Dosing Schedule Research Articles

DDDR-45. INVESTIGATING TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA USING A CLINICALLY RELEVANT DOSING REGIMEN

Abstract The standard of care of management for glioblastoma, the most common primary malignant brain tumor in adults, involves maximal safe surgical resection followed by adjuvant chemoradiotherapy and six cycles of adjuvant temozolomide (TMZ). Approximately half of all treated patients develop chemoresistance to TMZ. The evolution of chemoresistance to temozolomide in vitro has historically involved continuous exposure to drug, as opposed to clinical dosing schedules, which involve five days of treatment followed by 23 days of recovery. Thus, in this study, we examined the emergence of chemoresistance to TMZ in vitro, using a clinical dosing regimen. Temozolomide dose response to RN1, an MGMT promoter unmethylated, IDH-wildtype, patient-derived glioblastoma cell line, was determined using cell titer glo. Cells were treated with TMZ for five days, followed by 23 days of recovery, in cycles. In each subsequent cycle, the dose of TMZ used was adjusted to previous cycle’s IC50, the concentration at which 50% of cell growth is inhibited. This protocol was repeated over three rounds. Cells treated with TMZ, as compared to the DMSO-treated control population, gradually acquired chemoresistance with a continuous increase in IC50. Our protocol therefore highlights how a clinically relevant dosing regimen may help capture the trajectory by which chemoresistance emerges, also allowing for the exploration of the molecular mechanisms underlying this phenomenon.

A retrospective evaluation of supratherapeutic dosing of paracetamol among hospitalised adult patients

Abstract Introduction Paracetamol has a maximum daily dose of 4g/24 hours, with a lower maximum dose (60mg/kg/day) for those weighing under 50kg. Various studies have reported on the extent of supratherapeutic dosing in hospital inpatients.1,2,3 Furthermore, there have been a number of datix incidents of supratherapeutic dosing of paracetamol in our hospital. We investigated how often adult patients are administered too high a daily dose. Aim To ascertain the extent of greater than maximum administration (4g/24 hours) paracetamol for adult inpatients and where the patient’s weight has been recorded, to report on excessive administration for low body weight patients (less than 50kg). Method A retrospective analysis of inpatients 18 years and older administered paracetamol from August 1st 2022 to July 31st 2023. The download from the e-prescribing system (EPS) included various patient characteristics. This dataset was subsequently cleaned and duplicates identified. Microsoft Access was used to run queries to produce a working dataset. As this project falls under the definition of service evaluation, according to UK NHS Research Ethics Committees, formal ethical approval was not required. This project was registered on the hospital’s clinical audit database. Results 30,716 adults (mean age 59, 41% male) received one or more doses during their stay and 10.2% of these received a supratherapeutic daily dose. Females received 61.2% of the supratherapeutic doses, with 1,909 (10.6%) of 18,088 females receiving doses higher than should have been administered. Of the 30,716 adult patients, 1108 of them weighed less than 50kg and 420 (37.9%) of these received a supratherapeutic dose (based on their weight) on one or more days. Of the total 383,222 doses recorded, 82,327 (21.5%) doses were recorded and administered under “as required” (PRN) doses, and 78.5% (n=300,895) as scheduled doses. 2446 (10.4%) of 23,459 adults who received ≥1 scheduled doses had an unintentional overdose on one or more days, with 26,714 total overdoses recorded. 315 (2.2%) of 14,159 adults who received one or more doses PRN, received 1,873 total overdoses. Discussion / Conclusion Overall we found 10.2% of adult patients received a daily dose over their patient-specific maximum dose, on at least 1 day. Older studies report slightly lower proportions (6.01%, 6.6%)1,2 than a more recent study (at 17.4%).3 A greater proportion of relative overdosing based on weight, as we found, has been reported elsewhere.3 We also observed that scheduled doses were nearly five times more likely to be the final dose of a supratherapeutic dose on at least one day, and scheduled doses appeared to be present nearly twice as often as PRN when a patient received one or more supratherapeutic dose. It is unclear why such a discrepancy occurred. Our EPS database enabled more extensive data collection than some other published reports, however limitations include possibly counting overdoses not clinically relevant e.g. fifth dose scheduled for hour 25 but given at hour 24. We did not include paracetamol combination products in our analysis. These results will be shared with nursing staff and consideration will be given to any possible alert for our EPS.

Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer.

The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.

Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression.

STAT3 is an attractive therapeutic target for cancer and other human diseases. We have previously reported the discovery of potent, selective, and efficacious PROTAC STAT3 degraders SD-36 and SD-91. In this study, we have designed and synthesized a novel series of STAT3 degraders using a new, high-affinity STAT3 ligand with excellent chemical stability and cereblon ligands. Our efforts led to the discovery of SD-436, a highly potent and selective STAT3 degrader. A single intravenous administration of SD-436 at 5 mg/kg effectively induces rapid, complete, and durable depletion of STAT3 in mouse native and xenograft tumor tissues. SD-436 achieves complete and long-lasting tumor regression even with a weekly dosing schedule in leukemia and lymphoma xenograft models in mice. SD-436 represents a promising STAT3 degrader for advanced preclinical development as a new therapy for the treatment of human cancers and other human diseases.

The impact of COVID-19 on routine child immunisation in South Africa

BackgroundThe COVID-19 pandemic disrupted immunisation programs worldwide, reversing gains that had brought vaccine-preventable diseases largely under control. This study explored the impact of COVID-19 on the uptake of routine child immunisation services in South Africa.MethodsWe conducted qualitative research using in-depth interviews with 51 purposively selected parents/caregivers of children below the age of five who missed or delayed one or more scheduled immunisation doses in 2020–2022 and with 12 healthcare providers who provided public immunisation services during the pandemic.ResultsDuring the pandemic lockdowns, most caregivers perceived the risk of their child being infected with COVID-19 during a clinic visit as more salient than the risk of missing immunisation doses. Caregivers reported minimal exposure to routine immunisation communication, as well as shortages of routine vaccines for children at public health facilities, healthcare workers experienced anxiety and burnout. There was a post-pandemic shift to more active decision-making about immunisation, which had previously been an almost automatic behaviour, leading some caregivers to delay vaccinating their children. There was also evidence of a “bad vaccine” mental model among some caregivers regarding COVID vaccinations, which could lead to doubts about the safety of routine childhood vaccinations.DiscussionThe shift from default to active decision-making highlights a risk that routine immunisation will backslide in future pandemics. Governments should build resilient health systems at all levels and communicate clearly about the benefits and availability of RIs and the safety of vaccinations in general, alongside supply-side interventions.ConclusionRoutine immunisation is widely accepted in South Africa, driven by generational norms and provider recommendations. During the COVID-19 pandemic, many caregivers faced the dilemma of balancing COVID-19 exposure risk with the risk of their child developing a deadly VPD, leading to missed RI visits. This shift to active decision-making highlights a future pandemic risk. Governments should build resilient health systems and focus on understanding and engaging procrastinating and doubtful caregivers. Clear communication about RI benefits and vaccine safety is crucial, as misinformation can lead to distrust in new vaccines.

Evidence for an HPV one-dose schedule

The World Health Organization has recently updated their dosing schedule recommendations for the human papillomavirus (HPV) vaccine to include a single-dose schedule. We review the biologic plausibility of a single dose, the evidence from clinical trials, post-licensure observational studies, and mathematical modeling for a single-dose schedule. We also discuss the implications of countries switching to a single-dose program from a two or three-dose schedule. Finally, we review the countries that have currently switched to or introduced the vaccine with a single-dose schedule.

Interspecies interactions alter the antibiotic sensitivity of Pseudomonas aeruginosa.

Polymicrobial infections are infections that are caused by multiple pathogens and are common in patients with cystic fibrosis (CF). Although polymicrobial infections are associated with poor treatment responses in CF, the effects of the ecological interactions between co-infecting pathogens on antibiotic sensitivity and treatment outcome are poorly characterized. To this end, we systematically quantified the impact of these effects on the antibiotic sensitivity of Pseudomonas aeruginosa for nine antibiotics in medium conditioned by 13 secondary cystic fibrosis-associated bacterial and fungal pathogens through time-kill assays. We fitted pharmacodynamic models to these kill curves for each antibiotic-species combination and found that interspecies interactions changing the antibiotic sensitivity of P. aeruginosa are abundant. Interactions that lower antibiotic sensitivity are more common than those that increase it, with generally more substantial reductions than increases in sensitivity. For a selection of co-infecting species, we performed pharmacokinetic-pharmacodynamic modeling of P. aeruginosa treatment. We predicted that interspecies interactions can either improve or reduce treatment response to the extent that treatment is rendered ineffective from a previously effective antibiotic dosing schedule and vice versa. In summary, we show that quantifying the ecological interaction effects as pharmacodynamic parameters is necessary to determine the abundance and the extent to which these interactions affect antibiotic sensitivity in polymicrobial infections.IMPORTANCEIn cystic fibrosis (CF) patients, chronic respiratory tract infections are often polymicrobial, involving multiple pathogens simultaneously. Polymicrobial infections are difficult to treat as they often respond unexpectedly to antibiotic treatment, which might possibly be explained because co-infecting pathogens can influence each other's antibiotic sensitivity, but it is unknown to what extent such effects occur. To investigate this, we systematically quantified the impact of co-infecting species on antibiotic sensitivity, focusing on P. aeruginosa, a common CF pathogen. We studied for a large set co-infecting species and antibiotics whether changes in antibiotic response occur. Based on these experiments, we used mathematical modeling to simulate P. aeruginosa's response to colistin and tobramycin treatment in the presence of multiple pathogens. This study offers comprehensive data on altered antibiotic sensitivity of P. aeruginosa in polymicrobial infections, serves as a foundation for optimizing treatment of such infections, and consolidates the importance of considering co-infecting pathogens.

A prospective cohort study comparing efficacy of 1 dose of quadrivalent human papillomavirus vaccine to 2 and 3 doses at an average follow up of 12 years postvaccination

Abstract Background While recommending a human papillomavirus (HPV) single-dose vaccination schedule in 2022, the World Health Organization highlighted the need for long-term follow-up studies to monitor waning of protection. We report on vaccine efficacy against HPV infections in 1-, 2-, and 3-dose schedules and protection against cervical precancers at a median follow-up of 12 years postvaccination. Methods This randomized multicenter study in India was originally designed to vaccinate unmarried girls aged 10-18 years with either 2 or 3 doses of quadrivalent HPV vaccine. A ministerial decree to halt vaccination in trials resulted in the creation of cohorts receiving different doses, including just a single dose. Cohorts were assessed for incident and persistent infections by genotyping cervical samples collected yearly for 4 consecutive years after participants were married. Cervical screening with an HPV test was initiated at age 25 years for married participants. Age- and site-matched unvaccinated married women were recruited to be compared with vaccinated cohorts. Vaccine efficacy was assessed using proportional incidence ratios. Results The number of participants in the 1-, 2- (at 0 and 6 months), and 3-dose cohorts was 4949, 4980, and 4348, respectively. Of the recipients, 71%-82% in the different cohorts were eligible to provide samples for genotyping. Vaccine efficacy against persistent HPV 16 and 18 infection was 92.0% (95% confidence interval [CI] = 87.0% to 95.0%) in 3022 recipients of the single dose; and comparable with that observed in the 2-dose arm (94.8%, 95% CI = 90.0% to 97.3%) and the 3-dose arm (95.3%, 95% CI = 90.9% to 97.5%). No high-grade precancer associated with HPV 16 and 18 was detected among vaccinated participants compared with 8 precancers detected among the unvaccinated women. Conclusion This observational cohort study has established that a single dose of HPV vaccine provides high protective efficacy against persistent HPV 16 and 18 infections and associated neoplasia 15 years postvaccination.

Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial.

Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors. The safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Eligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle. A total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort. Adverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy. ClinicalTrials.gov, NCT02511795 (registration: 28 July 2015).

Protocol compliance in a multicentric phase III trial investigating scheduled adaptive radiotherapy and dose painting in head and neck cancer

PurposeTo report on quality assurance (QA) and protocol adherence (PA) in a multicentre phase III trial for head and neck cancer, evaluate patterns of protocol deviations and investigate the effect of PA on study outcomes. MethodsAll 221 patients from the ARTFORCE trial (NCT01504815) were included in this study. Pre- and per-treatment QA measures included protocol guidelines, a dummy run, early case reviews and trial meetings. FDG-PET-guided dose painting and scheduled adaptive radiotherapy were reviewed in patients in the experimental arm (eRT). Patient and disease characteristics, as well as institutes’ accrual rate and timing were examined for correlation with PA. Cox regression was used to determine the impact of PA on outcome. ResultsThe dummy run was completed in all nine institutes and early case reviews were completed in five out of nine institutes that contributed 190 out of 221 patients. Among all patients randomized to eRT, 64 % had at least one deviation of the experimental trial components. Protocol deviations were significantly correlated with the institute patients were treated at (Cramer’sV 0.34–0.48). Despite early identification of institute-specific deviations in QA, these continued during the trial. No significant associations were seen between deviations and accrual timing or rate (P ≥ 0.26). Within eRT, no significant relation was observed between experimental PA and locoregional control (LRC), the primary endpoint of the trial (P≥.15). ConclusionsDespite QA, protocol deviations persisted during the trial, which were mostly institute-specific. However, deviations of the experimental treatment strategy did not significantly impact LRC and therefore the trial conclusion.

Population-level health impact of hypothetical waning 1-dose human papillomavirus vaccination and 2-dose mitigation strategies in a high cervical cancer burden setting

Abstract Background We simulated the impact of hypothetical waning scenarios of a 1-dose human papillomavirus (HPV) vaccination paired with switching to 2-dose mitigation strategies guided by empirical vaccine trial reporting timelines. Methods Using 2 independent mathematical models fitted to a high-burden setting, we projected the cumulative cervical cancer cases averted over 85 years for alternative HPV vaccination scenarios under 2 program adoption timelines: 1) de novo introduction of a 1-dose HPV vaccination and 2) a switch from an existing 2-dose HPV vaccination program to a 1-dose vaccination. We assumed 80% vaccination coverage with the bivalent vaccine and an average duration of a 1-dose HPV vaccine protection of either 30 or 25 years with 100% efficacy. We varied the eligible age group(s) at program introduction and the 2-dose mitigation (single-age cohort or multi-age cohort). If needed for mitigation, reintroduction of 2-dose vaccination was assumed to occur in 2036 (ie, 30 years after initiation of the Costa Rica Vaccine Trial). Results Under both vaccine adoption timelines, the models projected that countries could achieve the same level of health benefits by switching to 2 doses in 2036 using a multi-age cohort approach as with initiating a 2-dose or 1-dose vaccination program with no waning. With only a single-age cohort 2-dose mitigation approach, 98%-99% of cases would be prevented compared with the health benefits of 2 doses or a noninferior, durable 1 dose. Conclusions Countries hesitant to adopt a 1-dose HPV vaccination program may have opportunities to leverage the benefits and efficiency of a 1-dose schedule while awaiting longer-term reporting from 1-dose durability studies, including Costa Rica Vaccine Trial.

Improvement of fatigue, depression, and processing speed two weeks post Natalizumab infusion in Multiple Sclerosis: No difference between standard and extended interval dosing schedules

BackgroundFatigue, depression and slow processing speed are debilitating symptoms in people with Relapsing-Remitting Multiple Sclerosis (RRMS) that significantly impacts on the quality of life. Natalizumab, a disease-modifying treatment, improves clinical symptoms but questions remain about the comparative efficacy between its standard interval dosing (SID) and extended interval dosing (EID) schedules. ObjectiveTo examine the impact of short term natalizumab dosing schedules—SID versus EID—on the so called “invisible symptoms”, specifically focusing on symptom exacerbation during the 'wearing-off' phase before infusion and the subsequent relief post-infusion. MethodsForty-two RRMS patients were assessed one week before (T0) and two weeks after pre-and post-natalizumab infusion (T1) for fatigue symptoms using the Fatigue Scale for Motor and Cognitive Functions (FSMC), the Modified Fatigue Impact Scale (MFIS), and the Fatigue Symptoms and Impacts Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS). Processing speed and depression were measured by the symbol digit modality test (SDMT), and the Beck Depression Inventory-II (BDI-II). Participants were categorized into either the SID or EID dosing schedules of natalizumab, and their outcomes were compared. ResultsForty-two patients (21 SID; 21 EID) completed the study. Fatigue severity scales, SDMT, and BDI-II scores improved from T0 to T1. No significant differences in fatigue symptoms were found between the SID and EID groups, whether during the "wearing-off" period (T0) or post-infusion (T1). ConclusionsBoth SID and EID dosing regimens of natalizumab are similarly effective in reducing fatigue symptoms, depression and improving processing speed in individuals with RRMS, with no observed differences during the "wearing-off" periods or after re-infusion.

Comparison of Peripheral Neurotoxicity of Weekly Paclitaxel Versus Thrice Weekly Paclitaxel Chemotherapy Among Cancer Patients

Objective: To compare peripheral neurotoxicity of weekly Paclitaxel vs thrice weekly Paclitaxel chemotherapy among cancer patients. Study Design: Quasi-experimental study. Place and Duration of study: Oncology Department, Combined Military Hospital, Rawalpindi, Pakistan from Feb to Nov 2021. Methodology: We enrolled 200 patients with diagnosed malignancies taking Paclitaxel chemotherapy for more than three months and less than one year. They were divided into two groups: Group-A received Paclitaxel weekly while Group-B received this medication thrice weekly. Peripheral neurotoxicity was assessed by consultant oncologist on the basis of Eastern Cooperative Oncology Group score and patients in both groups were categorised into four grades from 0 to 3, on the basis of clinical symptoms described in ECOG score. Results: Out of 200 cancer patients prescribed Paclitaxel, 67(33.5%) were male while 133(66.5%) were female, 107(53.5%) received Paclitaxel weekly while 93(46.5%) received thrice weekly, 65(32.5%) had Grade 0 neuropathy, 90(45%) had Grade-I, 42(21%) had Grade-II while 03(1.5%) had Grade-III neuropathy. Dosage schedule was not associated with presence and severity of neurotoxicity. Conclusion: A significant number of cancer patients using Paclitaxel had presence of neuropathy in our study, regardless of weekly or thrice weekly dosing of Paclitaxel.

Cardioprotective effects of novel antioxidants post-myocardial infarction: An integrative review of preclinical and clinical data

Myocardial infarction (MI), is still a major public health problem, and oxidative stress contributes to the degree of myocardial damage after MI. Oxygen-derived free radicals (ODFR) worsen myocardial injury and result in chronic heart failure in many patients. These harms have led to interest in antioxidant treatment to reduce these adverse effects; new antioxidants with the potential for cardioprotection are the subject of significant interest. This review summarizes basic and clinical research comparing the effectiveness of newly synthesized antioxidants in attenuating oxidative stress and enhancing recovery after myocardial infarction. The review synthesizes evidence of a reduction in infarct size, enhancement of cardiac function, and repression of apoptosis in myocardial cells by the use of antioxidants from animal models. Melatonin, N-acetylcysteine, edaravone, and coenzyme Q10 demonstrated a wide range of preclinical positive effects by acting as ROS free radicals scavengers, modulating mitochondria dysfunction, and reducing inflammation. These findings are extrapolated from humans, although advances in antioxidant therapy are beginning to be viewed in initial clinical trials. From human data, although clinical trials are scarce, the evidence of new antioxidants can improve point and long-term outcomes in patients undergoing MI, help to increase the contractility of the injured myocardium, and decrease the mortality level. However, some issues are still there, such as high inter- and intra-individual variability in patient response and dosing schedule, as well as adverse effects such as pro-oxidant activity at high Oral administered doses of melatonin. The limitations of the current research discussed in this review include the general lack of large-scale, well-controlled clinical trials and the need for long-term follow-up studies. This review also proposed future research directions for improving antioxidant applications in post-MI management.

Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes.

Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. Here, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of CNS-specific outcomes. This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and OS. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on D1-7 of each 21-days cycle. In previously published cohort 1, olaparib was dosed on D1-7; in cohort 2 olaparib was dosed continuously. Sixty-six patients were enrolled across the two cohorts, 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, best overall intracranial response was CR in 6/15 patients, PR in 4/15 patients, and SD in 3/15 patients for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination in SCLC.

Recombinant Erwinia asparaginase (JZP458) in ALL/LBL: complete follow-up of the Children’s Oncology Group AALL1931 study

AbstractThe Children’s Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli–derived asparaginases. Each pegylated E coli asparaginase dose remaining in a patient’s treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% confidence interval [CI], 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed administration of IM and IV (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on a combination of observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.

Bilateral Greater Occipital Nerve Block for Preventing the OnabotulinumtoxinA Wear-off Phenomenon in the Treatment of Chronic Migraine: A Case Series of 12 Patients

Purpose: OnabotulinumtoxinA is widely used to treat chronic migraines; however, the wear-off phenomenon before the next scheduled dose has emerged as a challenge. This study suggests a new strategy for preventing the wear-off phenomenon using bilateral greater occipital nerve block. Methods: We conducted a retrospective review of patients diagnosed with chronic migraine who were treated with onabotulinumtoxinA and bilateral greater occipital nerve block at St. Vincent Hospital from January 2023 to December 2023. Twelve chronic migraine patients with a history of the wear-off phenomenon received a greater occipital nerve block 8 weeks after the initial onabotulinumtoxinA injection for two sessions. Responses to treatment were evaluated with regular follow-ups and daily headache diaries. Results: All patients who had previously experienced the wear-off phenomenon with conventional onabotulinumtoxinA treatment did not experience the wear-off phenomenon during two sessions with an additional greater occipital nerve block administered 8 weeks after each onabolulinumtoxinA injection. Conclusion: Bilateral greater occipital nerve block administered 8 weeks after the initial onabotulinumtoxinA injection effectively prevents the wear-off phenomenon, enabling sustained therapeutic benefits in chronic migraine patients. Further research is needed to confirm these findings in larger cohorts.

Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer.

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGFβRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients.

Review article: Novel therapies in inflammatory bowel disease - An update for clinicians.

Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision-making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre-initiation requirements, dosing schedules and adverse event profiles. To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. We comprehensively searched the published literature and major conference abstracts to identify phase III placebo-controlled and active comparator trials for Crohn's disease and ulcerative colitis. Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine-1 receptor modulators and p19 interleukin (IL)-23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head-to-head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL-23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long-term extension studies, real-world studies and head-to-head trials are warranted to better inform the long-term safety and optimal sequencing of treatments for patients living with IBD.

A Review of Polymyxin-B Dosage for Patients with Renal Impairment

Since polymyxin B has a restricted therapeutic range and increased danger of both neurological damage and kidney damage, it is no longer the first choice for treating emerging gram-negative bacteria with multiple antibiotic resistance. The optimal dose schedule for patients with renal impairment regarding polymyxin B, it is provided as a chemically active formulation and primarily removed via methods other than kidney, is still up for debate. Similar to colistin, polymyxin-B effectively combats gram-negative aerobic bacterium that is resistant to several drugs such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli that produces carbapenemase, and Klebsiella pneumoniae. As a result, polymyxins cause cell apoptosis by inducing pan-caspase activation through many routes in a manner that is dependent on time and concentration. One of the most frequent and undesirable side effects of polymyxins is the development of AKI. A great deal of pharmacokinetic studies that have been published to far concur that creatinine clearance affects polymyxin B clearance; nevertheless, there is ongoing debate on the extent of this influence Keywords: Polymyxin-B, kidney damage, gram-negative bacterial infection, creatinine clearance.