phase-II Trials Research Articles

Safety and short-term outcomes of esophagectomy after neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell cancer: analysis of two phase-II clinical trials.

Preoperative chemotherapy (CT) or chemoradiotherapy (CRT) show survival benefits in patients with locally advanced esophageal squamous cell carcinoma (ESCC); however, ESCC patients still have a dismal prognosis. We conducted two phase-II, single-armed clinical trials to assess the potential benefits, efficacy, feasibility, and safety of esophagectomy after combining preoperative CT or CRT and neoadjuvant programmed cell death protein 1 (PD-1) inhibitors in the treatment of ESCC. Patients were included with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase-II, single-arm trials (NCT04506138 and NCT03940001). Patients underwent two doses of intravenous PD-1 inhibitor (either camrelizumab or sintilimab) every 3 weeks, combined with two cycles of either CT or CRT. The primary endpoint of the study was the safety and short-term outcomes of esophagectomy as measured by the risk of developing complications within 30 days, after the combination of preoperative PD-1 inhibitor and CT or CRT Secondary endpoint was to evaluate the pCR rates (pT0N0), primary tumor pCR rates (pT0), operation time, postoperative stay, and 30-day mortality rate between both groups. Results between both groups were compared using a multivariable log-binomial regression model to obtain the adjusted relative risk ratios (RRs). Between May 2019 and June 2022, 55 patients were included. All patients completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group (P=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group (P=0.19). The minimally invasive surgery rates were 89.2% (33/37) in the nICT group and 94.1% (16/17) in the nICRT group. The risk of developing pulmonary, anastomotic, or other complications were similar between the two groups. Esophagectomy was safe after the addition of the PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and the exploratory endpoints, including biomarkers analyses, are ongoing.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Stapokibart in Healthy Volunteers and Adult Subjects with Atopic Dermatitis.

Stapokibart, a novel humanized anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits the signaling of IL-4 and IL-13, which are key drivers of type2 inflammation in atopic dermatitis (AD). This study aimedto assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of stapokibart in a randomized, double-blind, placebo-controlled single ascending dose (SAD) study and a multiple ascending dose (MAD) study. The SAD study enrolled 33healthy male adults aged 18-65years at a single center. The MAD study enrolled 39 patients with moderate-to-severe AD aged 18-70years at seven centers. Enrolled subjects were randomized to subcutaneous (SC) doses of stapokibart (75-600mg) or placebo. Serum thymus and activation-regulated chemokine (TARC) and total immunoglobulinE (IgE) were measured as PD biomarkers for stapokibart. Similar PK characteristics were observed in healthy volunteers and subjects with AD after the initial administration. Stapokibart exhibited non-linear pharmacokinetics in both types of subjects. Following single doses, the mean maximum serum concentration (Cmax) ranged from 5.3 to 63.0μg/mL, median Tmax ranged from 3.0 to 7.0days, mean terminal half-life (t1/2z) ranged from 2.39 to 7.43days, and mean apparent volume (Vz/F) ranged from 3.64 to 6.73L in healthy subjects. The mean AUC accumulation ratio was 2.29 in subjects with AD after three doses of stapokibart 300mg administered every 2weeks. The median serum total IgE and TARC levels on day43 decreased from baseline by 14.9-25.2% and 48.6-77.0%, respectively, among subjects with AD receiving three doses of stapokibart. No subjects developed grade ≥ 3 adverse events (AEs) or serious AEs or discontinued the study because of AEs. The incidence of AEs was similar between stapokibart and placebo groups. Stapokibart showed favorable pharmacokinetics, pharmacodynamics, safety, and tolerability in the SAD and MAD studies. Based on these results, phaseII and phaseIII trials of stapokibart have been performed in subjects with moderate-to-severe AD. ClinicalTrials.gov Identifier NCT06161090 (29 November, 2023), NCT04893941 (15 May, 2021).

Prophylactic Versus Reactive Megestrol Acetate Use for Critical Body Weight Loss in Patients with Pharyngeal and Laryngeal Squamous Cell Carcinoma Undergoing Concurrent Chemoradiotherapy

This study compared the effects of megestrol acetate (MA) prophylactic (p-MA) versus reactive (r-MA) use for critical body-weight loss (>5% from baseline) during concurrent chemoradiotherapy (CCRT) in patients with advanced pharyngolaryngeal squamous cell carcinoma (PLSCC). Patients receiving CCRT alone in two phase-II trials were included for analyses. Both the p-MA and r-MA cohorts received the same treatment protocol at the same institution, and the critical body-weight loss, survival, and adverse event profiles were compared. The mean (SD) weight loss was 5.1% (4.7%) in the p-MA cohort (n = 54) vs. 8.1% (4.6%) in the r-MA cohort (n = 50) (p = .001). The percentage of subjects with body-weight loss >5% was 42.6% in the p-MA cohort vs. 68.0% in the r-MA cohort (p = .011). Tube feeding was needed in 22.2% of p-MA vs. 62.0% of r-MA patients (p < .001). Less neutropenia (26.0% vs. 70.0% [p < .001]) and a shorter duration of grade 3-4 mucositis (2.4 ± 1.4 vs. 3.6 ± 2.0 wk [p = .009]) were observed with p-MA treatment. Disease-specific survival, locoregional control, or distant metastasis-free survival did not differ. Less competing mortality from secondary primary cancer resulted in a better overall survival trend in the p-MA cohort. p-MA may reduce body-weight loss and improve adverse event profiles during CCRT for patients with PLSCC.

Oral NRC-2694-A in combination with paclitaxel as therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) that progressed on or after an immune checkpoint inhibitor (ICI): A multi-center, single-arm, phase 2 trial.

TPS6108 Background: HNSCC is the seventh most common cancer worldwide. Patients with R/M disease have limited treatment options and a poor prognosis. The USFDA has approved two ICI agents to treat R/M-HNSCC: pembrolizumab given as monotherapy or with platinum-based chemotherapy for first-line treatment of R/M disease and nivolumab (or pembrolizumab) monotherapy for treatment of disease that progressed on or after platinum-containing chemotherapy. In each setting, the ICI improved overall survival (OS); however, the absolute magnitude of the OS benefit was modest and most patients experienced disease progression within one year. There are no agents with regulatory agency-approval that are used to treat R/M-HNSCC that progressed on or after an ICI. Drugs commonly used in this setting have limited activity and include cetuximab (an epidermal growth factor receptor [EGFR] inhibitor), paclitaxel, docetaxel, a platinum, or 5-fluorouracil. Hence, there is an important unmet medical need to develop more effective treatments for R/M-HNSCC that progressed on or after an ICI. NRC-2694-A is an orally administered EGFR tyrosine kinase inhibitor, discovered and developed by NATCO Pharma Ltd., India. Based on the responses from Phase-I and Phase-II trials of NRC-2694-A in India, NAT2694US study is designed to evaluate the safety and efficacy of Oral NRC-2694-A in combination with paclitaxel in patients with R/M-HNSCC, who progressed on or after ICI therapy. Methods: NAT2694US is a multi-center, single-arm, Phase 2 study (NCI ClinicalTrials.gov Identifier: NCT05283226) with an estimated enrolment of 46 patients. Eligible patients are &gt;18 years of age with an ECOG performance status of 0-2 and histologically confirmed unresectable, measurable R/M-HNSCC (of the oral cavity, oropharynx, hypopharynx, and larynx), radiological disease progression on or after ICI therapy, and no prior taxane for R/M disease. Patients receive 300 mg of oral NRC-2694-A once daily and 175 mg/m² of paclitaxel IV infusion once every 21-day cycle for 6 cycles or more. Tumor response assessment with CT/MRI scans is performed every 6 weeks. The primary endpoint is objective response rate (ORR) using RECIST v1.1 performed by the investigator. The study uses a Simon’s 2-stage design with ORR H0: 30% and H1: 50% using a one-sided Type-1 error rate = 0.05). In Stage 1, fifteen patients are to be enrolled for tumor assessment. If objective response is observed in at least 6 of these 15 patients, then Stage 2 would be opened with the inclusion of 31 additional patients, leading to a total enrolment of 46 patients. The observation of objective response in at least 19 of 46 patients would reject the null hypothesis in favour of the alternative hypothesis. Enrolment to the NAT2694US trial is currently ongoing in USA. Clinical trial information: NCT05283226 .

Improving Cognitive Function Through High-Intensity Interval Training in Breast Cancer Patients Undergoing Chemotherapy: Protocol for a Randomized Controlled Trial

More than 75% of patients with breast cancer treated with chemotherapy experience cognitive impairments (eg, memory and attention problems), commonly known as chemo-brain. Exercise, especially aerobic high-intensity interval training (HIIT), is associated with better cognitive function in healthy populations. However, clinical trials testing the impact of exercise interventions on chemotherapy-induced cognitive decline in patients with cancer are lacking, and the mechanisms through which exercise could improve cognitive function are unclear. The objective of the Improving Cognitive Function Through High-Intensity Interval Training in Breast Cancer Patients Undergoing Chemotherapy trial is to examine the effects of HIIT on cognitive function in patients with breast cancer undergoing chemotherapy. This 2-arm, single-center, pilot randomized controlled trial will randomize 50 patients with breast cancer undergoing chemotherapy to HIIT or attention control. The HIIT group will perform a supervised 16-week, thrice-weekly intervention, with each session including a 5-minute warm-up at 10% maximal power output (POmax), 10 sets of alternating 1-minute high-intensity (90% POmax) and 1-minute recovery (10% POmax) intervals, and a 5-minute cooldown (10% POmax). The attention control group will receive a stretching program with no exercise components and be asked to maintain their exercise levels for 16 weeks. The primary outcomes of the study are executive function and memory measured using the National Institutes of Health toolbox and resting-state connectivity and diffusion tensor imaging microstructure evaluated using magnetic resonance imaging. The secondary and tertiary outcomes include cardiorespiratory fitness, body composition, physical fitness, and psychosocial health. The study has been approved by the institutional review board of the Dana-Farber Cancer Institute (20-222). The trial was funded in January 2019, with recruitment started in June 2021. As of May 2022, a total of 4 patients have consented and been randomized (n=2, 50% to exercise; n=1, 25% to control; and n=1, 25% nonrandomized). Trial completion is expected in January 2024. This first-of-its-kind study incorporates a novel exercise intervention (ie, HIIT) and comprehensive cognitive measures. If positive, our findings will establish the pilot efficacy of HIIT on chemotherapy-induced cognitive function in patients with breast cancer, providing the foundation for future larger phase-II and phase-III trials to confirm the findings and potentially establish HIIT as a standard of care for women undergoing chemotherapy for breast cancer. ClinicalTrials.gov NCT04724499; https://clinicaltrials.gov/ct2/show/NCT04724499. DERR1-10.2196/39740.

PEDT-18 PHASE I/II TRIAL OF OP-10 (ONC201) IN JAPANESE PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE MIDLINE GLIOMA

Abstract Background Diffuse midline glioma (DMG) occurs mainly in the brain stem and most of patients have the mutation of histone (H3K27M). The prognosis is poor, and median overall survival (OS) is less than 12 months. OP-10 (ONC201) have antagonistic activity against dopamine D2 ha and to activate ClpP, a mitochondrial protease, leading tumor cells to apoptosis. We conducted a multicenter, single-arm, open-label phase I/II study of OP-10 in Japan. Methods A 3 + 3 design was used to determine the recommended dose of OP-10 for nine patients with recurrent or refractory glioma in the phase-I trial. Patients with recurrent or refractory DMG in the phase-II trial orally received OP-10 once weekly until discontinuation because of progression or adverse events. The efficacy and safety of OP-10 were evaluated in the phase-II part. The tumor objective response rate (ORR), the primary endpoint of the phase-II trial, was assessed through a blinded, independent central review according to RANO-LGG criteria. Results A total of 9 (age: 24-72 years) and 31 (age: 4-39 years) patients were administered in the phase-I and phase-II trials, respectively. Although the lower limit of the 90% confidence interval for ORR did not exceed the pre-specified threshold (5%), nine of 31 patients showed tumor regression on T2/FLAIR images. In the phase-II trial, the median OS was 28.4 weeks, and the OS rate at 6 months was 54.8%. Adverse events of grade ≥ 3 were reported in five of 31 (16.1%) patients in the phase-II part, with death of disease, hyperuricemia, malaise, pyrexia, alanine transaminase elevation, and aspartate transaminase elevation. Conclusion The results of this study suggested that OP-10 might be efficacious in some patients with recurrent or refractory DMG, without major safety concerns.

CD20 Expression as a Possible Novel Prognostic Marker in CLL: Application of EuroFlow Standardization Technique and Normalization Procedures in Flow Cytometric Expression Analysis.

Simple SummaryUp to 50% of patients with chronic lymphocytic leukemia relapse within four years after anti-CD20-directed treatment with a need for a subsequent treatment, which can potentially include anti-CD20 agents again. To retrospectively study the influence of CD20 expression in CLL patients receiving anti-CD20 directed therapy on therapy response, we designed and evaluated a bead-based normalization approach for the analysis of CD20 expression levels to reduce variation of flow cytometric measurements due to technical issues. Normalization significantly reduced the variability of median fluorescence intensities of fluorochrome-conjugated beads without artificially rendering the instruments’ performances, and longitudinal biological variations of marker expression based on MFI values could be robustly assessed. In a cross-trial comparison, strong MRD response correlated with the CD20 expression level before therapy started in patients receiving Ofatumumab, but not in patients receiving Obinutuzumab.Background: CD20 expression is a controversial issue regarding response prediction to anti-CD20 therapy in chronic lymphocytic leukemia (CLL). Methods: Median fluorescence intensities (MFIs) of standard fluorescence beads from the daily calibration of flow cytometers according to EuroFlow protocols were used to establish a normalization approach to study CD20 expression on CLL cells. CD20 MFI was retrospectively assessed prior to and during treatment from flow cytometric measurements of peripheral blood in patients with different depths of molecular response in the four phase-II CLL2-BXX trials (BIG; BAG; BIO; BCG; N = 194) administering either Obinutuzumab or Ofatumumab in combination with targeted agents. Results: No significant difference was observed between the normalized and measured MFIs of CD19 and CD20 on CLL cells. During treatment, CD20 expression levels on CLL cells did not significantly differ between the four investigated different treatment schemes, but a strong molecular response to Ofatumumab seemed to correlate with higher CD20 expression prior to therapy. Conclusions: Standardized staining and instrument monitoring enable a robust assessment of longitudinal biological variations of marker expression based on MFI values. Obinutuzumab showed a higher proportion of patients with a strong MRD response independent from initial CD20 expression, whereas high pre-therapeutic CD20 expression levels seem to correlate with a profound response to Ofatumumab.

3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Therapy in Hawaii: A Brief Review.

The Food and Drug Administration (FDA) granted breakthrough therapy status to 3,4-methyl​enedioxy​methamphetamine-assisted therapy (MDMA-AT) in 2017 due to preliminary evidence supporting its efficacy and safety in treating post-traumatic stress disorder (PTSD). A series of six phase-II clinical trials studying MDMA-AT for treatment-resistant PTSD found that 54% of MDMA-AT full-dose participants no longer met the diagnosis of PTSD after two MDMA sessions, compared to 23% in the control group. In the first phase-III clinical trial, 67% no longer met the criteria for PTSD after three sessions. The effects are durable, with 67% no longer diagnosable after one year and 74% at nearly four years. The MDMA-AT is being fast-tracked for potential FDA approval by 2023. In 2021, Hawaii’s Senate Bill 738 unsuccessfully proposed that psilocybin be removed from the Schedule I controlled substances list due to its clinical efficacy for major depressive disorder. Methyl​enedioxy​methamphetamine is also a Schedule I controlled substance and has proven to be a treatment option that could potentially benefit the people of Hawaii.

Hypofractionation with simultaneous integrated boost after breast-conserving surgery: Long term results of two phase-II trials

PurposeTo analyze long-term results of two multicenter prospective single-arm trials (ARO-2010-01 and ARO-2013-04) investigating adjuvant hypofractionated radiotherapy (HF) with simultaneous integrated boost (SIB) after breast-conserving surgery (BCS). MethodsEligible patients had histopathologically confirmed unifocal breast cancer planned for whole breast irradiation plus boost radiotherapy to the tumor bed. In both studies, a total dose of 40 Gy was applied to the whole breast and of 48 Gy to the tumor bed in 16 fractions of 2.5 and 3.0 Gy. Radiotherapy could be given either as three-dimensional conformal radiotherapy (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The primary study objectives were feasibility and security within an observation period of six months. The current investigation focuses on long-term efficacy and toxicities. ResultsBetween 2011 and 2014, both trials enrolled 300 patients in total. Data from 274 of these patients could be used for the current analysis. The median follow-up time was 60 months and the 5-year disease-free survival 92.1%. Three patients suffered a local recurrence (after 36–72 months) while a regional recurrence occurred in one patient (after 17 months). The 5-year local control rate in the breast was 99.6%. 63.5% of all patients did not report any late radiation-related toxicity, 28.5% reported grade 1 and 7.3% grade 2 toxicities. The highest late toxicity was grade 3 in 2 women (0.7%, telangiectasia and lymphedema of the breast). ConclusionOur analysis demonstrates favorable efficacy and low rates of long-term side effects of HF with SIB after BCS. Randomized controlled phase III trials are ongoing.

A Sensitive Spectrofluorimetric Method for Curcumin Analysis

Curcumin (CUR), a natural polyphenolic compound extracted from the rhizomes of Curcuma longa, is used as a pharmaceutical agent, spice in food, and as a dye. Currently, CUR is being investigated for cancer treatment in Phase-II clinical trials. CUR also possesses excellent activities like anti-inflammatory, anti-microbial, and anti-oxidant, therefore quality control is crucial. The present research work was to develop a new, simple, validated and time-saving rapid 96-well plate spectrofluorimetric method for the determination of CUR. The developed method was compared with routinely used high performance liquid chromatography (HPLC) technique. The developed method were found to be linear in the concentration range of 15 to 3900 ng/mL with R2 ≥ 0.9983 for spectrofluorimetric and 50-7500 ng/mL with R2 ≥ 0.9999 for HPLC method. Accuracy, intraday and interday precision was adequate, with RSD lower than the suggested limits. The limits for the detection and the quantification of CUR were 7 and 15 ng/mL for spectrofluorimetric, and 25 and 50 ng/mL for HPLC respectively. The Bland-Altman analysis demonstrated the similarities between the two methods. The 96-well plate method was successfully applied to determine CUR in solid lipid nanoparticles (SLNs) and chitosan nanoparticles (Chi-NPs). The developed spectrofluorimetric method can hence serve as a possible replacement for the HPLC method for the quantification of CUR in healthcare and food products.

Highlights from the 2021 ASCO and ESMO annual meetings on radiotherapy of head and neck cancer

At this year's annual meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), several studies on radiotherapy of locally advanced head and neck cancer were presented. For the indication of definitive radiochemotherapy, particularly the administration of immune checkpoint inhibitors concomitant to radiotherapy was investigated. In the phaseIII GORTEC-REACH trial, combined inhibition of epidermal growth factor receptor (EGFR) and programmed death-ligand (PD-L1) concomitant to radiotherapy of locally advanced head and neck cancer was inferior to platinum-based chemoradiotherapy. However, this therapeutic approach may be more efficient than radiotherapy with simultaneous EGFR inhibition alone. The concept of the phaseII CheckRad-CD8 trial with induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy after appropriate patient selection also proved to be highly efficient. In initial phaseII trials, dose de-escalation of radiotherapy seems feasible for HPV-positive oropharyngeal cancer after appropriate patient selection both postoperatively (ECOG-ACRIN E3311 trial) and after induction therapy (OptimaII trial). However, dose de-escalation should currently not be performed outside of clinical trials. In addition, first studies indicate abenefit of functional imaging (diffusion-weighted magnetic resonance imaging [MRI] or F‑fluoromisonidazole positron-emission tomography [FMISO-PET]) to establish personalized dose concepts in radiotherapy.

Efficacy of Immune Checkpoint Inhibitors in Patients with Mismatch Repair-Deficient or Microsatellite Instability-High Metastatic Colorectal Cancer: Analysis of Three Phase-II Trials.

Programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) inhibitors are increasingly used in a variety of solid tumors. In patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer, their efficacy has been demonstrated in recently published phase-II trials. However, an indirect comparison of effectiveness between pembrolizumab, nivolumab, and nivolumab+ipilimumab is not yet available.After a standard literature search, we analyzed four overall survival (OS) curves from three phase-II trials. Individual patient data were reconstructed from each curve using a specific web-based technique (Shiny method). Indirect statistical comparisons were made based on hazard ratio (HR) and restricted mean survival time (RMST).Nivolumab+ipilumumab had a better HR compared with pembrolizumab (0.65, 95% confidence interval [CI], 0.43 to 1.002, p=0.051); the difference being close to statistical significance. In the analysis based on RMST, the combination of nivolumab+ipilimumab showed a significantly longer OS than pembrolizumab (improvement in RMST, 1.08 mos; 95%CI, 0.11 to 2.06; p=0.029). The other two pairwise differences in RMST (nivolumab vs. pembrolizumab and nivolumab+ ipilimumab vs. nivolumab) had a smaller magnitude (0.25 mos, 95%CI, -0.99 to 1.48, and 0.84 mos, 95%CI, -0.40 to 2.07, respectively) and were far from statistical significance.Our results favoring the combination of nivolumab+ipilimumab in metastatic colorectal cancer must be viewed with caution owing to the indirect nature of our statistical comparisons. With this limitation in mind, the magnitude of the incremental benefit for the above combination treatment was estimated to be around one month over a follow-up of 15 months.

Evaluating posaconazole, its pharmacology, efficacy and safety for the prophylaxis and treatment of fungal infections

ABSTRACT Introduction Invasive fungal diseases (IFDs) are a significant cause of morbidity and mortality among immunocompromised patients. Safe and effective antifungal medications used for prophylaxis and treatment are pivotal in their management. Posaconazole is a promising triazole antifungal agent. Areas covered The authors discuss the pharmacological properties of posaconazole, including pharmacokinetics/pharmacodynamics, safety and tolerability profile, together with efficacy data for prophylaxis and treatment as well as its use in special populations based on current literature. Expert opinion Posaconazole has a favorable safety and tolerability profile; however, caution is advised when co-administered with agents that are CYP3A4 inhibitors, because their concentration may significantly increase, and their levels should be closely monitored. It has an extended spectrum of activity against yeasts and filamentous fungi. It is successfully used as prophylaxis for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and post-hematopoietic cell transplantation (HCT) with graft-versus-host disease (GVHD). It is the first line treatment for oropharyngeal candidiasis and is also used as a salvage treatment for refractory IFDs. Currently available formulations include the oral suspension, delayed-release tablets and solution for intravenous infusion, all with different PK/PD properties and indications. Its use in children and adolescents is currently being examined in Phase-II clinical trials.

Molnupiravir-A Novel Oral Anti-SARS-CoV-2 Agent.

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly resulted in a global pandemic with approximately 4 million deaths. Effective oral antiviral agents are urgently needed to treat coronavirus disease-2019 (COVID-19), block SARS-CoV-2 transmission, and prevent progression to severe illness. Molnupiravir (formerly EIDD-2801), a prodrug of beta-d-N4-hydroxycytidine (EIDD-1931) and an inhibitor of RNA-dependent RNA polymerase, possesses significant activity against SARS-CoV-2. Its prophylactic efficacy has been evidenced in a ferret model. Two phase-I trials (NCT04392219 and NCT04746183) have demonstrated that oral molnupiravir is safe and well-tolerated at therapeutic doses. After five-days of oral molnupiravir therapy, satisfactory efficacies, assessed by eliminating nasopharyngeal virus in patients with early and mild COVID-19, were disclosed in two phase-II trials (NCT04405739 and NCT 04405570). Two phase-II/III trials, NCT04575597 and NCT04575584, with estimated enrollments of 1850 and 304 cases, respectively, are ongoing. The NCT04575597 recently released that molnupiravir significantly reduced the risk of hospitalization or death in adults experiencing mild or moderate COVID-19. To benefit individual and public health, clinical applications of molnupiravir to promptly treat COVID-19 patients and prevent SARS-CoV-2 transmission may be expected.

1292P Two single-arm, multicenter phase-II trials of PD-1 inhibitors in patients with pulmonary sarcomatoid carcinoma (NCCH1603/NCCH1703)

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer, occurring in <1% of all lung tumors. PSC is highly resistant to conventional cytotoxic chemotherapies and confers a poor prognosis. Two single-arm, multicenter phase-II trials were conducted to evaluate the efficacy and safety of PD-1 inhibitors in patients with PSC.

Successive Osteosarcoma Relapses after the First Line O2006/Sarcome-09 Trial: What Can We Learn for Further Phase-II Trials?

Simple SummaryOsteosarcoma is the most common primary malignant bone tumour in adolescents and young adults. The survival of osteosarcoma patients has not improved for four decades. The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. Among the 434 patients with a confirmed osteosarcoma who achieved CR1 during first line treatment, 157 patients experienced at least one relapse. The 3-year progression-free and overall survival rates were 21% and 37%, respectively. Only a quarter of the patients were included in clinical trials at first recurrence. We want to promote randomised phase-II trials in osteosarcoma relapses, with broad inclusion criteria at study entry in terms of age and disease status, and PFS as primary endpoint. Surgery/local treatment of all residual lesions should be allowed when feasible. Single-arm trial design could be used for subsequent relapses.The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5–7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase-II Trial: AdrenoMedullin for Ischemic Stroke Study

Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke. The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30μg/kg of AM in total for 7 days, n=20) or placebo group (n=10). In the second cohort, patients will be assigned to the investigation treatment B (56μg/kg of AM in total for 7 days, n=20) or placebo group (n=10). Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups. AM is expected to be a safe and effective treatment for ischemic stroke.

Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research.

BackgroundOptimal Phase‐II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined.ObjectivesRecurrent/refractory ES phase‐I/II trials analysis to improve trials design.MethodsComprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e‐cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase‐I or Phase‐II).ResultsThe 146 trials identified (77 phase‐I/II, 67 phase‐II, and 2 phase‐II/III) tested targeted (34%), chemo‐ (23%), immune therapies (19%), or combined therapies (24%). Twenty‐three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single‐arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression‐free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%–25% and 20%–50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3–14.7) and 7.6 months (5–30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%–30%), 4.5 (1.3–10), and 16.6 months (6.9–30), respectively.ConclusionThis review supports the need to develop the international randomized phase‐II trials across all age ranges with PFS as primary endpoint.

Telacebec (Q203): Is there a novel effective and safe anti-tuberculosis drug on the horizon?

High prevalence and stronger emergency of various forms of drug-resistant tuberculosis (DR-TB), including the multidrug-resistant (MDR-TB) as well as extensively drug-resistant (XDR-TB) ones, caused by variously resistant Mycobacterium tuberculosis pathogens, make first-line anti-tuberculosis (anti-TB) agents therapeutically more and more ineffective. Therefore, there is an imperative to develop novel highly efficient (synthetic) agents against both drug-sensitive-TB and DR-TB. The exploration of various heterocycles as prospective core scaffolds for the discovery, development and optimization of anti-TB drugs remains an intriguing scientific endeavour. Telacebec (Q203; TCB), a molecule containing an imidazo[1,2-a]pyridine-3-carboxamide (IPA) structural motif, is considered a novel very promising anti-TB agent showing a unique mechanism of action. The compound blocks oxidative phosphorylation by inhibiting a mycobacterial respiratory chain due to interference with a specific cytochrome b subunit (QcrB) of transmembrane bc1 menaquinol-cytochrome c oxidoreductase as an essential component for transporting electrons across the membrane from menaquinol to other specific subunit, cytochrome c (QcrC). Thus, the ability of mycobacteria to synthesize adenosine-5´-triphosphate is limited and energy generating machinery is disabled. The TCB molecule effectively fights drug-susceptible, MDR as well as XDR M. tuberculosis strains. The article briefly explains a mechanism of an anti-TB action related to the compounds containing a variously substituted IPA scaffold and is focused on their fundamental structure-anti-TB activity relationships as well. Special consideration is paid to TCB indicating the importance of particular structural fragments for maintaining (or even improving) favourable pharmacodynamic, pharmacokinetic and/or toxicological properties. High lipophilicity of TCB might be regarded as one of the key physicochemical properties with positive impact on anti-TB effect of the drug. In January 2021, the TCB molecule was also involved in phase-II clinical trials focused on the treatment of Coronavirus Disease-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2.

An Oculus to Profile and Probe Target Engagement In Vivo: How T-REX Was Born and Its Evolution into G-REX.

Here we provide a personal account of innovation and design principles underpinning a method to interrogate precision electrophile signaling that has come to be known as "REX technologies". This Account is framed in the context of trying to improve methods of target mining and understanding of individual target-ligand engagement by a specific natural electrophile and the ramifications of this labeling event in cells and organisms. We start by explaining from a practical standpoint why gleaning such understanding is critical: we are constantly assailed by a battery of electrophilic molecules that exist as a consequence of diet, food preparation, ineluctable endogenous metabolic processes, and potentially disease. The resulting molecules, which are detectable in the body, appear to be able to modify function of specific proteins. Aside from potentially being biologically relevant in their own right, these labeling events are essentially identical to protein-covalent drug interactions. Thus, on what proteins and even in what ways a covalent drug will work can be understood through the eyes of natural electrophiles; extending this logic leads to the postulate that target identification of specific electrophiles can inform on drug design. However, when we entered this field, there was no way to interrogate how a specific labeling event impacted a specific protein in an unperturbed cell. Methods to evaluate stoichiometry of labeling, and even chemospecificity of a specific phenotype were limited. There were further no generally accepted ways to study electrophile signaling that did not hugely disturb physiology.We developed T-REX, a method to study single-protein-specific electrophile engagement, to interrogate how single-protein electrophile labeling shapes pathway flux. Using T-REX, we discovered that labeling of several proteins by a specific electrophile, even at low occupancy, leads to biologically relevant signaling outputs. Further experimentation using T-REX showed that in some instances, single-protein isoforms were electrophile responsive against other isoforms, such as Akt3. Selective electrophile-labeling of Akt3 elicited inhibition of Akt-pathway flux in cells and in zebrafish embryos. Using these data, we rationally designed a molecule to selectively target Akt3. This was a fusion of the naturally derived electrophile and an isoform-nonspecific, reversible Akt inhibitor in phase-II trials, MK-2206. The resulting molecule was a selective inhibitor of Akt3 and was shown to fare better than MK-2206 in breast cancer xenograft mouse models. Recently, we have also developed a means to screen electrophile sensors that is unbiased and uses a precise burst of electrophiles. Using this method, dubbed G-REX, in conjunction with T-REX, we discovered new DNA-damage response upregulation pathways orchestrated by simple natural electrophiles. We thus emphasize how deriving a quantitative understanding of electrophile signaling that is linked to thorough and precise mechanistic studies can open doors to numerous medicinally and biologically relevant insights, from gleaning better understanding of target engagement and target mining to rational design of targeted covalent medicines.