Standard Of Care For Treatment Research Articles

Trial in progress: Phase I study of SY-5609, a potent, selective CDK7 inhibitor, with initial expansion in adults with metastatic pancreatic cancer.

TPS4180 Background: SY-5609 is an oral, selective, potent CDK7 inhibitor that targets two fundamental processes in cancer: transcription and cell cycle control. Early results from the Phase 1 dose escalation portion in patients (pts) with advanced solid tumors reported improved tolerability of the intermittent 7 days on followed by 7 days off (7/7) schedule with ongoing dose escalation beyond the continuous daily dosing maximum tolerated dose. Single-agent clinical activity was demonstrated with durable stable disease, target lesion regressions, and reduction in tumor markers observed in multiple tumor types, notably in pancreatic cancer with a disease control rate (DCR) of 38.5% (Sharma 2021). Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 11% (ACS Cancer Facts and figures, 2022) with limited treatment options and therefore, is a disease in need of novel effective therapies. Oncogenic KRAS mutations are prevalent in PDAC. Mutant KRAS is a potent stimulator of mitogenic MAPK signaling and downstream transcriptional programs for cell proliferation. Preclinical studies have shown that CDK7 inhibition via SY-5609 inhibits tumor growth in KRAS mutant PDAC xenograft models, in many cases leading to regressions. SY-5609 also potentiates gemcitabine (gem) activity in PDAC cells in vitro and in xenografts in vivo (Henry 2021). Therefore, combining SY-5609 with gem +/- nab-paclitaxel (nab-pac) offers a potential new treatment strategy for metastatic PDAC (mPDAC). The expansion portion of this Phase 1 study will evaluate SY-5609 in combination with gem +/- nab-pac in mPDAC pts. Gem +/- nab-pac will be administered on a biweekly schedule as it has shown better tolerability and similar clinical activity compared to the standard of care (SOC) administration schedule (Rehman 2020). Methods: This is an ongoing Phase 1, multi-center study in select solid tumors, amended to open expansion cohorts for mPDAC and expected to enroll approximately 80 mPDAC pts who have progressed on SOC treatments. Objectives of the expansion cohorts include evaluation of safety and efficacy of SY-5609 in combination with gem +/- nab-pac. Key objectives of the two parallel safety lead-in cohorts 1) SY-5609 + gem and 2) SY-5609 + gem + nab-pac are safety and determination of the recommended combination dose of the doublet and triplet for subsequent cohort expansions using a 3+3 escalation design. Key objectives of expansion cohorts are to describe efficacy, defined by progression-free survival, overall response rate, and DCR. Additional objectives include evaluation of pharmacokinetics and pharmacodynamics of SY-5609 in combination with gem +/- nab-pac. SY-5609 will be administered orally once daily on a 7/7 regimen and gem +/- nab-pac will be administered intravenously, in a 4-week cycle. The expansion portion is now open to enrollment. Clinical trial information: NCT04247126.

A RANDOMIZED CONTROLLED TRIAL OF INDIVIDUALIZED HOMOEOPATHIC TREATMENT TO REDUCE ANGER & THEREBY REDUCING HYPERTENSION

Objective: Despite improved detection and treatments, rates of hypertension (HT) are not decreasing. More and more people experience increased anger, anxiety, depression brought on by globalisation and stress leading to high-risk behaviours. There is the possibility that blood pressure (BP) may positively correlate with anger variables leading to essential hypertension (EHT). Homoeopathy works holistically, helping the patient to cope up with these changes. The study aims to demonstrate the efficacy of similimum on mild to moderate essential hypertension by modifying the underlying anger state, trait, and expressions, thus making the patient more capable of coping with the changing life situations than standard care treatment. Design and method: 172 patients (108 males and 64 females) between 18–65 years were enrolled after consent. They were allocated to the placebo and intervention groups by simple randomisation. Thorough homoeopathic case-taking was done, and the STAXI-2 scale was applied at the beginning and after a 6-months study period to measure the change in anger. Regular follow up was done every two weeks to evaluate the subjective and objective parameters. Results: After six months, in the control arm 16%, had to be prescribed standard AHT. Whereas in the intervention arm, the BP of all patients were maintained on similimum. The patients on standard AHT, in the control arm 98%, continued with the same dose of their medicines. However, standard AHT stopped in 33% of patients in the intervention group, and in 28%, the dose was reduced. Reduction in blood pressure and anger variables at the end of the study period was statistically significant (p = 0.001) in both arms. However, the difference was significantly more in all variables in the intervention arm than in the control arm. Conclusions: Most hypertension patients, especially with a family history of HT, suppress their anger & hostile impulses. Individualised homoeopathic treatment reduces anger & thereby have a reduction in elevated BP. Also, it relieves associated ailments.

Clinical and patient (pt)-reported outcomes (PROs) in a phase 3, randomized, open-label study evaluating axicabtagene ciloleucel (axi-cel) versus standard-of-care (SOC) therapy in elderly pts with relapsed/refractory (R/R) large B-cell lymphoma (LBCL; ZUMA-7).

7548 Background: Elderly pts with R/R LBCL are at risk of inferior outcomes, increased toxicity, and inability to tolerate second-line (2L) SOC treatment (Tx) (Di M, et al. Oncologist. 2021). Further 2L SOC Tx is often associated with poor health-related quality of life (QoL) (Lin V, et al. J Clin Oncol . 2020;38:e20070). In the pivotal Phase 3 ZUMA-7 study, we assessed outcomes, including PROs, of 2L axi-cel (an autologous anti-CD19 CAR T-cell therapy) versus SOC in elderly pts with R/R LBCL. Methods: Pts aged ≥65 y were assessed in a planned subgroup analysis. Pts with ECOG PS 0-1 and R/R LBCL ≤12 mo after 1L chemoimmunotherapy (CIT) were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based CIT; pts with partial or complete response [CR] proceeded to HDT-ASCT). PRO instruments, including the EORTC QLQ-C30 (Global Health [GH] and Physical Functioning [PF]) and the EQ-5D-5L VAS, were administered at timepoints including baseline (BL; prior to Tx), Day (D) 50, D100, D150, and Month (M) 9, then every 3 mo up to 24 mo or time of event-free survival event (EFS), whichever occurred first. The QoL analysis set included all pts who had a BL PRO and ≥1 completed measure at D50, D100, or D150. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score, 7 points for EQ-5D-5L VAS score. Results: As of 03/18/2021, 51 and 58 elderly pts were randomized to the axi-cel and SOC arms, respectively, with median ages (range) of 70 y (65-80) and 69 y (65-81). At BL, more axi-cel versus SOC pts had high-risk features, including 2L age-adjusted IPI 2-3 (53% vs 31%) and elevated LDH (61% vs 41%). EFS was superior with axi-cel versus SOC (HR, 0.276, P< 0.0001), with higher CR rates (75% vs 33%). Grade ≥3 Tx-emergent adverse events (AEs) occurred in 94% and 82% of axi-cel and SOC pts, respectively, and Grade 5 Tx-related AEs occurred in 0 and 1 pt. In the QoL analysis set comprising 46 axi-cel and 42 SOC pts, there were statistically significant and clinically meaningful differences in mean change of scores from BL at D100 favoring axi-cel for EORTC QLQ-C30 GH ( P<0.0001) and PF ( P=0.0019) and EQ-5D-5L VAS ( P<0.0001). For all 3 domains, scores also favored ( P<0.05) axi-cel over SOC at D150. The mean estimated scores numerically returned to or exceeded BL scores earlier in the axi-cel arm (by D150) but never equaled or exceed BL scores by M15 in the SOC arm. Conclusions: Axi-cel demonstrated superiority over 2L SOC in pts ≥65 y with significantly improved EFS and a manageable safety profile. Compared with SOC, axi-cel also showed meaningful improvement in QoL over SOC, measured by multiple validated PRO instruments, with suggested faster recovery to pre-Tx QoL. The superior clinical outcomes and pt experience with axi-cel over SOC should help inform Tx choices in 2L R/R LBCL for pts ≥65 y. Clinical trial information: NCT03391466.

Analysis of phase I clinical trials (Ph1-CT) new enrollment patterns in the immuno-oncology era.

e14549 Background: Immuno-Oncology (IO) has revolutionized anticancer therapeutics and changed the early drug development paradigm. Positive results and limited access to IO drugs in some countries have led to increased enrollment in IO Ph1-CT at an earlier timepoint in patients (pts) disease journey. We evaluated the impact of IO era on enrollment patterns in Ph1-CT. Methods: We retrospectively reviewed pts with recurrent/metastatic solid tumors enrolled in Ph1-CT from January 2018 to June 2021 at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain. The primary goal was to assess Ph1-CT enrollment patterns, including use of molecular pre-screening/personalized drug matching, and the availability of alternative standard of care (SOC). Overall response rate (ORR) was assessed according to RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response+stable disease for ≥6 months. Median progression-free survival (mPFS) and overall survival (mOS) using Kaplan-Meier method were provided. Results: A total of 175 pts were enrolled in Ph1-CT. Median age was 54 years (range 43-75), Male:Female = 99:76, 99% had ECOG 0-1. The most prevalent tumors were: 32 (18%) breast, 31 (18%) colorectal, 25 (14%) urogenital and 23 (13%) glioblastoma multiforme. One hundred forty-six (83%) pts were enrolled in Ph1-CT with IO (alone or in combination) and 29 (17%) pts with targeted therapy (TT). Molecular pre-screening tests were required in 24 (14%) pts (22 pts IO vs 2 pts TT trial). Eleven (42%) pts were pre-screening failures. Screening failure (SF) rate was 19%, the main reason being clinical worsening for 7 (4%) pts. Thirty-three (19%) pts had an alternative SOC treatment available at time of enrollment. One hundred two (58%) pts had received ≤1 prior lines and 26 (89%) were IO-naïve. Finally, 129 (74%) out of 175 pts enrolled were treated within Ph1-CT. Out of 129 treated pts, ORR was achieved in 18 (14%) pts (3% complete response) and 44 (34%) had stable disease. CBR was observed in 36 (28%) pts. mPFS was 2.8 months and mOS was 10.9 months. Toxicity grade 3-4 occurred in 25 (19%) of pts and 6 (5%) pts had to interrupt treatment. Seventy-one (55%) pts received subsequent therapies: 22 (17%) in Ph1-CT; 49 (38%) SOC. Eleven (9%) pts received IO as subsequent therapy. Decline in ECOG status (baseline vs end of treatment) occurred in 65 (50%) pts. Conclusions: In our cohort of Ph1CT pts, there has been an increasing number of pts enrolled in IO trials compared to TT. Most pts received treatment within Ph1-CT at an earlier timepoint in the course of their disease (1st or 2nd lines). Our results suggest a clear impact of the IO era on the trends of Ph1-CT availability and enrollment patterns.

Real-world (RW) treatment patterns and clinical outcomes for chemotherapy-based regimens in first line (1L) MSI-H/dMMR metastatic colorectal cancer (mCRC).

e18755 Background: Until the global approval of pembrolizumab for the treatment of first line (1L) MSI-H/dMMR metastatic CRC (mCRC), newly diagnosed patients were managed with standard of care (SOC) treatments like chemotherapy with or without an EGFR/VEGF inhibitor, independent of biomarker testing or status. This study assessed the RW SOC treatment patterns and outcomes among 1L MSI-H/dMMR mCRC patients. Methods: A retrospective observational study was conducted among patients ≥18 years diagnosed with stage IV MSI-H/dMMR mCRC (index event) who received care in the US community-based Oncology Network. Eligible patients were identified between 01-Jun-2017 to 29-Feb-2020 and followed longitudinally until 31-Aug-2020, last patient record, or date of death: whichever occurred first. Baseline demographics, clinical characteristics, treatment patterns and clinical outcomes were reported descriptively. Key clinical outcomes of interest were time to treatment discontinuation (TTD), rw-progression free survival (rwPFS) and overall survival (OS). Kaplan-Meier survival analysis was conducted for all time-to-event variables. Results: 150 MSI-H/dMMR CRC patients treated in the 1L setting were included, of which 38.7% were treated with chemotherapy and 61.3% with chemotherapy + an EGFR/VEGF inhibitor. Nearly 75% of patients had an ECOG PS of 0-1, and the time from diagnosis of metastatic disease to initiation of 1L treatment was 5.2 (0.1, 1157.4) weeks. The median duration of follow-up was 12.9 (0.1, 37.1) and 16.2 (0.8, 36.2) months among patients treated with chemotherapy and chemotherapy + EGFR/VEGF inhibitors, respectively. Within the chemotherapy group, 86% received FOLFOX while 14% received FOLFIRI. Within the chemotherapy + EGFR/VEGF group, the most common regimen was FOLFOX+bevacizumab (67%). Conclusions: The totality of RW clinical outcomes in 1L MSI-h/dMMR mCRC suggest that despite the availability of chemotherapy and EGFR/VEGF inhibitors, an unmet need still exists that may be addressed with the recent availability of pembrolizumab for select patients. This data further supports the rationale for biomarker testing and personalized treatment of 1L CRC. Patient characteristics and clinical outcomes are summarized in the table.[Table: see text]

Subgroup analyses in patients with relapsed/refractory multiple myeloma (RRMM) receiving real-life current standard of care (SOC) in the LocoMMotion study.

8031 Background: Patients (pts) with RRMM who are triple-class exposed (proteasome inhibitor [PI], immunomodulatory drug [IMiD], and anti-CD38 monoclonal antibody [mAb]) have an urgent and currently unmet clinical need. LocoMMotion (NCT04035226) is the first prospective multinational study of real-life SOC in triple-class exposed pts with RRMM. Here we present efficacy in subgroups of pts treated with SOC therapies in the LocoMMotion study. Methods: LocoMMotion is a noninterventional study across 76 sites (63 European; 13 US). Eligible pts had received ≥3 prior lines of therapy (LOT) or were double refractory to a PI and an IMiD; received a PI, an IMiD, and anti-CD38 mAb; and had disease progression during/after their last LOT. Real-life SOC treatments were defined as those used in local clinical practice. Responses and disease progression were assessed by response review committee, per IMWG criteria. Subgroups were defined by baseline (BL) characteristics: age, Eastern Cooperative Oncology Group performance status (ECOG PS), renal function, ISS stage, presence of extramedullary plasmacytoma, LDH level, % of bone marrow plasma cells, number of prior LOT, triple-class or penta-drug exposure, and refractoriness. Results: As of May 21, 2021 (median follow-up 11.0 mo), 248 pts were enrolled and treated with median 4.0 (range, 1–20) cycles of SOC therapy. Evaluation of efficacy outcomes in subgroups demonstrated that refractoriness to 3 classes of antimyeloma therapy, presence of extramedullary plasmacytomas, high LDH, and ECOG PS ≥1 were associated with generally worse outcomes, compared with pts who did not have these characteristics (Table). Overall response rate (ORR) ranged from 20.0–43.1% across all subgroups. Age and number of prior LOT did not have an impact on efficacy outcomes. Conclusions: Subgroup analyses of this first prospective study of real-life SOC tx in triple-class exposed pts with RRMM indicate that specific pt and disease characteristics were associated with poor outcomes. Triple-class refractory and non-triple-class refractory pts had poor outcomes, although the latter had longer median progression-free survival (PFS). These findings should be considered when planning bridging strategy for CAR-T therapy. Clinical trial information: NCT04035226. [Table: see text]

Health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma (RRMM) receiving real-life current standard of care (SOC) in the LocoMMotion study.

8030 Background: Evaluation of patient (pt)-reported outcomes provides insight into how real-life SOC treatments (tx) affect HRQoL for pts with RRMM. LocoMMotion (NCT04035226) is the first prospective, multinational study of real-life SOC in triple-class exposed pts with RRMM. Here, we present measures of symptoms, functioning, and overall HRQoL. Methods: LocoMMotion is a prospective, noninterventional study across 76 sites (63 European; 13 US). Pts had received ≥3 prior lines of therapy (LOT) or were refractory to PI and IMiD; received PI, IMiD, and anti-CD38 mAb; and had disease progression during/after last LOT. Real-life SOC tx were defined as those used in local clinical practice. The questionnaires were EORTC QLQ-C30, 4 single items from EORTC QLQ-MY20, and EQ 5D-5L. HRQoL was assessed at baseline (BL), day 1 of each tx cycle, end of tx visit, and during the follow-up period (every 4 weeks). Improvement compared to BL health status was evaluated using established thresholds. Within-group change was assessed using mixed models for repeated measures. Results: Questionnaire completion for pts in the LocoMMotion study (N=248; 54.4% male; median age 68 yrs; median 4.0 [range, 1–20] cycles of SOC) was 75.6% during SOC tx. Most pts did not achieve meaningful improvement in PRO scores, defined by a literature-based minimally important difference of 10 points in mean score. This was most pronounced in pain symptoms (62% of pts had no meaningful improvement during the first 3 months of tx; 55% had no improvement during full tx duration). For the overall population, the least square (LS) mean changes from BL during SOC tx and subsequent LOT are described (Table). Pts who achieved very good partial response and better during SOC tx had greater improvement in PRO scores, including in LS mean change for pain score (-14.9 [95% confidence interval (CI): -22.9, -7.0]). Conclusions: In this first prospective study of real-life current SOC in triple-class exposed pts, limited gains in HRQoL were reported, most notably in pain symptoms. There is an urgent need for effective therapies that can help pts achieve deep responses and delay disease progression, as these are associated with improved HRQoL. Clinical trial information: NCT04035226. [Table: see text]

Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression

Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model. We identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressors cells in end-stage tumors, an evolution that parallels breakdown of the blood–brain barrier and extensive growth of epidermal growth factor receptor+ GBM cells. A similar relationship was found between microglia and macrophages in patient biopsies of low-grade glioma and GBM. Temozolomide decreased the accumulation of myeloid-derived suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB+ CD8+T cells but also increased CD4+ regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression.

Impact of Early Rehabilitation on Outcomes in Patients With Acute Ischemic Stroke After Endovascular Treatment.

BackgroundThis study aims to examine the effects of early rehabilitation on functional outcomes in patients with acute ischemic stroke treated with endovascular treatment (EVT).MethodsEligible patients with large vessel occlusion stroke treated with EVT, who received early rehabilitation or standard care treatment during hospitalization, were enrolled in a multicenter registration, prospective observational study, a registration study for Critical Care of Acute Ischemic Stroke After Recanalization. Early rehabilitation was defined as rehabilitation interventions initiated within 1 week after acute stroke. The primary outcome was the favorable functional outcome (defined as modified Rankin Scale scores of 0 to 2) at 90 days. Independent association between early rehabilitation and the primary outcome was investigated using multivariable logistic regression in the entire sample and in subgroups.ResultsA total of 1,126 patients (enrolled from July 2018 to May 2019) were included in the analyses, 273 (24.2%) in the early rehabilitation group and 853 (75.8%) in the standard care group. There was no significant difference in favorable functional outcomes at 90 days between the two groups (45.4 vs. 42.6%, p = 0.41). Patients in the early rehabilitation group had a lower death rate within 90 days compared with the standard care group (6.2 vs. 20.5%, p < 0.01). The multivariable logistic regression analyses showed that the early rehabilitation was not significantly associated with the favorable functional outcome at 90 days (adjusted odds ratio, 1.01 [95% CI, 0.70–1.47]; p = 0.95). There was no significant difference between subgroups in the favorable functional outcome at 90 days. No significant interaction was found between subgroups.ConclusionsPatients with stroke receiving early rehabilitation had a lower death rate. However, these clinically meaningful effects of early rehabilitation did not show on functional outcome at 90 days in patients with large vessel occlusion stroke treated with EVT.RegistrationURL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

Faster Than Projected Healing in Chronic Venous and Diabetic Foot Ulcers When Treated with Intact Fish Skin Grafts Compared to Expected Healing Times for Standard of Care: An Outcome-Based Model from a Swiss Hospital.

Purpose: Inadequate response to wound management is defined as a reduction in the wound area of <40-50% following four weeks of standard of care (SOC) and should be managed with a skin substitute product. We set out to evaluate a novel outcome-based model focusing on the management of hard-to-heal venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs) using SOC treatment or intact fish skin grafts (FSGs) in a regional hospital. Methods: We built an outcome-based model applying surrogate markers and endpoints of wound healing for VLU and DFU to determine the healing trajectory with SOC treatment. We could predict if VLU and DFU would heal by weeks 20 and 24, respectively, after four weeks of evaluating the initial wound area reduction. 51 patients were recruited (26 VLUs and 25 DFUs) and 42 wounds were randomized. 17 wounds deemed unlikely to heal by week 8 received management with FSG as per the Swiss Society for Dermatology and Venereology (SGDV) and the Swiss Association for Woundcare (SAfW) guidelines for the use of skin replacement products, and 26 wounds continued SOC for weeks 5-8. Results/Discussion: 12 wounds managed with FSG beat the modeled SOC healing predictions, with the majority healed >50% sooner and as early as <10% of the time than was predicted. Of these 17, five wounds failed to achieve the required size reduction in Week 4-8 (over 25% improvement in wound area vs. SOC). The FSG were assigned to treatment-resistant VLU and DFUs and were still able to heal these wounds most of the time and even changed the wound's healing trajectory that increased in size in the initial four weeks. Conclusion: This pilot study showed that management with FSG results in faster healing wounds than SOC predicted, while SOC-treated wounds mostly followed model predictions.

Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial

BackgroundThe standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates.The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration.MethodsExtrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5–6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life.DiscussionThe aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control.Trial registrationClinicalTrials.gov Identifier: NCT04946357; Retrospectively registered June 30, 2021.

Efficacy of levamisole with standard care treatment vs. standard care in clinical presentations of non-hospitalized patients with COVID-19: a randomized clinical trial

Objective: The aim of this study was to evaluate the influence of adding a 10-day course of levamisole (LVM) to the standard care compared with standard care alone, on the clinical status of COVID-19 patients with mild to moderate disease.&#x0D; Methods: In this randomized open-label trial, we enrolled non-hospitalized patients with mild to moderate COVID-19 at nine health centers in Tehran province, Iran, in 2021. Patients were randomly assigned to receive a 10-day course of LVM with standard care (n=185) or standard care alone (n=180) in a 1:1 ratio. On days 1 to 10, LVM was administered orally at a dosage of 50 mg. The participants were called and followed on days 1, 3, 5, 7, 9, and 14. The measured parameters were general health condition, hospitalization rate, signs and symptoms, and adverse events. The generalized estimating equations model was used for analysis.&#x0D; Results: Among 507 randomized patients, 473 patients started the experiment and received LVM plus standard care or received the standard care alone; 385 patients included in the analysis; 346 (98%) patients completed the trial. The median age of the patients was 40 years [IQR: 32-50.75]; and ‎201 (55.1%)‎ patiens were male. The mean age, sex ratio, and frequency of the underlying diseases of the patients in the two study groups had no ‎statistically significant differences (P&gt;0.05). Compared to the control group, LVM improved the general health condition of the patients (B=-0.635; 95% CI: -0.041,-0.329; P&lt;0.001). Patients receiving LVM compared with standard care group had significantly lower odds of developing fever (OR=0.260; 95% CI: 0.11‎‎3‎,0.59‎‎9‎; P=0.002), chills (OR=0.223; 95% CI:‎‎ 0.07‎‎6,‎0.64‎‎8‎; P= 0.006), fatigue (OR=0.576; 95% CI:‎ 0.34‎‎6,‎0.96‎‎0‎‎; P=0.034), and myalgia (OR=0.54‎‎4‎; 95% CI:‎ 0.31‎‎7‎,0.93‎‎2‎‎; P=0.027). No significant difference was observed in the rate of hospitalization. Although the intervention group had greater adverse effects than the control group, the difference was not statistically significant.&#x0D; Conclusion: Findings of this study suggest that LVM has clinical benefits in improving patients’ health condition with mild to moderate COVID-19.

Sofosbuvir/ledipasvir in combination or nitazoxanide alone are safe and efficient treatments for COVID-19 infection: A randomized controlled trial for repurposing antivirals

Background and study aimsCurrently, there is no therapy approved for COVID-19. We evaluated the efficacy and safety of sofosbuvir/ledipasvir and nitazoxanide for the treatment of patients with COVID-19 infection. Patients and methodsA multicenter, open-label randomized controlled trial included one hundred and ninety patients with non-severe COVID-19 infection. Patients were randomized into three groups. All groups received standard care treatment (SCT). In addition, group 1 received sofosbuvir/ledipasvir, and group 2 received nitazoxanide. Follow-up by reverse-transcriptase polymerase chain reaction (RT-PCR) was done at intervals of 5, 8, 11, and 14 days. The primary endpoint was viral clearance. ResultsViral clearance was significantly higher in the sofosbuvir/ledipasvir and nitazoxanide groups compared to the SCT group in all follow-up intervals (p < 0.001). In the sofosbuvir/ledipasvir arm, 36.9% showed early viral clearance by day 5. By day 14, 83.1% of the sofosbuvir/ledipasvir group, 39.7% of the nitazoxanide group, and 19.4% of the SCT group tested negative for SARS-CoV-2. Sofosbuvir/ledipasvir and nitazoxanide treatment were the only significant factors in Cox regression of negative RT-PCR with the highest OR (17.88, 95% CI: 6.66–47.98 and 2.59, 95% CI: 1.11–6.07, respectively). No mortality or serious adverse events were recorded. ConclusionThe addition of sofosbuvir/ledipasvir or nitazoxanide to the SCT results in an early and high viral clearance rate in mild and moderate patients with COVID-19. These drugs represent a safe and affordable treatment for COVID-19.

Management of stage II seminoma: a contemporary UK perspective.

Background and AimsTesticular Germ Cell Tumours (TGCTs) are the commonest young adult male cancer, with excellent survival outcomes even with metastatic disease. Chemotherapy, radiotherapy, and surgery are international guideline-dictated standard of care (SOC) treatments for International Germ Cell Cancer Collaborative Group (IGCCCG) “good risk” TGCT, but are associated with significant toxicities. Therapy de-escalation aims to reduce treatment morbidity whilst preserving cure rates, and has been adopted by some centres for stage IIA/B seminoma. Here, we report on the contemporary UK treatment landscape for stage IIA/B seminoma.MethodsA questionnaire-based survey of NHS England-designated specialist cancer centres hosting supra-regional specialist multi-disciplinary team (sMDT) services (n = 13) as well those within NHS Scotland, NHS Wales and Health and Social Care Northern Ireland. Respondents were asked to order preferences of SOC and therapy de-escalation treatments for stage IIA/B seminoma.ResultsWe identified significant geographical heterogeneity in treatment preferences. Whilst up to a third of centres have adopted a treatment de-escalation regimen, the majority deliver combination chemotherapy or radiotherapy.ConclusionA wider recognition of UK treatment heterogeneity and consideration of therapy de-escalation strategies at supra-regional sMDTs will increase stage IIA/B seminoma treatment options as part of clinical trials with oncological and quality of life endpoints.

Effect of Standard of Care Treatment on Tumor Membrane Vesicle Vaccine for Triple-Negative Breast Cancer

Abstract Metastatic triple-negative breast cancer (TNBC) has a poor prognosis primarily due to metastatic potential and resistance to currently available therapies. Recent studies suggest that TNBC may be a viable target for immunotherapy due to the presence of high levels of infiltrating lymphocytes. However, many TNBC patients do not respond due to high intra-tumoral and inter-patient heterogeneity. Utilizing a novel protein transfer method, we generate a personalized vaccine based on tumor membrane vesicles (TMVs) derived from whole tumor tissues modified with glycolipid-anchored forms of the immunostimulatory molecules (GPI-ISMs) B7-1 and IL-12. In prior studies we observed that simultaneous delivery of TMVs along with biological adjuvants enhanced CD8 T cell immunity. Herein, we investigated the impact of standard-of-care (SOC) chemotherapy on the resulting quality of the TMV vaccine. Mice were injected with 4T1 TNBC cells subcutaneously and treated with three rounds of SOC drugs starting at day 15. Chemotherapies affected tumor growth to varying degrees. Mice were euthanized and tumors were harvested for TMV preparation. Results show that depending on the treatment, the yield and particle size of TMVs was impacted. While SOC drugs affected some surface markers on TMVs, expression of CD24 and CD11b was unchanged. Further, there was reduced uptake of TMVs by dendritic cells prepared from cisplatin and 5-fluorouracil treated tumors. GPI-ISMs were equally incorporated by protein transfer onto TMVs despite SOC treatments. In summary, our studies in the 4T1 model show that a TMV vaccine can be successfully prepared after chemotherapy, but the impact on TMV yield and size justifies further investigation. Supported by R01 CA202763

Abstract 47: Tapering And Discontinuation Of Background Therapies During The Transition To Rilonacept Monotherapy In Rhapsody, A Phase 3 Clinical Trial Of Rilonacept In Patients With Recurrent Pericarditis

Background: Post-episode tapering of Standard of Care (SoC) medication in patients with recurrent pericarditis (RP) varies considerably. Gradual tapering of corticosteroids (CS) is recommended in ESC guidelines (decreasing by 1-2.5 mg/day every 2-6 weeks over 1-2 years) to prevent recurrence. We describe successful faster tapering of SoC treatment onto rilonacept monotherapy during RHAPSODY, a Phase 3, placebo-controlled, randomized-withdrawal (RW) trial in RP. Methods: Patients with acute symptomatic RP despite stable doses of NSAIDs, colchicine, and/or CS in any combination enrolled in a 12-week run-in period in which weekly rilonacept was initiated. After 1-week of stabilization, tapering of CS began at a rate dependent on baseline dose, to be completed by Week 10 for randomization at Week 12 when clinical response was confirmed by reduced pain and normalized CRP levels. Colchicine tapering/discontinuation was initiated no earlier than Week 4. This analysis evaluates time to rilonacept monotherapy in subgroups receiving different combinations of background therapies. Results: 79 of 86 patients were receiving pharmacotherapy at run-in baseline. Median (95% CI) time to monotherapy (n=79) was 7.9 (7.0-8.1) weeks. Of the patients receiving CS at baseline (41/86 [48%]), 39 (95%) tapered to rilonacept monotherapy, and median time to monotherapy was 7.9 (7.1-8.1) weeks. Of the patients receiving colchicine at baseline (65/86 [76%]), 61 (94%) patients achieved rilonacept monotherapy, and median time to monotherapy was 8.0 (7.1-8.3) weeks. Patients receiving only one SoC therapy achieved rilonacept monotherapy faster (6.1 [0.4-8.1] weeks) than those receiving 2 (8.0 [6.7-9.9] weeks) or 3 (7.7 [7.0-8.3] weeks) therapies. All patients who did not achieve monotherapy had withdrawn from the study for reasons unrelated to pericarditis. Conclusion: All patients randomized in the RHAPSODY trial discontinued SoC and transitioned to rilonacept monotherapy (median time 7.9 weeks) without a recurrent pericarditis episode during run-in. With rilonacept, time to successful discontinuation of SoC, including high dose CS, was substantially more rapid than current treatment practices. RHAPSODY data helped support FDA approval of the first therapy for RP.

Haemophilia gene therapy-Update on new country initiatives.

Gene therapy is emerging as a potential cure for haemophilia. Gene therapy is a one-time treatment that can elevate factor levels for many years and minimize or eliminate the need for clotting factor concentrate (CFC) replacement therapy. However, there is a paucity of reports on gene therapy efforts in countries outside of North America or Europe, especially in low-and-middle-income countries (LMIC). All indications are that gene therapy will be one of standard care treatments for haemophilia in the future. Still, it may not be accessible to many countries due to various barriers and challenges. At the same time, each country may formulate solutions that may be used globally. To summarize the approaches taken to establish haemophilia gene therapy in Japan, China, India, South Africa, and Brazil, and to describe the US-initiated multi-LMIC haemophilia gene therapy development program to include Peru, Vietnam, Thailand, Nepal, and Sri Lanka. A review of related published information or as accessible by each country's author. Different starting conditions, differing input and level of support from the multitude of stakeholders, and strong leadership have led to various approaches for facilitating research and developing needed infrastructure and regulatory and financing models. Gene therapy programs are at various stages of development and include both adeno-associated viral and lentiviral vectors. Global partnerships and collaboration, exchange of knowledge and experience, and alignment of processes across borders will promote further progress towards global access to gene therapy for haemophilia.

Assessing Opioid Use Disorder Treatments in Trials Subject to Non-Adherence via a Functional Generalized Linear Mixed-Effects Model

The opioid crisis in the United States poses a major threat to public health due to psychiatric and infectious disease comorbidities and death due to opioid use disorder (OUD). OUD is characterized by patterns of opioid misuse leading to persistent heavy use and overdose. The standard of care for treatment of OUD is medication-assisted treatment, in combination with behavioral therapy. Medications for opioid use disorder have been shown to improve OUD outcomes, including reduction and prevention of overdose. However, understanding the effectiveness of such medications has been limited due to non-adherence to assigned dose levels by study patients. To overcome this challenge, herein we develop a model that views dose history as a time-varying covariate. Proceeding in this fashion allows the model to estimate dose effect while accounting for lapses in adherence. The proposed model is used to conduct a secondary analysis of data collected from six efficacy and safety trials of buprenorphine maintenance treatment. This analysis provides further insight into the time-dependent treatment effects of buprenorphine and how different dose adherence patterns relate to risk of opioid use.

Evaluation of the anti-tumour activity of Coriolus versicolor polysaccharopeptide (I'm-Yunity) alone or in combination with doxorubicin for canine splenic hemangiosarcoma.

Canine splenic hemangiosarcoma (HSA) is an aggressive tumour of vascular endothelium that carries a grave prognosis following standard of care treatment with surgery and doxorubicin. A previous pilot study revealed potential anti-tumour activity of I'm-Yunity polysaccharopeptide (PSP) for canine HSA. The aim of this prospective study was to assess patient outcome when treated with PSP alone or in combination with doxorubicin post-splenectomy compared to patients treated with surgery and doxorubicin that received a placebo in place of PSP. Dogs undergoing splenectomy for splenic HSA were eligible. Following splenectomy, owners were offered treatment with PSP alone or adjuvant doxorubicin chemotherapy (unblinded). Patients with owners that selected to proceed with doxorubicin chemotherapy were blindly randomized to receive placebo or PSP. Dogs were evaluated weekly for 15 weeks, then scheduled for monthly visits until death. One hundred and one dogs were included in the final analysis: 51 PSP alone, 25 doxorubicin/placebo, and 25 combination PSP/doxorubicin. On multivariate analysis, dogs treated with single agent PSP, female dogs, decreased haematocrit at diagnosis, and stage III disease were negatively significantly associated with outcome; however, an interaction between treatment group and sex was documented. Gender-specific outcomes revealed no significant difference in survival between treatment groups for male dogs, but female dogs treated with PSP alone had significantly reduced survival compared to females receiving doxorubicin/placebo (HR 0.21; p=.004). Anaemia (HR 5.28; p < .001) and stage III disease (HR 2.9; p=.014) remained negatively associated with survival when controlling for sex and treatment group. The addition of PSP to doxorubicin post-splenectomy did not improve survival in dogs with splenic HSA.

Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis

ABSTRACT This study investigated the efficacy and safety of interleukin-6 (IL-6) receptor antagonists with standard care treatment in patients with coronavirus disease 2019 (COVID-19). The randomized controlled trials were identified through systematic searches of electronic databases through February 10, 2022. In total, 17 trials comprising 8,614 patients were included. Compared with exclusive standard care or placebo, IL-6 receptor antagonists with standard of care treatment were associated with a significantly reduced all-cause mortality at 28 days (pooled risk ratios [RR], 0.88; 95% confidence interval (CI), 0.82–0.95; 17 studies) and progression to invasive mechanical ventilation (RR, 0.79; 95% CI, 0.71–0.88; nine studies). Particularly, the subgroup of patients with moderate-to-severe COVID-19 showed a significant mortality benefit (RR, 0.89; 95% CI, 0.81–0.96; four studies) and a reduced risk for mechanical ventilation (RR, 0.80; 95% CI, 0.70–0.91; three studies) with tocilizumab treatment. The frequency of serious adverse events was lower in the tocilizumab treatment group than in the standard of care treatment group (RR, 0.83; 95% CI, 0.71–0.97; 11 studies), with no significant difference in the sarilumab treatment group (RR, 1.12; 95% CI, 0.89–1.40; four studies). Our meta-analysis demonstrated that tocilizumab treatment showed promising results in reducing 28-day mortality and progression to mechanical ventilation in patients with moderate-to-severe COVID-19, without the burden of serious adverse events. Trial registration: PROSPERO: registration number CRD42021294120.