. Participants: Veterans with CNCP and on chronic opioid therapy were identified using data from fiscal years 2008–15. The Veteran sample was approximately 90% male and 70% white. Measurements Dose escalators [increase of > 20% average morphine milligram equivalent (MME) daily dose] were compared with dose maintainers (change of ±20% average MME daily dose). A composite measure of subsequent substance use disorders (SUDs: opioid, non‐opioid and alcohol use disorders) and opioid‐related adverse outcomes (AOs: accidents resulting in wounds/injuries, opioid‐related and alcohol and non‐opioid medication‐related accidents and overdoses, self‐inflicted injuries) as well as the individual SUDs and AOs was examined. The primary analyses were conducted among a 1 : 1 matched sample of escalators and maintainers matched on propensity score and index date. Propensity scores were generated using demographic characteristics, medical comorbidities, medication and health‐care utilization characteristics. Subgroup analyses were conducted by quartile of the propensity score. Sensitivity analyses were conducted using adjusted logistic regression, logistic regression using stabilized inverse probability of treatment weighting (SIPTW) and instrumental variable (IV) models using geographic variation in opioid dose escalation as the IV. Findings There were 32 420 maintainers and 20 767 escalators resulting in 19 358 (93.2%) matched pairs. Composite AOs [odds ratio (OR) = 1.31, 95% confidence interval (CI) = 1.23, 1.40], composite SUDs (OR = 1.31, 95% CI = 1.22, 1.41) and individual SUD and AO subtypes were higher among dose escalators, except for opioid‐related accidents and overdoses and violence‐related injuries. Subgroup analyses within the propensity score quartiles found similar results. Sensitivity analyses with the adjusted and SIPTW logistic regressions found similar results to the primary analyses for all outcomes except for opioid‐related accidents and overdoses, which were found to be significantly higher among escalators. Sensitivity analyses with IV models provided mixed results with SUDs and the individual types of AOs. Conclusion: Escalating the opioid dose for those with chronic, non‐cancer pain is associated with increased risks of substance use disorder and opioid‐related adverse outcomes. [ABSTRACT FROM AUTHOR]

Background and aims: Strong and high‐dose opioids are associated with opioid overdose and death. The objective of this study was to determine the rate and predictors of transitioning to high‐dose or strong opioids among people initiating opioids. Design Retrospective cohort study. Setting: Australia. Participants: People initiating opioid analgesics from July 2013 to January 2018 were identified from a random 10% sample of Australia's Pharmaceutical Benefits Scheme eligible population. Measurements Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the predictors of escalating to ≥ 50 mg oral morphine equivalents (OMEs)/day (cohort 1); ≥ 90 mg OMEs/day (cohort 2) and transitioning from weak opioids to strong opioids (cohort 3) over 12 months of follow‐up. Predictors included age, sex, number of comorbidities, history of depression, prior treatment for cancer and selected other medication use. Findings In total, 861 691 people initiated opioids at average doses < 50 mg OMEs/day (cohort 1), 874 401 at < 90 mg OMEs/day (cohort 2) and 603 884 initiated weak opioids (cohort 3). Overall, 1.4% of people escalated to doses ≥ 50 mg OMEs/day, 0.8% to doses ≥ 90 mg OMEs/day and 7.3% transitioned to strong opioids. The strongest predictors of transitioning included prior treatment for cancer [cohort 1: HR = 3.19, 95% CI = 3.00–3.40; cohort 2: HR = 4.19, 95% CI = 3.90–4.51; cohort 3: HR = 2.07, 95% CI = 1.95–2.18] and age ≥ 75 years (cohort 1: HR = 3.04, 95% CI = 2.73–3.38; cohort 2: HR = 2.51, 95% CI = 2.17–2.89; cohort 3: HR = 1.88, 95% CI = 1.80–1.96). Females transitioned to high doses and strong opioids less rapidly than males (cohort 1: HR = 0.79, 95% CI = 0.76–0.82; cohort 2: HR = 0.70, 95% CI = 0.66–0.73; cohort 3: HR = 0.95, 95% CI = 0.93–0.96). Conclusions: In Australia, more than one in every 13 people initiating weak opioids transition to strong opioids. By extrapolation, more than 26 000 Australian adults initiating opioids escalate to high doses each year. People with cancer treatment history, older people and males transition to strong and high‐dose opioids more rapidly than others. [ABSTRACT FROM AUTHOR]

Background: To report outcomes of localized prostate cancer treated with radical external beam radiation therapy (EBRT) in our institution over a 14‐year period, and to determine the impact of dose escalation of prostate cancer outcomes. Methods: Patients with T1–T4 N0 M0 prostate cancer who received radical EBRT between January 2002 and December 2015 were reviewed retrospectively. Clinical data were obtained via the institutional electronic medical records. The primary endpoint was 5‐year overall survival (OS). The secondary endpoints were 5‐year freedom from biochemical failure (FFBF) and treatment toxicities. Results: A total of 200 eligible patients were identified. Median follow‐up duration was 48 months. 13%, 36% and 51% of patients had low‐, intermediate‐ and high‐risk disease. Median dose was 79.2 Gy. The 5‐year OS were 90%, 87% and 78% and FFBF were 94%, 100% and 81% for low‐, intermediate‐ and high‐risk patients, respectively. Multivariable analysis showed that Eastern Cooperate Oncology Group performance status 2 and Gleason grade group 5 were independent predictors of worse OS. The incidence of grade ≥2 proctitis was 24.5%. Dose escalation was significantly associated with increased incidence of grade ≥2 proctitis (odd ratio, 4.42; 95% confidence interval, 1.95–10.08; P < 0.01). Conclusion: Men with localized prostate cancer treated with EBRT in our population had excellent 5‐year OS and biochemical outcomes. Dose escalation did not significantly improve these outcomes but was associated with significantly increased risk of grade ≥2 proctitis in our population. Future studies should be performed to identify patients who will benefit the most from dose‐escalated EBRT. [ABSTRACT FROM AUTHOR]

Blockade of programmed cell death ligand‐1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non‐randomized, open‐label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose‐escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, and efficacy. Twenty‐two patients (median age, 61.5 years; range, 41‐76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events (AE). The most common treatment‐related AE (trAE) were rash (18%) and pruritus (14%); two patients had grade ≥3 trAE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose‐limiting toxicity (DLT) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose‐proportional pharmacokinetics across the 1‐20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Adalimumab (ADA) is one of the tumor necrosis factor (TNF)‐α monoclonal antibodies used for the treatment of psoriasis. In Japan, standard dosing of ADA for adults is an initial s.c. injection of 80 mg, followed by 40 mg every other week. Some patients who initially do not respond to treatment are allowed an increased dose of 80 mg every other week. However, studies on the efficacy and safety of ADA dose escalation to 80 mg every other week are few. In this study, we retrospectively studied 92 patients with psoriasis who received ADA therapy in our hospital. In 45 out of 92 patients, the dose of ADA 80 mg was administrated every other week, and the efficacy was observed within 12 weeks. The most common adverse drug reaction was upper respiratory infection, followed by diarrhea. In three patients, malignancies occurred during the observation period. No deaths or other severe complications were observed. In conclusion, this study showed the efficacy and safety of ADA dose escalation to 80 mg every other week in patients with psoriasis. [ABSTRACT FROM AUTHOR]

Background: Chordomas and chondrosarcomas are a rare but challenging subset of tumors to treat; however, previous studies have shown benefits from proton therapy, which are thought to be primarily driven by prescription conformality permitting homogeneous tumor dosing and the allowance of higher doses. No retrospective studies to date have directly compared the outcomes of conventional and particle therapy or examined the role of high doses (specifically ≥70 Gy) in definitive radiotherapy (DRT) or perioperative radiotherapy (PRT) for both types of malignancies.Methods: A total of 863 patients with chondrosarcoma and 715 patients with chordoma treated with nonpalliative proton or conventional radiation therapy with a dose range of 20 to 80 Gy and at least 15 months of follow-up were identified from the National Cancer Data Base for the years 2003-2014. The primary endpoint of overall survival (OS) was evaluated, and clinical features, including age, sex, grade, clinical stage, and Charlson-Deyo comorbidity index, were compared.Results: Patients receiving DRT were older and had more advanced disease. In DRT for chondrosarcoma, a high dose (40.6% vs 16.9%; P = .006) and proton therapy (75.0% vs 19.1%; P = .046) were associated with improved OS at 5 years in a multivariate analysis. In DRT for chordoma, proton therapy was associated with improved OS at 5 years in a multivariate analysis (100% vs 34.1%; P = .031), and a high dose for chordoma was significant for improved OS in a univariate analysis with both DRT (79.0% vs 54.1%; P = .027) and PRT (83.3% vs 77.4%; P = .007).Conclusions: In the largest retrospective series to date, dose escalation and proton radiotherapy were associated with improved OS in patients with chondrosarcoma and chordoma despite limited follow-up and access to particle therapy. [ABSTRACT FROM AUTHOR]

Background: To evaluate the role of definitive radiotherapy using higher‐than‐standard‐dose radiation of 50 Gy for carcinoma of the cervical esophagus (CCE). Methods: We reviewed 79 patients with stage I‐III CCE, treated between 2000 and 2012. Patients received 5‐fluorouracil/cisplatin‐based chemotherapy concurrently and were divided into high‐dose (≥59.4 Gy, n = 44) and standard‐dose (<59.4 Gy, n = 35) groups. Results: The median follow‐up was 35 months for surviving patients. The high‐dose group had significantly better 3‐year local (90.0% vs 60.4%, P = .001) and locoregional (70.4% vs 45.3%, P = .04) control. Progression‐free (45.4% vs 37.5%, P = .32) and overall (58.4% vs 49.1%, P = .69) survival rates were not different. High‐dose radiation was an independent prognostic factor for locoregional control (P = .04). No differences in late toxicities (esophageal stenosis or tracheoesophageal fistula) were observed. Conclusion: High‐dose radiation for CCE improves local and locoregional control, without increasing severe toxicities. [ABSTRACT FROM AUTHOR]

Purpose: Dose painting techniques based on dose escalation to hypoxic regions are usually governed by the spatial distribution of Oxygen Enhancement Ratio (OER) derived from PET or MRI images. The goal of this article is to show that the volume of the hypoxic region is also a parameter which may affect the radiobiological effectiveness of hypoxia‐targeted dose escalation. Methods: Our analysis is performed using the equation for Tumor Control Probability (TCP) derived from Poisson statistics. A tumor response model based on two levels of oxygenated and hypoxic cells with the survival curves described by the Linear Quadratic (LQ) model was used in the calculations. The model allows for analytical solutions which can be used for additional validation of our numerical simulations. The model was used to compute the average tumor cell survival that defines TCP. Dependence of average tumor cell survival on the relative hypoxic volume and dose escalation was computed for the conventional 30 × 2 Gy and hypofractionated 4 × 12 Gy dose regimens in a model problem with radiobiological parameters for nonsmall cell lung cancer. Results: We show that equal average tumor cell survival and TCP can be achieved with smaller hypoxia‐targeted dose escalation for smaller relative hypoxic volumes if the dose escalation does not exceed 50% of dose in the oxygenated region. This effect is explained by the dependence of average tumor cell survival and TCP mostly on the hypoxic tumor volume in this dose escalation range. Assuming a linear relationship between the number of clonogens and the hypoxic volume, smaller hypoxic volumes have smaller number of clonogens, therefore, smaller doses are needed to eradicate them. Conclusions: The theoretical analysis performed in this article predicts that tumors with smaller relative hypoxic volumes may require smaller hypoxia‐targeted dose escalation to maintain equal TCP. The results of this research can be used for dose de‐escalation strategies in dose painting techniques which may reduce dose to normal tissue and normal tissue complications without deterioration of TCP. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of escalated dose radiation therapy (EDR, defined as doses >50.4 Gy in 28 fractions [59.5 Gy BED]) on overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) of patients with unresectable extrahepatic cholangiocarcinoma (EHCC). Methods: A consecutive cohort of 80 patients who underwent radiotherapy for unresectable EHCC from 2001 to 2015 was identified. Demographic, tumor, treatment, toxicity, and laboratory variables were collected. The maximal RT doses ranged from 30 to 75 Gy (median 50.4 Gy, at 1.8‐4.5 Gy/fraction). Gross tumor volume (GTV) coverage by maximal dose in EDR group ranged from 38% to 100%. Kaplan–Meier method was used to estimate OS, FFLP, and FFDP. Univariate and multivariate Cox regression models were analyzed. Results: After radiotherapy, median OS, FFLP, and FFDP were 18.7, 22.6, and 24.3 months, respectively. There was no significant difference in OS or FFLP between patients who received EDR to portions of the GTV and patients who did not. On multivariate analysis, bigger GTV, age, and ECOG performance status were independently associated with shorter OS. Local progression on chemotherapy prior to RT was independently associated with shorter FFLP. High baseline neutrophil/lymphocyte ratio (>5.3) was independently associated with shorter FFDP. Toxicity grades were similar in EDR and lower doses except lymphopenia which was higher in EDR (P = 0.053). Conclusions: EDR to selective portions of the GTV may not benefit patients with unresectable EHCC despite having acceptable toxicity. New methods to improve local control and survival for unresectable EHCC are needed. We have investigated the role of escalated radiation dose in treatment of unresectable extrahepatic cholangiocarcinoma. Escalated dose radiation therapy did not significantly improve overall survival or local control. [ABSTRACT FROM AUTHOR]

The cyclin D‐CDK4/6‐INK4‐Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single‐agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single‐agent ribociclib on a 3‐weeks‐on/1‐week‐off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose‐escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose‐limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3‐weeks‐on/1‐week‐off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Background The purpose of this study is to investigate the feasibility of a simultaneously integrated boost to the hypoxic subvolume of nasopharyngeal carcinomas (NCPs) under the guidance of 18F-fluoromisonidazole (FMISO) positron emission tomography (PET)/CT using volumetric-modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) techniques. Methods Eight patients with NPC were treated with simultaneous integrated boost-IMRT (treatment plan named IMRT70) with dose prescriptions of 70 Gy, 66 Gy, 60 Gy, and 54 Gy to the gross tumor volume (GTV), positive neck nodes, the planning target volume (PTV), and the clinically negative neck, respectively. Based on the same datasets, experimental plans with the same dose prescription plus a dose boost of 14 Gy (an escalation of 20% of the prescription dose) to the hypoxic volume target contoured on the pretreatment 18F-FMISO PET/CT imaging were generated using IMRT and VMAT techniques, respectively (represented by IMRT84 and VMAT84). Two or more arcs (approximately 2-2.5 arcs, totally rotating angle <1000 degrees) were used in VMAT plans and 9 equally separated fields in IMRT plans. Dosimetric parameters, total monitor units, and delivery time were calculated for comparative study of plan quality and delivery efficiency between IMRT84 and VMAT84. Results In experimental plans, hypoxic target volumes successfully received the prescribed dose of 84 Gy in compliance with other dose constraints with either the IMRT technique or the VMAT technique. In terms of the target coverage, dose homogeneity, and organs at risk (OAR) sparing, there was no statistically significant difference between the actual treatment plan of IMRT70 and experimental plans. The total monitor unit of VMAT84 (525.7 ± 39.8) was significantly less than IMRT70 (1171.5 ± 167; P = .001) and IMRT84 (1388.3 ± 151.0; P = .001) per fraction, with 55.1% and 62.1% reduction. The average machine delivery time was 3.5 minutes for VMAT plans in comparison with approximately 8 minutes for IMRT plans, resulting in a reduction factor of 56.2%. For experimental plans, the 3D gamma index average was over 98.0% with no statistical significant difference when a 3%/3 mm gamma passing rate criteria was used. Conclusion With the guidance of 18F-FMISO PET/CT imaging, dose escalation to hypoxic zones within NPC could be achieved and delivered efficiently with the VMAT technique in comparison with the IMRT technique. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to report the long-term outcome of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)-guided dose painting for head and neck cancer in comparison to conventional intensity-modulated radiotherapy (IMRT) in a matched case-control study. Methods Seventy-two patients with nonmetastatic head and neck cancer treated with dose painting were compared with 72 control patients matched on tumor site and T classification. Either 18F-FDG-PET-guided dose painting by contour (DPBC) or voxel intensity-based dose painting by number (DPBN) was performed; control patients underwent standard IMRT. A total median dose to the dose-painted target was 70.2-85.9 Gy/30-32 fractions versus 69.1 Gy/32 fractions with conventional IMRT. In 31 patients, dose painting was adapted to per-treatment changes in the tumor and organs-at-risk (OAR). Results Median follow-up in living dose-painting and control patients was 87.7 months (range 56.1-119.3) and 64.8 months (range 46.3-83.4), respectively. Five-year local control rates in the dose-painting patients were 82.3% against 73.6% in the control ( P = .36); in patients treated to normalized isoeffective doses >91 Gy (NID2Gy) local control reached 85.7% at 5 years against 73.6% in the control group ( P =.39). There was no difference in regional ( P = .82) and distant control ( P = .78). Five-year overall and disease-specific survival rates were 36.3% versus 38.1% ( P = .50) and 56.5% versus 51.7% ( P = .72), respectively. A half of the dose-painting patients developed acute grade ≥3 dysphagia ( P = .004). Late grade 4 mucosal ulcers at the site of dose escalation in 9 of 72 patients was the most common severe toxicity with dose painting versus 3 of 72 patients with conventional IMRT ( P = .11). Patients in the dose-painting group had increased rates of acute and late dysphagia ( P = .004 and P = .005). Conclusion Dose-painting strategies can be used to increase dose to specific tumor subvolumes. Five-year local, regional, and distant control rates are comparable with patients treated with conventional IMRT. Volume and intensity of dose escalation should be further tailored, given the possible increase in severe acute and chronic toxicity. Adapting treatment and decreasing dose to the swallowing structures might contribute to lower toxicity rates when applied in smaller tumor volumes. Whether adaptive DPBN can significantly improve outcomes is currently being investigated in a novel clinical trial. [ABSTRACT FROM AUTHOR]

Aim In prostate cancer, fiducial marker image-guided radiotherapy (FMIGRT) allows correction of setup errors and interfraction physiological motion resulting in improved accuracy of target and sparing of at risk organs. We aim to report outcomes and toxicities observed in patients treated with dose escalation to 78Gy with FMIGRT in our center. Methods and Materials Retrospective review of consecutive patients with histologically confirmed T1-4N0M0 localized prostate cancer treated with dose escalation to 78Gy with FMIGRT in our center. All patients had 3-D conformal radiotherapy. Duration of androgen deprivation therapy use was tailored to risk group. Toxicity was scored according to CTCAE.v04. Kaplan-Meier analysis was performed for freedom from biochemical failure (FFBF), prostate cancer-specific survival and overall survival. Results Median follow-up was 48.6 months. Median duration of androgen deprivation therapy was 6 and 23 months in the intermediate- and high-risk group, respectively. FFBF at 5 years was 88.8%. FFBFs when stratified to risk groups were 100% for low risk, 88.9% for low-intermediate risk, 89.9% for high-intermediate risk and 85.4% for high risk, respectively. Acute severe toxicity (grade≥3) rate for both genitourinary (GU) and gastrointestinal (GI) was 1%. Late moderate-to-severe toxicity (grade≥2) rates for GU and GI were 15% and 17%, respectively, with severe (grade≥3) toxicity rate for GU and GI at 2% and 3%, respectively. Conclusion Dose escalation to 78Gy with FMIGRT in our series achieved good FFBF at 5 years with low acute and late toxicity rates. These results provide a good comparator cohort to our current use of image-guided intensity modulated radiotherapy. [ABSTRACT FROM AUTHOR]

We aimed to compare the overall survival ( OS) of patients with bone metastases ( BM) from solid tumors after standard-dose radiotherapy ([ RT]; 30 Gy administered in 10 fractions; EQD2Gy = 32.5 Gy) and dose-escalated RT (EQD2Gy > 32.5 Gy). We retrospectively reviewed the clinical charts of 1795 patients (median age, 62.3 years; age range, 18-96 years) with BM from solid tumors who were referred for RT to our institute between 2000 and 2013. These patients were assigned to the standard-dose ( n = 1125; 63%) and dose-escalated ( n = 670; 37%) RT groups. OS, estimated as the duration between the first RT session and death, served as the main outcome measure. The dose-escalated RT group had a significantly better OS than the standard-dose RT group ( P = 0.000). After allowing potential confounders in multivariate analysis, the RT dose retained its independent association with OS (hazard ratio [ HR], 0.837; 95% confidence interval [ CI], 0.753-0.929, P = 0.001). After propensity score matching of the baseline characteristics of both groups, RT dose retained its independent association with OS ( HR, 0.887; 95% CI, 0.737-0.951; P = 0.011) on multivariate analysis. Dose-escalated RT exerted more favorable effects on OS in patients with non-lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. Dose-escalated RT was significantly associated with better OS in patients with BM from solid malignancies, particularly among those with non-lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma ( mRCC). Patients and Methods Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily ( BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events ( AEs). The primary endpoint was objective response rate ( ORR) in the modified intent-to-treat ( mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival ( PFS) and safety. Results In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [ n = 8/18; 95% confidence interval ( CI) 21.5-69.2] and 17.9% ( n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0-11.7) months ( ITT). The most common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%). Conclusion Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored. [ABSTRACT FROM AUTHOR]

Purpose The goal of this article is to compute the cell survival during fractionated radiotherapy with non-uniform hypoxia-targeted dose distribution relative to cell survival for a uniform dose distribution with equal integral tumor dose. The analysis is performed for different parameters of radiotherapy with conventional and hypofractionated dose regimens. Methods Our analysis is done using a parsimonious tumor response model that describes the major components of tumor response to radiotherapy such as radiosensitivity, cell proliferation, and hypoxia using as few variables as possible. Two levels of oxygenated and hypoxic cells with the survival curves described by the linear quadratic ( LQ) model are implemented in the model. The model allows for analytical solutions for relative cell survival in a single fraction simulation which can be used for additional validation of our numerical simulations. The relative cell survival was computed for conventional and hypofractionated dose regimens in a model problem with radiobiological parameters for the non-small-cell lung cancer. Sensitivity of cell survival to different parameters of radiotherapy such as the relative volume of hypoxic fraction, boost dose ratio, re-oxygenation rate, and delivery errors was investigated. Results Our computational and analytical results show that relative cell survival for non-uniform and uniform dose distributions is larger than 1.0 during the first few fractions of radiotherapy with conventional fractionation. This indicates that the uniform dose distribution produces a higher cell killing effect for the equal integral dose. This may stem from domination of linear contribution to the cell killing effect seen in the dose range of 1-2 Gy and a steeper slope of survival curve in the oxygenated tumor region. This effect can only happen if the distribution of clonogens is nearly uniform; therefore, after the first few fractions, the non-uniform dose distributions outperform the uniform dose distribution and relative cell survival becomes less than 1.0. However, re-oxygenation and delivery errors can also reduce the effectiveness of hypoxia-targeted non-uniform dose distributions toward the end of treatment. For hypofractionated radiotherapy with fractional dose >3 Gy, the relative cell survival was always below 1.0, which means the non-uniform dose distributions produced higher cell killing effect than the uniform dose distribution during the entire treatment. Conclusion The data obtained in this work suggest that non-uniform hypoxia-targeted dose distributions are less effective at cell killing than uniform dose distributions at the beginning of radiotherapy with conventional fractionation. However; non-uniform dose distributions can outperform uniform dose distribution by the end of the treatment if the effects of re-oxygenation and delivery errors are reduced. In hypofractionated radiotherapy, non-uniform hypoxia-targeted dose distributions are more efficient than uniform dose distributions during the entire treatment. [ABSTRACT FROM AUTHOR]

Although infliximab is approved for psoriasis, its efficacy is reduced over time in some patients. The aim of this phase III trial is to evaluate efficacy and safety of infliximab dose escalation in Japanese psoriasis patients with loss of efficacy to standard-dose therapy. Patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis or psoriatic erythroderma who showed loss of efficacy to standard-dose therapy received infliximab dose escalation (10 mg/kg every 8 weeks) from weeks 0 to 32. Loss of efficacy was defined as not maintaining 50% reduction in the Psoriasis Area and Severity Index (PASI 50) after achieving PASI 75. Efficacy and safety were evaluated up to week 40. Fifty-one patients received dose escalation and 43 completed the study. PASI 75 and median improvement rate of PASI score at week 40 were 44% and 70.0%, respectively, showing efficacy in skin symptoms. Efficacies in quality of life, nail psoriasis and joint pain were also obtained. Median serum infliximab level increased from less than 0.1 to 1.1 μg/mL from weeks 0 to 40, showing positive correlation between efficacy and serum infliximab level at week 40. Favorable efficacy was observed in patients with detectable serum infliximab levels (≥0.1 μg/mL) at baseline. Incidences of adverse events, serious adverse events, serious infections and serious infusion reactions were 92%, 10%, 4% and 0%, respectively. No marked difference was observed in both efficacy and safety among psoriasis types. No new safety concerns were observed. Infliximab dose escalation was effective and well-tolerated in psoriasis patients with loss of efficacy to standard-dose therapy, suggesting that dose escalation may be a useful therapeutic option for these patients. [ABSTRACT FROM AUTHOR]

Adaptive, model-based, dose-finding methods, such as the continual reassessment method, have been shown to have good operating characteristics. One school of thought argues in favor of the use of parsimonious models, not modeling all aspects of the problem, and using a strict minimum number of parameters. In particular, for the standard situation of a single homogeneous group, it is common to appeal to a one-parameter model. Other authors argue for a more classical approach that models all aspects of the problem. Here, we show that increasing the dimension of the parameter space, in the context of adaptive dose-finding studies, is usually counter productive and, rather than leading to improvements in operating characteristics, the added dimensionality is likely to result in difficulties. Among these are inconsistency of parameter estimates, lack of coherence in escalation or de-escalation, erratic behavior, getting stuck at the wrong level, and, in almost all cases, poorer performance in terms of correct identification of the targeted dose. Our conclusions are based on both theoretical results and simulations. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The purpose of this study is to determine the recommended dose ( RD) of proton beam therapy ( PBT) for inoperable stage III non-small cell lung cancer ( NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [ RBE]) in 33 fractions and 74 Gy ( RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume ( PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m2, day 1) and oral S-1 (80, 100 or 120 mg based on body surface area, days 1-14), repeated as four cycles every 4 weeks. Dose-limiting toxicity ( DLT) was defined as grade 3 or severe toxicities related to PBT during days 1-90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow-up time was 43 months, and the median progression-free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy ( RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585) [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) infects more than 180 million people worldwide, with long-term consequences including liver failure and hepatocellular carcinoma. Quercetin bioflavonoids can decrease HCV production in tissue culture, in part through inhibition of heat shock proteins. If quercetin demonstrates safety and antiviral activity in patients, then it could be developed into an inexpensive HCV treatment for third world countries or other affected populations that lack financial means to cover the cost of mainstream antivirals. A phase 1 dose escalation study was performed to evaluate the safety of quercetin in 30 untreated patients with chronic HCV infection and to preliminarily characterize quercetin's potential in suppressing viral load and/or liver injury. Quercetin displayed safety in all trial participants. Additionally, 8 patients showed a "clinically meaningful" 0.41-log viral load decrease. There was a positive correlation (r = 0.41, p = 0.03) indicating a tendency for HCV decrease in patients with a lower ratio of plasma quercetin relative to dose. No significant changes in aspartate transaminase and alanine transaminase were detected. In conclusion, quercetin exhibited safety (up to 5 g daily) and there was a potential for antiviral activity in some hepatitis C patients. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the safety, pharmacokinetics and antitumor activity of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Methods: HCC patients of Child--Pugh A or B who progressed on, or were intolerant to, sorafenib were eligible for this phase 1 trial. We used a standard 3 + 3 dose-escalation design with a 28-day cycle at dose levels of 50, 100, 200 and 400mg/day. Tumor responses were assessed using the modified Response Evaluation Criteria in Solid Tumors. Results: Twenty-four patients were enrolled, of whom 23 received OPB-31121 (20 males; median age, 65 years). The most common adverse drug reactions were nausea (87.0%), vomiting (82.6%), diarrhea (69.6%), fatigue/malaise (52.2%), anorexia (47.8%) and peripheral sensory neuropathy (26.1%). The recommended dose for OPB-31121 was determined to be 200mg. Six patients had stable disease for 8 weeks or more, resulting in disease control rates of 25.0-42.9%. In the 200-mg dose cohort, three of seven patients had stable disease and a median time to progression of 61.0 days. The maximum concentration and area under the plasma concentration--time curve of OPB-31121 were dose proportional. Conclusion: OPB-31121 demonstrated insufficient antitumor activity for HCC. Furthermore, peripheral nervous system-related toxicities may negatively affect long-term administration of OPB-31121. Therefore, it was deemed difficult to continue the clinical development of OPB-31121 for treating advanced HCC and further investigation is expected in the agent with favorable profile in this category. [ABSTRACT FROM AUTHOR]

Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness. [ABSTRACT FROM AUTHOR]

Background 'Dose tailoring' of anti-tumour necrosis factor alpha ( TNF-α) therapy in Crohn disease ( CD), by dose escalation, or shortening of dosing intervals, has been suggested to regain clinical response following a flare in a proportion of patients. However, reported outcome data are sparse and none exists from Australia. Method In an observational multicentre, retrospective study, the impact of anti- TNF-α dose tailoring on corticosteroid use, the need for surgery and physician perception of clinical efficacy was examined in a real-world setting at six Australian adult teaching hospitals. Demographics, disease characteristics, medications, indication for and duration of dose tailoring were documented. Results Fifty-five CD patients were identified as requiring dose tailoring and secondary loss of response was the indication in 96%. Either adalimumab (64%) or infliximab (36%) was dose escalated for a median of 5 months (range 1-47), with a median of 20 months follow up (range 3-65). At 3 months, dose tailoring reduced the mean number of days on high-dose corticosteroids (45 vs 23, P = 0.01). Most (78%) patients remained resection free, and 73% of physicians reported good clinical efficacy of dose tailoring. Of those who de-escalated therapy due to induction of remission, long-term (>12 months) follow up and complete data on steroid use were available in 15/28, with 12/15 (80%) remaining steroid free at 1 year. Conclusion Short-term dose tailoring regains disease response in the majority of patients with CD. Of these, most will remain free of corticosteroids at 1 year after de-escalating therapy. [ABSTRACT FROM AUTHOR]

Background The benefits of escalating the dose of donepezil in patients who are already receiving long-term treatment with it have not been well evaluated. Therefore, an exploratory study to assess the effects of donepezil dose escalation in patients with Parkinson's disease with dementia, and specifically on patients receiving long-term treatment with donepezil, was performed. Methods Patients treated with 5-mg/day donepezil for at least 3 months and having a Mini- Mental State Examination ( MMSE) score between 10 and 26 were included in this study. Donepezil dosage was then increased to 10 mg/day for 12 weeks. The outcome measures were a modified form of the Neuropsychiatric Inventory ( NPI) with an extra domain for additional evaluation of fluctuation in cognitive functions ( NPI-11) and the MMSE. Results Of the nine patients enrolled, two withdrew because of nausea and inability to be assessed on the predetermined date; this left seven participants (four men and three women) with a mean age of 74.6 ± 6.9 years, a mean period of Parkinson's disease of 11.7 ± 7.5 years, and median donepezil use of 7 months (range: 3-56 months). At baseline, the mean total NPI-11 and mean MMSE scores were 18.3 ± 5.6 points and 21.3 ± 5.3 points, respectively. At week 12, they improved by 8.3 points ( P < 0.01) and 3.0 points ( P = 0.08), respectively, from the baseline. The NPI symptom domains that improved by 1 or more points were hallucination (1.3 points), depression (1.0 points), anxiety (1.6 points), and aberrant motor behaviour (1.7 points). None of the patients withdrew because of worsening of parkinsonism. Conclusions The present results suggest that treatment with dose escalation of donepezil from 5 mg/day to 10 mg/day may be therapeutically useful for patients with Parkinson's disease with dementia who have taken donepezil 5 mg/day in the long term. [ABSTRACT FROM AUTHOR]

Nowadays, treatment regimens for cancer often involve a combination of drugs. The determination of the doses of each of the combined drugs in phase I dose escalation studies poses methodological challenges. The most common phase I design, the classic '3+3' design, has been criticized for poorly estimating the maximum tolerated dose (MTD) and for treating too many subjects at doses below the MTD. In addition, the classic '3+3' is not able to address the challenges posed by combinations of drugs. Here, we assume that a control drug (commonly used and well-studied) is administered at a fixed dose in combination with a new agent (the experimental drug) of which the appropriate dose has to be determined. We propose a randomized design in which subjects are assigned to the control or to the combination of the control and experimental. The MTD is determined using a model-based Bayesian technique based on the difference of probability of dose limiting toxicities (DLT) between the control and the combination arm. We show, through a simulation study, that this approach provides better and more accurate estimates of the MTD. We argue that this approach may differentiate between an extreme high probability of DLT observed from the control and a high probability of DLT of the combination. We also report on a fictive (simulation) analysis based on published data of a phase I trial of ifosfamide combined with sunitinib.Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Dose finding for combined drugs has grown rapidly in oncology drug development. The escalation with overdose control (EWOC) method is a popular model-based dose-finding approach to single-agent phase I clinical trials. When two drugs are combined as a treatment, we propose a two-dimensional EWOC design for dose finding on the basis of a four-parameter logistic regression model. During trial conduct, we continuously update the posterior distribution of the maximum tolerated dose (MTD) combination to find the most appropriate dose combination for each cohort of patients. The probability that the next assigned dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile level of the MTD distribution such as to reduce the possibility of overdosing. We determine dose escalation, de-escalation, or staying at the same doses by searching the MTD combination along the rows and columns in a two-drug combination matrix, respectively. We conduct simulation studies to examine the performance of the two-dimensional EWOC design under various practical scenarios, and illustrate it with a trial example. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

GSK1322322 is the first in a new class of antibiotics that targets peptide deformylase (PDF), an essential bacterial enzyme required for protein maturation. This randomized, double-blind, placebo-controlled, eight-cohort phase I trial enrolled 62 healthy volunteers to assess safety, tolerability, and pharmacokinetic profiles of GSK1322322. GSK1322322 was administered as a single oral or intravenous (IV) dose, escalating from 500 to 3,000 mg or repeat IV doses escalating from 500 to 1,500 mg twice daily. Upon repeat IV administration, GSK1322322 exhibits linear pharmacokinetics over time upon repeat doses as shown by time-invariant pharmacokinetics. A dose-proportional increase in area under concentration-time curve was observed after single or repeat IV dosing, whereas clearance at steady state remained generally unchanged across doses. There was minimal accumulation of GSK1322322 after repeat IV twice-daily administration. After oral tablet doses of GSK1322322 1,000 and 1,500 mg, absolute bioavailability was 69% and 56%, respectively. GSK1322322 administration at single and repeat IV doses and at supratherapeutic single IV doses of 2,000 and 3,000 mg was associated with mild-to-moderate drug-related adverse events. On the basis of the pharmacokinetics and tolerability demonstrated in this study, GSK1322322 has the potential to become the first-in-class PDF inhibitor for clinical use. [ABSTRACT FROM AUTHOR]

Objectives To compare the relative importance of radiation dose escalation vs androgen deprivation therapy ( ADT) in the definitive treatment of prostate adenocarcinoma., Patients and Methods In total, 2427 patients with prostate adenocarcinoma were treated with definitive brachytherapy or brachytherapy with external beam radiation with or without ADT., Over the 20-year period of the present study (median follow-up of 78 months), patients were treated with a range of doses that were converted to the biological effective dose ( BED) and/or ADT as the treatment paradigms were optimized., Using univariate and multivariate analysis, the relative impact on the biochemical control and post-treatment prostate biopsy results of BED vs ADT was determined., Results The 10-year freedom from biochemical failure ( FBF) was significantly affected by BED group: ≤150 Gy2 (64%), >150-200 Gy2 (88%), >200-220 Gy2 (89%) and >220 Gy2 (89.5%) ( P < 0.001)., When stratified into dose groups, ADT improved FPF on multivariate analysis for the BED group (<150 Gy2, hazard ratio = 0.55; >150-200 Gy2, hazard ratio = 0.39) but not for the higher BED groups., Among patients receiving ADT, a significant difference in 10-year FBF was seen when stratifying BED into groups ≤150 Gy2 (78%) vs >150 Gy2 (87%) ( P = 0.01)., On logistic regression, ADT had a significant impact on obtaining a negative biopsy (hazard ratio = 0.21) with BED <200 Gy2, although there was no difference with BED >200 Gy2., Conclusions When treated with brachytherapy with or without EBT, ADT improves FBF only in the setting of lower doses., The benefit of ADT may be primarily as an enhancer of local control, explaining why high radiation doses can compensate for its absence. [ABSTRACT FROM AUTHOR]