Experimental Regimen Research Articles

A Phase 2 Study of Magrolimab Combination Therapy in Patients with Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Novel combination therapies are needed to extend the survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC). Magrolimab is a humanized monoclonal antibody that blocks the immune checkpoint CD47, a "do not eat me" signal, overexpressed on cancer cells. Magrolimab binding to CD47 leads to phagocytosis of cancer cells and enhances antitumor efficacy through stimulation of both innate and adaptive immune responses. The current study (NCT04854499) is investigating the safety, tolerability, recommended Phase 2 dose (RP2D), and efficacy of three experimental magrolimab-containing regimens: 1) magrolimab + pembrolizumab + 5-fluorouracil + platinum (cisplatin or carboplatin) [MPFP]; 2) magrolimab + pembrolizumab (MP); and 3) magrolimab + docetaxel (MD). <h3>Materials/Methods</h3> This Phase 2, open-label study includes two safety run-in cohorts and three Phase 2 cohorts. The primary endpoints of the two run-in cohorts are to evaluate the incidence of adverse events and laboratory abnormalities as dose-limiting toxicities with MPFP in patients with untreated RM-HNSCC, and with MD in patients with RM-HNSCC treated with 1 to 2 lines of prior systemic therapy. The primary endpoints of Phase 2 are to evaluate the progression-free survival with MPFP versus PFP in patients with untreated RM-HNSCC (cohort 1), and the investigator-assessed objective response rates with MP in patients with untreated RM-HNSCC with PD-L1 CPS ≥1 (cohort 2) and with MD in patients with RM-HNSCC treated with 1 to 2 lines of prior systemic therapy (cohort 3). Magrolimab is administered IV on days 1, 8 and 15 of cycles 1 and 2, and day 1 of cycle 3 onward. Pembrolizumab, 5-fluorouracil, cisplatin, carboplatin, and docetaxel will be administered according to manufacturer's prescribing information. Patients will continue treatment until unacceptable toxicity or disease progression. Planned enrollment is ∼233 participants. Recruitment is ongoing. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Hormonal, metabolic, and angiogenic responses to all-out sprint interval exercise under systemic hyperoxia

ObjectiveHyperoxic gas inhalation during exercise may negatively affect all-out sprint interval exercise (SIE)-induced hormonal, metabolic, and angiogenic responses. We investigated the effects of acute all-out SIE under systemic hyperoxia on hormonal, metabolic, and angiogenic responses. DesignThis was a randomised-crossover trial. Ten healthy males (mean ± standard error of age = 23.1 ± 0.9 years; height = 171.0 ± 1.6 cm; body mass = 66.2 ± 2.0 kg; body mass index = 22.6 ± 0.5 kg/m2) completed the following two experimental regimens: 1) SIE under normoxia and 2) SIE under systemic hyperoxia (FiO2 = 60%). The subjects performed four bouts of 30-s maximal cycling efforts with 4 min recovery between efforts. The circulating levels of hormonal (growth hormone, epinephrine, and norepinephrine), metabolic (glucose, free fatty acid, and lactate), and angiogenic (vascular endothelial growth factor, matrix metalloproteinase-2 and -9, and endostatin) markers were measured before and at 0 (immediately after the regimen), 30, and 120 min after both regimens. ResultsIn response to both SIE regimens, the peak and mean power outputs gradually decreased over the intermittent exercise session compared with those in the first bout (p < 0.01) with no significant differences between the regimens. Both regimens significantly increased the circulating concentrations of all hormonal, metabolic, and angiogenic markers (p < 0.01). However, there were no significant differences in the levels of these markers in response to the two regimens at any time point (p > 0.05). ConclusionThese findings suggest that acute systemic hyperoxia does not influence the hormonal, metabolic, and angiogenic responses to all-out SIE.

Lower Amounts of Daily and Prolonged Sitting Do Not Lower Free-Living Continuously Monitored Glucose Concentrations in Overweight and Obese Adults: A Randomised Crossover Study.

This study compared the short-term continuously monitored glucose responses between higher and lower amounts of prolonged sitting in overweight and obese adults under free-living conditions. In a randomised crossover design, 12 participants (age 48 ± 10 years, body mass index 33.3 ± 5.5 kg/m2) completed two four-day experimental regimens while wearing a continuous glucose monitor, as follows: (1) uninterrupted sitting (participants were instructed to sit for ≥10 h/day and accrue ≥7, 1 h sitting bouts each day), and (2) interrupted sitting (participants were instructed to interrupt sitting every 30 min during ten of their waking hours with 6–10 min of activity accrued in each hour). Linear mixed models compared outcomes between regimens. None of the continuously monitored glucose variables differed between regimens, e.g., 24 h net incremental area under the glucose curve was 5.9 [95% CI: −1.4, 13.1] and 5.6 [95% CI: −1.7, 12.8] mmol/L∙24 h, respectively (p = 0.47). Daily sitting (−58 min/day, p = 0.001) and sitting bouts lasting ≥30 min (−99 min/day, p < 0.001) were significantly lower and stepping time significantly higher (+40 min/day, p < 0.001) in the interrupted sitting than the uninterrupted sitting regimen. In conclusion, lower amounts of daily and prolonged sitting did not improve free-living continuously measured glucose among overweight and obese adults.

Salvage Therapy in Early Relapse of T-Lymphoblastic Leukemia/Lymphoma Using Daratumumab/Nelarabine Combination: Two Consecutive Cases

Treatment of early relapses of T lymphoblastic leukemia/lymphoma is often unsuccessful. We tested an experimental regimen containing daratumumab and nelarabine in two young patients with early relapses of T lymphoblastic lymphoma and T-ALL, respectively. Both patients achieved a deep complete remission. Combining daratumumab with chemotherapy may have a role in relapsing T lymphoblastic leukemia/lymphoma.

Prehabilitation sessions can be provided more frequently in a shortened regimen with similar or better efficacy in people with non-small cell lung cancer: arandomised trial.

In people with non-small cell lung cancer, what is the effect of condensing 15 prehabilitation sessions into a 3-week regimen compared with a 5-week regimen? Randomised controlled trial with concealed allocation, intention-to-treat analysis and blinded assessment of the primary outcome. People with diagnosed or suspected non-small cell lung cancer and moderate-to-high risk of postoperative complications. Fifteen supervised prehabilitation sessions delivered with either a dense regimen of five sessions/week for 3 weeks (experimental group) or a non-dense regimen of three sessions/week for 5 weeks (control group). The primary outcome was the change in cardiorespiratory fitness measured by the V̇O2peak in ml/kg/min. The secondary outcomes were the change in other variables of interest measured during cardiopulmonary exercise testing, non-invasive nutritional markers, quadriceps maximal voluntary isometric contractions, maximal inspiratory pressure, quality of life, adherence and postoperative complications. Changes with the experimental regimen were similar to or better than changes with the control regimen for: V̇O2peak (MD 1.2 ml/kg/min, 95% CI-0.1 to 2.6); V̇E/V̇CO2 slope (MD-3.6 points, 95% CI-8.7 to 1.5); and work rate at ventilatory threshold (MD 3.7 W, 95% CI-5.6 to 13.0). The two regimens had similar effects on: peak work rate (MD 1.3 W, 95% CI-6.4 to 9.0), V̇O2 at ventilatory threshold (MD 0.0 ml/kg/min, 95% CI-1.4 to 1.4); body mass index (MD-0.2 kg/m2, 95% CI-0.5 to 0.1); and maximal inspiratory pressure (MD-0.7 cmH2O,95% CI -9.8 to 8.4). The relative effect was uncertain for quadriceps maximal voluntary isometric contractions, quality of life and complications. Condensing prehabilitation sessions led to similar or better improvement in cardiorespiratory fitness and did not decrease adherence or increase adverse events. This could increase the number of patients who can be referred for prehabilitation, despite short presurgical periods. NCT03936764.

Immuno-oncology therapy in metastatic bladder cancer: A systematic review and network meta-analysis.

Three first line and three second-line clinical trials tested the effect of immunotherapy (IO) relative to standard chemotherapy (CT) on overall survival. However, network meta-analysis-based comparisons have not yet been presented. We addressed this void. To provide comparisons of overall survival (OS), progression-free survival (PFS), complete response (CR), partial response (PR), stable disease (SD), objective response rates (ORR), disease control rates (DCR) and adverse events (AEs) associated with 1st and 2nd line IO-based regimens. PubMed was searched for phase III randomized controlled trials from 2016 to 2021, including conference abstracts. We identified three first line [IMvigor130 (atezolizumab + CT vs atezolizumab vs CT), DANUBE (durvalumab vs durvalumab + tremelimumab vs CT), and KEYNOTE-361 (pembrolizumab + CT vs pembrolizumab vs CT)] and two second line [KEYNOTE-045 (pembrolizumab vs CT) and IMvigor211 (atezolizumab vs CT)] RCTs. Overall, 3255 and 1452 patients were respectively included in the first- and second-line settings. In 1st line setting, compared with CT, no IO-based regimen exhibited survival benefit. However, all exclusive IO regimens resulted in lower rates of grade 3+ AEs. In 2nd line setting, compared with CT, only pembrolizumab improved OS benefit. Conversely, atezolizumab only showed OS benefit in exploratory analyses. Compared to second-line CT, no experimental regimen (atezolizumab or pembrolizumab) exhibited statistically significant ORR benefit. Both pembrolizumab and atezolizumab resulted in lower rates of grade 3+ AEs compared to 2nd line CT. In metastatic UC, IO-based regimens do not hold a survival benefit relative to CT in 1st line setting. However, pembrolizumab holds a survival benefit in 2nd line compared to CT. Several IO-based clinical trials are ongoing and will provide more and possibly better treatment alternatives for locally advanced and metastatic UC.

Association of Platelet Thromboxane Inhibition by Low-Dose Aspirin With Platelet Count and Cytoreductive Therapy in Essential Thrombocythemia.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced platelet production and thrombotic complications. The inhibition of platelet cyclooxygenase (COX) activity by the standard once‐daily aspirin is mostly incomplete due to accelerated thrombopoiesis. The phase II Aspirin Regimens in EsSential thrombocythemia (ARES) trial has recently compared the efficacy of once‐ vs. twice‐ or three‐times daily low‐dose aspirin in inhibiting platelet thromboxane (TX) A2 production, as reflected by serum (s) TXB2 measurements. The present substudy characterized the determinants of the highly variable response to the standard aspirin 100 mg once‐daily regimen in fully compliant patients with ET and the effects of the experimental dosing regimens on response variability. By multivariable analysis, the platelet count (directly) and cytoreductive treatment (inversely) were significantly associated with sTXB2 values in 218 patients with ET. However, the platelet count positively correlated with sTXB2 in patients not being treated with cytoreductive drugs (ρ = 0.51, P < 0.01, n = 84), but not in patients on cytoreduction. Patients in the lowest sTXB2 quartile were older, more often on cytoreductive drugs, had lower platelet count and Janus‐Associated Kinase2 (JAK2)‐V617F allele frequency as compared with patients in the upper sTXB2 quartiles. After 2 weeks of a twice‐ or 3‐times daily aspirin regimen, the association between the platelet count and sTXB2 became similar in cytoreduced and non‐cytoreduced patients. In conclusion, the platelet count appears the strongest determinant of TXA2 inhibition by once‐daily low‐dose aspirin in ET, with different patterns depending of cytoreductive treatment. More frequent aspirin dosing restores adequate platelet inhibition and reduces interindividual variability, independently of cytoreduction.

Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial, a Mantle Cell Lymphoma Network Study

Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial, a Mantle Cell Lymphoma Network Study

Design of placebo-controlled randomized trials of anticancer agents: Ethical considerations based on a review of published trials.

Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen. Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk-benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p ≤ 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise. Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk-benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials. A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial

BackgroundTreatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.MethodsendTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.DiscussionThe lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.Trial registrationClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Exploring the Impact of Treatment Switching on Overall Survival from the PROfound Study in Homologous Recombination Repair (HRR)-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BackgroundIn oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy.ObjectiveThis study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib.Patients and methodsThe primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation.ResultsThe RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5–0.97) to between 0.42 (0.18–0.90) and 0.52 (0.31–1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control.ConclusionsThe magnitude of the statistically significant (P < 0.05) survival benefit of olaparib versus control observed in Cohort A of PROfound is likely to be underestimated if adjustment for treatment switching from control to olaparib is not conducted. The RPSFTM was considered the most plausible method, although further development and validation of robust methods to estimate the magnitude of impact of treatment switching is needed.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00837-y.

Diagnostic Accuracy of Magnetic Resonance Imaging in Predicting Malignancy in Musculoskeletal Tumors

Background: Tumors of the musculoskeletal system may arise in bone or soft tissues including muscle and cartilage. Because of experimental chemotherapeutic medications and regimens, as well as improvements in imaging and surgical methods, the prognosis of patients with musculoskeletal tumors has increased dramatically. Aim: To determine the diagnostic accuracy of magnetic resonance imaging in detection of musculoskeletal tumor taking histopathology as gold standard Study Design: It was cross sectional study Setting: Department of Radiology, Mayo Hospital, Lahore Duration: six months i.e. July 2020 to Dec 2020. Methods: After meeting the inclusion criteria 135 cases were enrolled. Informed consent and demographic information was taken from all the patients. All malignancies were confirmed by surgical histology. MRI was performed routinely on 1.5 Tesla and 3 Tesla. Patients were considered as the confirmed cases of tumors on MRI and histopathology as per operational definition. All the collected data was analyzed on SPSS vr 21. Results: In this study the mean age of the patients was 42.59±10.16 years, male to female ratio of the patients was 0.68:1. The mean value of duration of disease of the patients was 2.95±1.42 months. The sensitivity, specificity, and diagnostic accuracy of MRI for detecting musculoskeletal tumors was 89.23%, 88.57%, &amp; 88.89% respectively taking histopathology as gold standard. Conclusion:This finding concluded that the magnetic resonance imaging is very useful and reliable technique in detection of musculoskeletal tumor with high diagnostic accuracy Keywords: Magnetic Resonance Imaging, Musculoskeletal Tumor, Histopathology

Assessing the competency of a semi-parametric expert system in the realms of response characterization uncertainty in premixed methanol dual fuel diesel combustion strategies: In critique to RSM

Engine response characterization endeavours of the day are faced with the contradictory obligations of developing an accurate engine response map in face of an ever-expanding parametric space and decreasing test-bench based prototype development time cycles. Under such imperatives of sparse experimental regimens, the present study focuses on the pivotal notions of reliability in a data-driven multi-variate response modelling endeavour in the complex realms of a premixed methanol dual fuel diesel operation. In the study, the Gene Expression Programming (GEP) technique with its distinguishing features of adaptivity in model evolution has been critically examined for its credibility as an expert system in such emerging combustion strategies. The relevance and competency of the GEP method has been rationalized to this end by comparing its performance with the traditional Response Surface Methodology which has been the mainstay in such engine response characterization objectives. Model integrity has been analysed and compared through a multitude of conventional and improvised statistical goodness-of-fit measures encompassing absolute and relative error metrics. Model reliability was adjudged through an exhaustive uncertainty analysis. Information theoretic measures of Kullback-Leibler divergence and improvised Thiel uncertainty coefficients were employed to compare the quality of system knowledge gained by the competing techniques. Generalization capability was reckoned through all the respective metrics applied across a test data set held blind to the meta-model training sequence. Comparable regression scores across conventional and standardized correlation measures notwithstanding, all GEP evolved meta-models registered substantially lower footprints in all statistical error metrics together with lower uncertainty bandwidths of estimation and information loss across both training and test data simultaneously for all responses explored. The outcome of the study arguably evokes considerable reconsideration on the choice of conventional RSM based characterization strategies in the paradigms of system response uncertainty prevalent in the emergent engine combustion strategies involving significant yet unknown degrees of non-linearity in its parametric operational space.

Improved Outcome with a Pediatric-Inspired Regimen for Philadelphia-Negative Acute Lymphoblastic Leukemia in the Elderly

Background: Approximately 30% of adult acute lymphoblastic leukemia (ALL) occurs after the age of 60. The improvements observed in the past decade in adults with pediatric-inspired regimen do not translate in this population with increase treatment related toxicity and early deaths. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Our center report the outcome of a regimen designed to improve the outcome of the EWALL backbone taking advantage of the favorable results of pediatric-inspired protocols in younger adults and retrospectively compared it to an historical cohort.Methods: Since 2012, patients > 60 y-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase followed by a third consolidation course. Monthly maintenance course was then started for CR patients. CNS prophylaxis included intrathecal injections and cranial irradiation. Consolidations included 9 cycles alternating cytarabine (8000mg/m2) intermediate-dose methotrexate (1500mg/m2) and cyclophosphamide (1000mg/m2) plus VP-16 (150mg/m2). Patients aged more than 70 years received reduced doses of chemotherapy during consolidation. Treatments are detailed in the table. We retrospectively compared the outcomes with those observed in patients > 60 y-old treated according to the EWALL induction and consolidation backbone (Goekbuget et al. 2008) in our center between 2007 and 2011.Results: Twenty-four patients were included in the study. Median age was 67 [IQR: 64-71]. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Twenty-one patients were included in the historical cohort treated according to the EWALL backbone from 2007 to 2011. Main baseline characteristics were well balanced between the two study cohorts. Complete remission (CR) rate was 81% in the experimental cohort versus 79% in the historical cohort. The induction deaths were 4% in the experimental cohort versus 14% in the historical cohort. All patients in CR (19) in the experimental group were eligible to intensive consolidations and late intensification. Two of these patients were unable to reach maintenance phase (1 deterioration of general status and 1 relapse) and 1 patients omitted late intensification because of renal failure. During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days [IQR: 4-14]. Six patients (32%) developed an infection during consolidation courses and 3 patients during late intensification course. Major toxicities during pediatric-inspired consolidation courses included infections (9 patients, including three with bacteremia, two with pyelonephritis and one with pneumonia), grade 3-4 liver toxicity (6), acute kidney failure (3) and hyperglycemia requiring insulin (1). Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. No death was observed during consolidations or late intensification. The median follow up times were 2,6 years and 8,2 years for the experimental cohort and the historical cohort, respectively. The experimental regimen translated into a significantly longer two years disease-free survival (57% [IC95% 31-76] vs 29% [IC95% 11-51] p=0.007 by log-rank test) and a longer two years overall survival than the historical cohort (54% [CI95% 30-73] vs 24% [CI95% 12-47] p=0.01 by log-rank test). The OS and DFS of the experimental and historical cohorts are show in the figure.Conclusion: Results presented here strongly suggest that an intensified pediatric-inspired protocol after an age-adapted induction course might yield significantly better results than former protocols in older adults with Ph-negative ALL. The intensity of this consolidation treatment was tolerable, and the low rate of relapse is promising in this population with an unmet medical need. [Display omitted] DisclosuresForcade:Neovii: Other: Travel grant.

Comparative efficacy evaluation of different penetration enhancement strategies for dermal delivery of poorly soluble drugs – A case with sertaconazole nitrate

The aim of this study was to compare the efficacy of different approaches for enhancement of dermal availability of the highly lipophilic antifungal model drug – sertaconazole nitrate (SN). For this purpose, a physical penetration enhancer – dissolving microneedles (MNs) was fabricated by filling moulds with liquid formulation based on polyvinylpyrrolidone and loaded with SN. Dissolving MNs were characterised regarding their morphological and mechanical characteristics. A penetration enhancement efficacy of MNs was evaluated in vitro using porcine ear skin in parallel with the efficacy of formerly developed chemical penetration enhancer – biocompatible microemulsion (ME) formulation. Moreover, an ability of solid silicon MNs to significantly improve delivery of SN from ME into the skin has also been investigated. The obtained results showed that dissolving MNs had satisfying morphological properties and mechanical strength. This type of MNs provided comparable drug deposition in the skin as ME formulation, but also revealed an indication of percutaneous absorption of a portion of the administered drug dose. However, the penetration/permeation study results were largely influenced by experimental setup and dosing regimen. Although solid silicon MNs assisted SN dermal delivery led to increase of drug cutaneous retention (1.9-fold) under infinite dosing regimen, the synergistic action of solid MNs and ME applied under finite dosing was more pronounced in comparison with the application either of physical (dissolving MNs) or chemical enhancer (ME) alone. Namely, SN amount accumulated into the skin increased up to 4.67 and 4.37 folds in comparison with ME and dissolving MNs alone, respectively, while reaching a significant decrease in drug permeation through the skin compared to the use of dissolving MNs. Application of ME per se was the only approach that provided selective in vitro dermal drug delivery without SN permeation across the skin. However, despite both types of the used MNs lead to SN permeation in vitro, the ratio between the drug amount deposited in the skin and SN content permeated was significantly higher for the combined approach (12.05) than for dissolving MNs (2.10). Therefore, a combination of solid silicon MNs and biocompatible ME favoured more pronouncedly SN skin accumulation, which is preferable in the treatment of skin fungal infections.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA study.

3511 Background: Preop CTRT is considered the standard of care in the management of LARC. RT can induce antigen release from a low neoantigen-burden tumor (such as a mismatch repair proficient colorectal cancer) and activate dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response. In LARC patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. Based on such considerations, we have designed the AVANA study to investigate the role of Ave in combination with preop CTRT in LARC. Methods: This is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features: cN+, cT4, high risk cT3, received standard preop CTRT (capecitabine 825 mg/sqm/bid 5 days/week+ 50.4 Gy in 28 fractions over 5.5 weeks) plus 6 cycles of Ave 10 mg/Kg every 2 weeks. Surgery with total mesorectal excision was performed at 8-10 weeks after the end of CTRT. The primary end-point was the pCR rate, defined as complete histological regression with no available tumor cells ypT0N0. Secondary end-points were R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile, and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-side), and a power of 80%, a sample size of 101 pts was needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen is considered for further studies if, in at least 22 pts, we observe a pCR. Results: From April 2019 to November 2020, a total of 101 resectable LARC pts were enrolled in 10 Italian Centers. The median age was 63 years (23-82), 62 (61.4%) pts were male, 93 (92%) had ECOG PS 0. At baseline, 94 (93%) and 16 (16%) pts had cN+ and cT4 LARC, respectively. All pts completed the induction phase. Out of 96 pts evaluable for pathological response, 22 (23%) pts achieved a pCR and 59 (61.5%) pts a major pathological response (a central review is ongoing). At this time, microsatellite status is available only in 39 pts, of which only one was instable. The rate of grade 3-4 non-immune and immune-related adverse events was 8% and 4%, respectively. Avelumab was early interrupted in 9 pts out 101, mainly due to toxicity. Conclusions: The combination of preop CTRT plus Ave showed a promising activity and a feasible safety profile. According to our statistical considerations, the experimental regimen will be considered for further studies. Updated results will be presented during the Congress. Sponsored by GONO and partially supported by Merck. EUDRACT 2017-003582-10. Clinical trial information: NCT03854799.

Phase II trial of perioperative chemotherapy + avelumab in locally advanced gastroesophageal adenocarcinoma: Preliminary results.

4046 Background: Perioperative chemotherapy improves cure rate in locally advanced gastroesophageal adenocarcinoma (GEA), and immune checkpoint inhibitors are active at the metastatic stage. This trial tests the hypothesis that the addition of avelumab to perioperative chemotherapy will increase the major pathologic response (MPR) rate in comparison with historical controls. Methods: Phase II study of avelumab + chemotherapy (docetaxel, cisplatin and 5-FU or mDCF) given every 2 weeks for 4 cycles before and after surgery. Main inclusion criteria: GEA, cT3 and/or cN+, M0, WHO PS 0-1. Main exclusion criteria: use of immunosuppressants, serious autoimmune disease, daily intake &gt;10 mg prednisone. Staging studies: CT, PET-CT, endoscopic ultrasound, diagnostic laparoscopy. Surgical resection: D2 lymphadenectomy, en-bloc esophagectomy for type I/II gastroesophageal junction (GEJ) tumors. Aim of the study: MPR as defined as tumor regression grades 0-1 (modified Ryan scheme); as per hypothesis, this experimental regimen will result in a 20% rate of MPR, compared with 7% with chemotherapy alone. Simon 2-stage design: if less than 2 MPR are seen in the first 16 patients, the study will be closed. The study hypothesis cannot be rejected if at least 6 MPR are seen in the first 50 patients. All adverse effects are prospectively recorded per CTCAE guidelines in patients who have received at least one treatment cycle. Survival rates are calculated with Kaplan-Meier method. Preliminary results are presented since the study has met its primary endpoint. Results: Feb 2018-Feb 2020: 28 patients enrolled (25 M/3 F, age 45-78). Location: GEJ (23), stomach (5). Staging: cT3 (25), cT4 (1), cN+ (20). Biomarkers expression: mismatch repair (MMR) protein loss (3/28); PD-L1(clone 73-10) expression in 1% (TPS) or more of tumor cells seen in 12/28 samples, and &gt;10% in 6 patients. Grade 3 toxicity: stomatitis (2/28); nausea (2/28); vomiting (1/28); diarrhea (1/28); hypothyroidism (1/28); arthralgia (3/28); neutropenia (1/28). Grade 4 toxicity: pneumonia (1/28); neutropenia (2/28). Postoperative 30-day mortality: 0%. One patient was excluded from efficacy analyses for M1 staging; 27 patients underwent surgery, 26 with R0 (96%). Six cases (22%) show MPR: 3 grade 0 (11%) and 3 grade 1 (11%) tumor regressions. No correlation was seen between MMR proteins or PD-L1 expression and tumor regression. With a median follow-up of 1.5 years (range 0.4-2.5), the disease-free survival rate is projected to be 0.92 (95% CI 0.83-1.00) at 12 months and 0.77 (95% CI 0.58-1.00) at 24 months. Conclusions: The combination of mDCF chemotherapy with Avelumab demonstrates a promising safety and activity profile. Ongoing laboratory investigations are underway to correlate our findings with tumor molecular features before exposure to treatment. Clinical trial information: NCT03288350.

Patient experience of early high grade symptomatic adverse events on early phase clinical trials using the PRO-CTCAE.

12051 Background: There are limited data describing the patients’ experience of symptomatic adverse events (syAEs) on early phase clinical trials. This information is critical to understand the tolerability of experimental agents. The patient reported outcome version of the CTCAE (PRO-CTCAE) evaluates syAE components such as severity and interference in daily life. The aim of this study was to correlate clinician reported early, high grade (grade 3-4) AEs with patients’ reported experience of these toxicities. Methods: Advanced solid tumor patients (pts) enrolled on early phase clinical trials at Princess Margaret Cancer Centre were surveyed electronically using the full library of 78 items for PRO-CTCAE v1.0, which was administered at baseline (prior to therapy), mid-cycle 1, and mid-cycle 2. AEs on study were recorded by physicians using the CTCAE v4.0. Worst responses for severity items are ‘severe’ and ‘very severe’ and for interference items are ‘quite a bit’ and ‘very much’. A logistic regression model was used to assess the association between CTCAE grade and PRO-CTCAE severity and interference. Results: A total of 292 pts were approached in phase 1 clinics from May 2017 to January 2019, and 219 pts were included in the analysis: median age 60 years (range 18-82), 111 (51%) were male; all were ECOG ≤1. A total of 140 pts (64%) received combination therapy (immunotherapy and targeted therapy), and 73 pts (33%) had received ≥3 previous lines of treatment. In terms of patient reported syAEs, a total of 114 pts (52%) reported a symptomatic AE as either severe or very severe at any timepoint and 79 pts (36%) reported a syAE with an interference that was either ‘quite a bit’ or ‘very much’. With regards to clinician reported AEs, a total of 82 pts (37%) had a clinician reported grade 3 or 4 syAE, and of these 34 pts (41%) reported these as either severe or very severe; and 26 pts (32%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Additionally 137 pts (66%) had a clinician reported grade 1 or 2 syAE, and of these 39 pts (28%) reported these as either severe or very severe; and 19 (14%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Higher grade clinician reported syAEs (CTCAE grade 3-4 vs 1-2) was associated with higher patient reported severity levels (odds ratio, OR = 1.78, 95% CI 1-3.16, p = 0.049), and was associated with higher patient reported interference levels (OR = 2.88, 95% CI 1.47-5.64, p = 0.002). Conclusions: A majority of patients had a very negative experience of syAEs on a phase I trial. Higher grades of clinician reported AEs correlated with greater severity and interference with daily living. Future phase I studies could incorporate the PRO-CTCAE and other PRO tools which could inform the tolerability of experimental regimens and enhance the description of symptomatic AEs.

Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy.

Simple SummaryMalignant pleural mesothelioma (MPM) is a rare cancer with an aggressive disease course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic therapy remains an accepted standard-of-care around the world. Given the rare incidence of MPM and the disease’s aggressive nature, novel clinical trial designs are required. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. In this study, a nomogram model was created to estimate survival with treatment with platinum-pemetrexed using covariates known to be associated with survival, including median age, gender, ECOG performance status, tumor stage, and tumor pathology subtype. Collaborative efforts can drive the change in the right direction, and appreciable progress has to be facilitated and newer trial designs may need to pave the way for future innovations in this rare disease.(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.