Neoadjuvant Exercise Therapy in Prostate Cancer: A Phase 1, Decentralized Nonrandomized ControlledTrial.

Importance: Observational data have shown that postdiagnosis exercise is associated with reduced risk of prostate cancer death. The feasibility and tumor biological activity of exercise therapy is not known. Objective: To identify recommended phase 2 dose of exercise therapy for patients with prostate cancer. Design, Setting, and Participants: This single-center, phase 1a dose-finding trial was conducted at a tertiary cancer center using a patientcentric, decentralized platform and included 53 inactive men with treatment-naive localized prostate cancer scheduled to undergo surgical resection between June 2019 and January 2023. Data were analyzed in June 2024. Intervention: Six escalated exercise therapy dose levels ranging from 90 to 450 minutes per week of individualized, moderate-intensity treadmill walking, allocated using adaptive continual reassessment. All exercise therapy sessions were conducted remotely with real-time monitoring. Main Outcomes and Measures: Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater. Activity end points were changes in tumor cell proliferation (Ki67) and plasma prostate-specific antigen levels between pretreatment and postintervention. Safety and changes in patient physiology were also assessed. Results: A total of 53 men were enrolled (median [IQR] age, 61 [56-66] years). All dose levels were feasible (≥75% REDI). The mean (95% CI) changes in Ki67 were 5.0% (-4.3% to 14.0%) for 90 minutes per week, 2.4% (-1.3% to 6.2%) for 150 minutes per week, -1.3% (-5.8% to 3.3%) for 225 minutes per week, -0.2% (-4.0% to 3.7%) for 300 minutes per week, -2.6% (-9.2% to 4.1%) for 375 minutes per week, and 2.2% (-0.8% to 5.1%) for 450 minutes per week. Changes in prostate-specific antigen levels were 1.0 ng/mL (-1.8 to 3.8) for 90 minutes per week, 0.2 ng/mL (-1.1 to 1.5) for 150 minutes per week, -0.5 ng/mL (-1.2 to 0.3) for 225 minutes per week, -0.2 (-1.7 to 1.3) for 300 minutes per week, -0.7 ng/mL (-1.7 to 0.4) for 375 minutes per week, and -0.9 ng/mL (-2.4 to 0.7) for 450 minutes per week. No serious adverse events were observed. Overall, 225 minutes per week (approximately 5 minutes per treatment at 5 times weekly) was selected as the recommended phase 2 dose. Conclusions and Relevance: The results of this nonrandomized clinical trial suggest that neoadjuvant exercise therapy is feasible and safe with promising activity in localized prostate cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03813615.

Impact of exercise on chemotherapy-induced peripheral neuropathy in survivors with post-treatment primary breast cancer.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of neurotoxic chemotherapy. Exercise activates neuromuscular function and may improve CIPN. We examined the association between exercise and CIPN symptoms in breast cancer survivors. METHODS: In a retrospective cross-sectional study, we included patients completing a survey assessing exercise exposure and neuropathy symptoms in a tertiary cancer center survivorship clinic. We evaluated exercise duration and intensity using a standardized questionnaire quantified in metabolic equivalent tasks (MET-h/wk). We defined exercisers as patients meeting the National Physical Activity Guidelines' criteria. We used multivariable logistic regressions to examine the relationship between exercise and CIPN and if this differed as a function of chemotherapy regimen adjusting for age, gender, and race. RESULTS: We identified 5444 breast cancer survivors post-chemotherapy (median age 62 years (interquartile range [IQR]: 55, 71); median 4.7 years post-chemotherapy (IQR: 3.3, 7.6)) from 2017 to 2022. CIPN overall prevalence was 34% (95% confidence interval [CI]: 33%, 36%), 33% for non-taxane, and 37% for taxane-based chemotherapy. CIPN prevalence was 28% (95% CI: 26%, 30%) among exercisers and 38% (95% CI: 37%, 40%) among non-exercisers (difference 11%; 95% CI: 8%, 13%; p < 0.001). Compared to patients with low (<6 MET-h/wk) levels of exercise (42%), 11% fewer patients with moderate (6-20.24 MET-h/wk) to high (>20.25 MET-h/wk) levels of exercise reported CIPN. Exercise was associated with reduced prevalence of all CIPN symptoms regardless of chemotherapy type. CONCLUSION: CIPN may persist several years following chemotherapy among patients with breast cancer but is significantly reduced by exercise in a dose-dependent manner.

The clinical efficacy and tolerability of a novel triple acid exfoliating blend for reducing signs of photoaging in sensitive skin.

BACKGROUND: Chemical exfoliation of the skin is a frequently utilized treatment in dermatology to improve the appearance and health of photoaged skin. Photodamaged skin is especially prone to dryness and irritation. Over-exfoliation with at-home products are partially to blame for the "epidemic" of sensitive skin affecting over half the population. Combining AHA, BHA, and PHA together creates a complementary blend that has the potential to target numerous age-related changes in the skin including the appearance of pores and smoothing skin texture, while firming skin and increasing its collagen and moisture content. OBJECTIVES: The following study tested the clinical efficacy of a triple acid blend designed specifically for sensitive skin and measured improvements in signs of photodamage and hydration levels in the skin over time. METHODS: Thirty females aged 35-60 with mild to moderate facial lines, wrinkles, sun damage, uneven skin tone/texture, dark spots, or pores were enrolled. Subjects were instructed to use the test article, DWB-EN, on a clean face at night 3 times weekly with 48 h between applications for 4 weeks. RESULTS: Statistically significant improvements were noted in all parameters of photoaging clinical assessments (wrinkles, pores, overall appearance, luminosity, visible texture, skin tone evenness, hyperpigmentation) at the end of the 4-week study period. There were no instances of skin irritation throughout the duration of this study despite half of the women having sensitive skin. CONCLUSIONS: Overall, this study demonstrated the clinical efficacy and tolerability of DWB-EN for treating photoaging in subjects with all skin types.

A clinical evaluation of the efficacy and tolerability of a novel topical antioxidant formulation featuring vitamin C, astaxanthin, and fermented turmeric.

BACKGROUND: Ultraviolet light, visible light, infrared light, and pollution are a few examples of environmental factors that exacerbate the formation of reactive oxygen species (ROS) that cause damage to skin cells' DNA, proteins, and lipids. By supplementing the skin with antioxidants, we can help neutralize ROS formed by these extrinsic factors before they can damage the skin. AIMS: This prospective open-label study explores the safety and efficacy of this novel topical formulation of antioxidants (vitamin C, astaxanthin, fermented turmeric, and vitamin E) designed to fight free radical damage and improve overall skin quality, as well as the appearance of fine lines, wrinkles, radiance, and hyperpigmentation of the skin. PATIENTS/METHODS: This single-center clinical study evaluated the efficacy of twice-daily application of the test article (Asta C™ Vitamin C Age Defense Serum, Dr. Whitney Bowe Beauty) in 32 subjects for 12 weeks. Healthy female subjects aged 35-60 with mild to moderate fine lines, wrinkles, and hyperpigmentation/uneven skin tone were enrolled in this study. Fitzpatrick skin types I-VI, all skin types (dry, normal, combination, oily), and subjects with sensitive skin were included. RESULTS: All subjects demonstrated improvement in overall skin quality (face, neck, and chest) by the end of the 12-week study period. One hundred percent of subjects demonstrated improvement in the appearance of fine lines at Week 12. CONCLUSIONS: Overall, the current clinical study demonstrates that Asta C™ is safe, well-tolerated, and effective in improving overall skin quality, as well as the appearance of fine lines, wrinkles, radiance, and hyperpigmentation of the skin.

Effectiveness of Manual Terminal Cleaning Varies on High-Touch Surfaces Near the Operative Field.

Background: Periprosthetic joint infection may result from pathogen to patient transmission within the environment. The purpose of this study is to evaluate the contamination level of selected high-touch surfaces in the operating room (OR) using a blacklight fluorescent marking system after a manual terminal clean. Methods: Prior to the manual terminal clean, 16 high-touch surfaces were marked using a blacklight fluorescent gel. The marked areas were assessed the next morning for thoroughness of cleaning. Surfaces were categorized based on the average percent of the marks removed as "clean" (>75%), "partially clean" (26%-74%), or poorly cleaned (<25%). This process was repeated randomly 12 times. Terminal cleaning was done in the standard fashion, and the perioperative team was unaware of the initiation of this study. Results: A total of 936 marks were analyzed. There was a significant difference in the number of marks completely clean (29.1%, 272/936) vs marks that were not touched (40.8%, 382/936), P < .001. Only the OR back table (75%) had a rating of clean. Partially clean areas included Mayfield table (72%), overhead lights (70.1%), infusion pump (61.1%), clock reset button (58.3%), table remote control (50%), tourniquet machine (50%), and the OR table (33.3%). Poorly cleaned surfaces included anesthesia medication cart (21.8%), door handles (20.8%), phone (16.7%), electrocautery unit (16.7%), foot pedal (16.7%), anesthesia cart (16.2%), nurses' station (14.1%), and supply cabinet doors (6%). Conclusions: Effectiveness of manual terminal cleaning varied greatly across surfaces. In general, surfaces further from the operative field were less likely to have markings removed.

Impact of Exercise on Susceptibility and Severity of COVID-19 in Patients with Cancer: A Retrospective Study.

BACKGROUND: Modifiable lifestyle-related factors heighten the risk and severity of coronavirus disease 2019 (COVID-19) in patients with cancer. Whether exercise lowers susceptibility or severity is not known. METHODS: We identified 944 cancer patients from Memorial Sloan Kettering Cancer Center (mean age: 64; 85% female; 78% White) completing an exercise survey before receiving a confirmed positive or negative SARS-CoV-2 test. Exercise was defined as reporting moderate-intensity ≥5 days per week, ≥30 minutes/session or strenuous-intensity ≥3 days per week, ≥20 minutes/session. Multivariable logistic regression was used to determine the relationship between exercise and COVID-19 susceptibility and severity (i.e., composite of hospital admission or death events) with adjustment for clinical-epidemiologic covariates. RESULTS: Twenty-four percent (230/944) of the overall cohort were diagnosed with COVID-19 and 35% (333/944) were exercisers. During a median follow-up of 10 months, 26% (156/611) of nonexercising patients were diagnosed with COVID-19 compared with 22% (74/333) of exercising patients. The adjusted OR for risk of COVID-19 was 0.65 [95% confidence interval (CI), 0.44-0.96, P = 0.03] for exercisers compared with nonexercisers. A total of 20% (47/230) of COVID-19 positive patients were hospitalized or died. No difference in the risk of severe COVID-19 as a function of exercise status was observed (P > 0.9). CONCLUSIONS: Exercise may reduce the risk of COVID-19 infection in patients with a history of cancer, but not its severity. IMPACT: This study provides the first data showing that exercise might lower the risk of COVID-19 in cancer patients, but further research is required.

Population pharmacokinetic and exploratory exposure-response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study.

PURPOSE: To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure-response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure-efficacy and -safety relationships and support the approved SC dosing regimen. METHODS: Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression. RESULTS: SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest. CONCLUSION: The approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit-risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

Impact of Dose Delays and Alternative Dosing Regimens on Pertuzumab Pharmacokinetics.

PERJETA (pertuzumab), administered with Herceptin (trastuzumab), is used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Pertuzumab is currently approved with an initial loading dose of 840 mg, followed by a 420-mg maintenance dose intravenously every 3 weeks. A reloading dose is required if there is a ≥6-week delay in treatment. In response to the potential treatment disruption due to COVID-19, the impact of dose delays and alternative dosing regimens on intravenous pertuzumab for human epidermal growth factor receptor 2-positive breast cancer treatment is presented. Simulations were conducted by using the validated population pharmacokinetic model for pertuzumab, and included (1) 4-, 6-, and 9-week dose delays of the 840 mg/420 mg every 3 weeks dosing regimen and (2) 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens. Simulations were compared with the currently approved pertuzumab dosing regimen. The simulations in 1000 virtual patients showed that a dose reload (840 mg) is required following a dose delay of ≥6 weeks to maintain comparable Ctrough (lowest concentration before the next dose is given) levels to clinical trials. The 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens decrease median steady-state Ctrough by ≈40% compared with the approved regimen, and <90% of patients will be above the target Ctrough . Thus, the alternative 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks pertuzumab dosing regimens are not recommended. Flexibility for intravenous PERJETA-based regimens is available with an alternative route of pertuzumab administration (subcutaneous vs intravenous).

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.

BACKGROUND: A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved by the US Food and Drug Administration (FDA) on June 29, 2020. We report the primary analysis of the FeDeriCa study, which was designed to assess the pharmacokinetics, efficacy, and safety of the fixed-dose subcutaneous formulation compared to intravenous pertuzumab plus trastuzumab in patients with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting. METHODS: FeDeriCa, a randomised, open-label, international, multicentre, non-inferiority, phase 3 study, was done across 106 sites in 19 countries. Patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1, HER2-positive, operable, locally advanced, or inflammatory stage II-IIIC breast cancer, and a left ventricular ejection fraction of 55% or more were randomly assigned (1:1), using a voice-based or web-based response system, to receive intravenous pertuzumab (840 mg loading dose, followed by 420 mg maintenance doses) plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance doses) or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (1200 mg pertuzumab plus 600 mg trastuzumab loading dose in 15 mL, followed by 600 mg pertuzumab plus 600 mg trastuzumab maintenance doses in 10 mL), both administered every 3 weeks with neoadjuvant chemotherapy. Patients were stratified by hormone receptor status, clinical stage, and chemotherapy regimen. The investigator selected one of the two protocol-approved standard chemotherapy regimens before randomisation. Four cycles of HER2-targeted therapy were administered concurrently with the taxane. After surgery, patients continued the HER2-targeted therapy to receive an additional 14 cycles (total of 18). The primary endpoint was non-inferiority of the cycle 7 pertuzumab serum trough concentration (Ctrough; ie, cycle 8 predose pertuzumab concentration) within the fixed-dose combination for subcutaneous injection versus intravenous pertuzumab plus trastuzumab in the per-protocol pharmacokinetic population (all enrolled patients who adhered to prespecified criteria for pharmacokinetic assessment). Non-inferiority was concluded if the lower bound of the 90% CI of the geometric mean ratio was 0·8 or higher. The safety population included all patients who received at least one dose of study medication, including chemotherapy or HER2-targeted therapy. Enrolment, neoadjuvant therapy, and surgery have been completed; adjuvant treatment and follow-up are ongoing. The trial is registered with ClinicalTrials.gov, NCT03493854. FINDINGS: Between June 14, 2018, and Dec 24, 2018, 252 patients were randomly assigned to the intravenous infusion group and 248 to the fixed-dose combination group. The geometric mean ratio of pertuzumab serum Ctrough subcutaneous to serum Ctrough intravenous was 1·22 (90% CI 1·14-1·31). The most common grade 3-4 adverse events occurring during neoadjuvant treatment with HER2-targeted therapy plus chemotherapy in 5% or more of patients were neutropenia (34 [13%] of 252 patients in the intravenous infusion group vs 35 [14%] of 248 patients in the fixed-dose combination group), decreased neutrophil count (31 [12%] vs 27 [11%]), febrile neutropenia (14 [6%] vs 16 [6%]), diarrhoea (12 [5%] vs 17 [7%]), and decreased white blood cell count (18 [7%] vs nine [4%]). At least one treatment-related serious adverse event was reported in 25 (10%) patients in the intravenous infusion group and 26 (10%) patients in the fixed-dose combination group. One patient in each treatment group had an adverse event that led to death (urosepsis in the intravenous infusion group and acute myocardial infarction in the fixed-dose combination group); neither death was related to HER2-targeted therapy. INTERPRETATION: The study met its primary endpoint: the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection provides non-inferior cycle 7 pertuzumab serum Ctrough concentrations to intravenous pertuzumab plus trastuzumab in the neoadjuvant setting with comparable total pathological complete response rates, supporting the FDA approval. Safety was similar between treatment groups, and in line with other pertuzumab, trastuzumab, and chemotherapy trials. Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety. FUNDING: F Hoffmann-La Roche and Genentech.

Effects of Breastfeeding, Formula Feeding, and Complementary Feeding on Rapid Weight Gain in the First Year of Life.

OBJECTIVE: To determine whether proportion of breast versus formula feeding and timing of complementary food introduction affect the odds of rapid gain in weight status in a diverse sample of infants. METHODS: Using data from Greenlight Intervention Study, we analyzed the effects of type of milk feeding (breastfeeding, formula, or mixed feeding) from the 2- to 6-month well visits, and the introduction of complementary foods before 4 months on rapid increase in weight-for-age z-score (WAZ) and weight-for-length z-score (WLZ) before 12 months using multivariable logistic regression models. RESULTS: Of the 865 infants enrolled, 469 had complete data on all variables of interest, and 41% and 33% of those infants had rapid increases in WAZ and WLZ, respectively. Odds of rapid increase in WAZ remained lowest for infants breastfeeding from 2 to 6 months (adjusted odds ratio [aOR] 0.34; 95% confidence interval [CI]: 0.17, 0.69) when compared to infants who were formula-fed. Adjusted for feeding, introduction of complementary foods after 4 months was associated with decreased odds of rapid increase in WLZ (aOR 0.64; 95% CI: 0.42, 0.96). CONCLUSIONS: Feeding typified by predominant breastfeeding and delaying introduction of complementary foods after 4 months reduces the odds of rapid increases in WAZ and WLZ in the first year of life.

Maintaining the validity of inference in small-sample stepped wedge cluster randomized trials with binary outcomes when using generalized estimating equations.

Stepped wedge cluster trials are an increasingly popular alternative to traditional parallel cluster randomized trials. Such trials often utilize a small number of clusters and numerous time intervals, and these components must be considered when choosing an analysis method. A generalized linear mixed model containing a random intercept and fixed time and intervention covariates is the most common analysis approach. However, the sole use of a random intercept applies a constant intraclass correlation coefficient structure, which is an assumption that is likely to be violated given stepped wedge trials (SWTs) have multiple time intervals. Alternatively, generalized estimating equations (GEE) are robust to the misspecification of the working correlation structure, although it has been shown that small-sample adjustments to standard error estimates and the use of appropriate degrees of freedom are required to maintain the validity of inference when the number of clusters is small. In this article, we show, using an extensive simulation study based on a motivating example and a more general design, the use of GEE can maintain the validity of inference in small-sample SWTs with binary outcomes. Furthermore, we show which combinations of bias corrections to standard error estimates and degrees of freedom work best in terms of attaining nominal type I error rates.

Pharmacokinetics of pertuzumab administered concurrently with trastuzumab in Chinese patients with HER2-positive early breast cancer.

In the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G), pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer. The objective of this analysis was to assess the pharmacokinetics of pertuzumab in combination with trastuzumab in Chinese patients with early breast cancer. Samples for pertuzumab and trastuzumab pharmacokinetic analysis were taken from Chinese patients during cycle 1 of treatment and at steady-state in cycle 10. Noncompartmental analysis was used to estimate minimum and maximum serum concentrations (Cmax and Cmin), area under the concentration-time curve, clearance, and other pharmacokinetic parameters. In 15 patients, mean steady-state Cmax and Cmin pertuzumab serum concentrations (368 ± 177 µg/ml, and 122 ± 47 µg/ml, respectively) were numerically higher than observed previously in a pharmacokinetic analysis of the global population in APHINITY and in patients treated in the metastatic setting. The geometric mean ratio and corresponding 90% confidence interval for trastuzumab Cmax and Cmin in the presence (n = 15) or absence (n = 17) of pertuzumab were 104.6 (91.09-120) and 98.23 (84.58-114), respectively, indicating no apparent impact of pertuzumab on the pharmacokinetics of trastuzumab. Increases in pertuzumab Cmax and Cmin were not associated with an increase in adverse events. The APHINITY Chinese pharmacokinetic substudy analysis supports the dosing regimen for pertuzumab (840 mg loading dose followed by 420 mg maintenance doses every 3 weeks administered by intravenous infusion) in a Chinese HER2-positive early breast cancer patient population.

Pharmacokinetic and exposure-response analysis of pertuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer.

PURPOSE: To characterize the pharmacokinetics (PK) of pertuzumab and trastuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer in the randomized, double-blind, phase III JACOB study (NCT01774786), and to evaluate the appropriateness of the pertuzumab regimen in these patients. METHODS: Patients received 840 mg intravenous pertuzumab or placebo plus trastuzumab q3w and chemotherapy. Pertuzumab and trastuzumab were administered until disease progression or unacceptable toxicity. Chemotherapy was administered for up to six cycles or disease progression or unacceptable toxicity. Serum concentrations of pertuzumab and trastuzumab were measured. Pertuzumab PK was characterized across treatment cycles. The impact of anti-drug antibodies (ADAs) on pertuzumab PK and the impact of pertuzumab on trastuzumab PK were assessed. An exploratory exposure-efficacy analysis was also conducted. RESULTS: In total, 374 patients in the pertuzumab arm had evaluable PK data. The mean observed pertuzumab steady-state serum trough (minimum) concentration (Cmin,ss) ± standard deviation was 114 ± 51.8 µg/mL. The target pertuzumab Cmin,ss of ≥ 20 µg/mL was reached in 99.3% of patients at Cycle 5 (steady state) and beyond. Greater than 90% of patients were above the PK target right after the first pertuzumab dose. There was no apparent impact of ADAs on pertuzumab PK nor of pertuzumab on trastuzumab PK. There were no differences in overall survival across Cycle 1 pertuzumab (Cmin) or Cycle 5 pertuzumab (Cmin,ss) exposure quartiles. CONCLUSIONS: Pertuzumab exposure in JACOB was consistent with prior studies in advanced gastric cancer and breast cancer. The 840 mg q3w dose allowed the majority of patients in JACOB to achieve target pertuzumab concentrations and appears to be an appropriate dose selection.

Pharmacokinetic and exploratory exposure-response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study.

PURPOSE: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure-response (E-R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G). METHODS: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug-drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, and AUClast geometric mean ratios with 90% CIs. Predictions of pertuzumab Cmax,ss, Cmin,ss, and AUCss were derived from individual parameter estimates and used in an exploratory E-R analysis. RESULTS: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E-R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E-R relationship was suggested with respect to other grade ≥ 3 AEs. CONCLUSION: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.

Cognitive flexibility: A distinct element of performance impairment due to sleep deprivation.

In around-the-clock operations, reduced alertness due to circadian misalignment and sleep loss causes performance impairment, which can lead to catastrophic errors and accidents. There is mounting evidence that performance on different tasks is differentially affected, but the general principles underlying this differentiation are not well understood. One factor that may be particularly relevant is the degree to which tasks require executive control, that is, control over the initiation, monitoring, and termination of actions in order to achieve goals. A key aspect of this is cognitive flexibility, i.e., the deployment of cognitive control resources to adapt to changes in events. Loss of cognitive flexibility due to sleep deprivation has been attributed to "feedback blunting," meaning that feedback on behavioral outcomes has reduced salience - and that feedback is therefore less effective at driving behavior modification under changing circumstances. The cognitive mechanisms underlying feedback blunting are as yet unknown. Here we present data from an experiment that investigated the effects of sleep deprivation on performance after an unexpected reversal of stimulus-response mappings, requiring cognitive flexibility to maintain good performance. Nineteen healthy young adults completed a 4-day in-laboratory study. Subjects were randomized to either a total sleep deprivation condition (n = 11) or a control condition (n = 8). Athree-phase reversal learning decision task was administered at baseline, and again after 30.5 h of sleep deprivation, or matching well-rested control. The task was based on a go/no go task paradigm, in which stimuli were assigned to either a go (response) set or a no go (no response) set. Each phase of the task included four stimuli (two in the go set and two in the no go set). After each stimulus presentation, subjects could make a response within 750 ms or withhold their response. They were then shown feedback on the accuracy of their response. In phase 1 of the task, subjects were explicitly told which stimuli were assigned to the go and no go sets. In phases 2 and 3, new stimuli were used that were different from those used in phase 1. Subjects were not explicitly told the go/no go mappings and were instead required to use accuracy feedback to learn which stimuli were in the go and nogo sets. Phase 3 continued directly from phase 2 and retained the same stimuli as in phase 2, but there was an unannounced reversal of the stimulus-response mappings. Task results confirmed that sleep deprivation resulted in loss of cognitive flexibility through feedback blunting, and that this effect was not produced solely by (1) general performance impairment because of overwhelming sleep drive; (2) reduced working memory resources available to perform the task; (3) incomplete learning of stimulus-response mappings before the unannounced reversal; or (4) interference with stimulus identification through lapses in vigilant attention. Overall, the results suggest that sleep deprivation causes a fundamental problem with dynamic attentional control. This element of performance impairment due to sleep deprivation appears to be distinct from vigilant attention deficits, and represents a particularly significant challenge for fatigue risk management.

Population pharmacokinetic and covariate analyses of intravenous trastuzumab (Herceptin®), a HER2-targeted monoclonal antibody, in patients with a variety of solid tumors.

PURPOSE: The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations. METHODS: Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling. RESULTS: A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range. CONCLUSIONS: Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.

Development of a Subcutaneous Fixed-Dose Combination of Pertuzumab and Trastuzumab: Results From the Phase Ib Dose-Finding Study.

Adding pertuzumab to trastuzumab (both monoclonal antibodies targeting human epidermal growth factor receptor 2 [HER2]) has proven survival benefits when combined with chemotherapy for patients with HER2-positive breast cancer. The combination of pertuzumab and trastuzumab together in 1 vial for subcutaneous (SC) administration is being developed as a ready-to-use formulation to reduce the treatment burden on patients while improving healthcare efficiency. An open-label, 2-part, phase Ib dose-finding study (NCT02738970) was undertaken in healthy male volunteers (part 1) and female patients with HER2-postive early breast cancer who had completed standard (neo)adjuvant treatment (part 2). This study aimed to identify an SC pertuzumab dose given with recombinant human hyaluronidase that results in comparable exposure to that of the intravenous (IV) pertuzumab dose, based on pertuzumab serum trough concentration and area under the serum concentration-time curve. Pharmacokinetics (PK), safety, and tolerability of a single dose of SC pertuzumab given alone or in a fixed-dose combination (comixed or coformulated) with trastuzumab were also assessed. A maintenance dose of 600 mg for SC pertuzumab resulted in an equivalent exposure to that of IV pertuzumab, and no new safety signals were identified for SC pertuzumab or trastuzumab. A loading dose of 1200 mg for SC pertuzumab was selected based on approximate dose proportionality. The PK and safety results support further development of a fixed-dose coformulation combination of pertuzumab and trastuzumab for SC administration, which will be investigated in an upcoming phase III trial in patients with HER2-positive early breast cancer.

Task and sex differences in muscle oxygenation during handgrip fatigue development.

The purpose of this study was to examine task and sex differences in forearm muscle oxygenation, measured using near infrared spectroscopy, during sustained submaximal handgrip exercises. Forty-eight adults (50% males) performed fatiguing handgrip exercises at 20, 40, 60 and 80% of their maximum handgrip strength. While males and females exhibited similar levels of relative fatigability, forearm oxygenation was found to be task (i.e. contraction intensity and phase of fatigue development) and sex dependent. Higher contraction intensities were associated with greater desaturation over time. Compared to females, males exhibited greater desaturation as fatigue progressed and this was augmented at higher contraction intensities. These may be likely affected by sex differences in muscle mass, morphology and strength differences during exercises at relative intensities. Future work that explores sex differences in muscle oxygenation during absolute force intensities are needed, which may have implications for muscle fatigue development and potential fatigue mitigation strategies. Practitioner Summary: Muscle oxygenation impacts fatigue development that can in turn affect worker health and productivity. Males exhibit greater forearm desaturation than females at higher relative work intensities, despite similar fatigue levels. Females may be predisposed to greater muscle delivery and oxygenation challenges that can increase their fatigability during work at absolute load levels.