Multicenter Phase Research Articles

Nelonemdaz Treatment for Patients With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Objectives: Nelonemdaz is a N-methyl d-aspartate receptor subtype 2B-selective N-methyl-D-aspartate receptor antagonist and a potent free-radical scavenger that might ameliorate hypoxic-ischemic brain injury after out-of-hospital cardiac arrest (OHCA). We investigated the efficacy of nelonemdaz for patients with OHCA. Design: A double-blind, placebo-controlled, randomized, multicenter phase II trial. Setting: This trial enrolled 105 patients at five sites in South Korea between November 18, 2018, and February 23, 2023. Participants: OHCA patients undergoing targeted temperature management. Interventions: Patients were randomly assigned to high-dose (5250 mg), low-dose (3250 mg), and placebo groups at a 1:1:1 ratio. Measurements and Main Results: Patients with a median age of 61 years (82% male) were assigned to the high-dose (n = 37), low-dose (n = 35), and placebo (n = 33) groups. The primary outcome, the serum level of neuron-specific enolase (NSE) at 48–52 hours, was evaluated in 93 patients. There was no difference in serum NSE between high-dose (median and interquartile range; 23.7, 15.0–69.9) and placebo (17.5, 13.6–113.0) groups, or between low-dose (26.6, 16.2–83.4) and placebo groups (all p > 0.05). Brain MRI fractional anisotropy was significantly higher in the high-dose group compared with the placebo group (0.465, 0.449–0.485 vs. 0.441, 0.431–0.464; p = 0.028), but not between low-dose (0.462, 0.439–0.480) and placebo groups (p > 0.05). At day 90, the common odds ratio (95% CI) indicating a numerically favorable shift in the modified Rankin Scale was 1.25 (0.48–3.24) and 1.22 (0.47–3.20) in the high-dose and low-dose groups, respectively, compared with placebo group (all p > 0.05). No serious adverse events were reported. Conclusions: Nelonemdaz treatment of patients after OHCA did not reduce serum NSE levels compared with controls. Patients treated with high-dose nelonemdaz showed higher brain MRI fractional anisotropy suggesting less cerebral white matter damage.

PARADIGM-PV: a randomized, multicenter phase 4 study to assess the efficacy and safety of ropeginterferon alfa-2b in patients with low- or high-risk polycythemia vera.

Polycythemia vera (PV) is characterized by clonal hematopoietic stem or progenitor cells with constitutively active somatic mutation(s) in the Janus kinase 2 gene. Phlebotomy (Phl) and aspirin are often used alone for low-risk PV patients. However, data from the Low-PV study demonstrated that Phl and aspirin may not be adequate for patients. Therapeutic intervention with disease-modifying treatment appears to be beneficial for patients with PV regardless of the risk category. Ropeginterferon alfa-2b (ropeg) is a novel interferon-based therapy with favorable dosing schedules. A higher starting-dose (250µg) regimen with simpler dose titrations was found to have a potent disease-modifying effect with respect to inducing a molecular response. PARADIGM-PV is a randomized, phase 4 study with the primary goal of assessing the efficacy of ropeg at this dosing regimen in alleviating Phl-dependence in both low- and high-risk patients with PV. The secondary endpoints include complete hematologic response, molecular response, symptom improvement, maintenance of median hematocrit (Hct) values < 45% without disease progression, and safety. Patients will be randomized equally to receive either ropeg every two weeks or to continue their current treatment with Phl or other cytoreductive agents (e.g., hydroxyurea, other interferons, or ruxolitinib) as applicable. All patients will receive Phl if their Hct values are elevated to ≥45% according to the National Comprehensive Cancer Network guidelines. The study will enroll approximately 70 patients internationally, including patients in the US. This study will provide new efficacy data, measured as the ability of ropeg to reduce Phl eligibility and modify the disease.

Phase II Study of Nanoliposomal Irinotecan (Nal-IRI) with 5-Fluorouracil and Leucovorin in Refractory Advanced High-Grade Neuroendocrine Cancer of Gastroenteropancreatic (GEP) or Unknown Origin

Background: Neuroendocrine carcinomas (NECs) are treated with a frontline platinum–etoposide combination with no standard second-line therapies. We explored a novel combination of nanoliposomal irinotecan (Nal-IRI), 5-fluorouracil (5-FU), and leucovorin (LV) in advanced refractory NECs and investigated the impact of UGT1A1*28 polymorphism on treatment outcomes and toxicity. Methods: We conducted an open-label, single-arm, multi-center Phase 2 trial in advanced NEC patients of gastroenteropancreatic (GEP) or unknown origin with progression or intolerance to first-line therapy. Eligible patients received nal-IRI 70 mg/m2 and leucovorin 400 mg/m2, followed by 5-FU 2400 mg/m2 biweekly till disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Next-generation sequencing (NGS) was performed on blood/tissue samples at baseline and during treatment. Results: Eleven patients were enrolled, with nine evaluable for the primary endpoint. Seven were male, the median age was 66.7 years, and the median Ki-67 was 90%. We observed partial response in one patient, stable disease in six patients, and progressive disease in two patients. The median OS was 9.4 months (95% CI 2.9–29.3), and the median PFS was 4.4 months (95% CI 1.7–6.7). The most common adverse events were diarrhea (45%), nausea (45%), vomiting (45%), and fatigue (45%). The most common genetic mutations on NGS were TP53 (88.9%), CHEK2 (88.9%), and APC (33.3%). Patients with CHEK2 and APC mutation had longer PFS (p = 0.005 and p = 0.013, respectively). UGT1A1*28 polymorphism was not associated with OS, PFS, or toxicity. Conclusion: Nal-IRI with 5-FU/LV is a safe and effective treatment for refractory high-grade NECs of GEP or unknown origin. Future studies should explore novel combinations with Nal-IRI in high-grade NECs both in frontline and refractory settings.

A phase Ia study of a novel anti-HER2 antibody–drug conjugate GQ1001 in patients with previously treated HER2 positive advanced solid tumors

BackgroundA novel anti-human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate (ADC) GQ1001 was assessed in patients with previously treated HER2 positive advanced solid tumors in a global multi-center phase Ia dose escalation trial.MethodsIn this phase Ia trial, a modified 3 + 3 study design was adopted during dose escalation phase. Eligible patients were enrolled, and GQ1001 monotherapy was administered intravenously every 3 weeks. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Extra patients were enrolled into 6.0, 7.2, and 8.4 mg/kg cohorts as dose expansion phase. The primary endpoints were safety and to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLTs). Pharmacokinetics and anti-tumor efficacy of GQ1001 were assessed. The plasma concentration of free DM1, the payload of GQ1001, was quantitated.ResultsA total of 32 patients were enrolled, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland cancer (4). Median number of prior-line of therapies was 3 (0–11) and 37.5% patients received ≥ 2 lines of anti-HER2 therapies. No DLT was observed during dose escalation. MTD was not reached and dose recommended for dose expansion (DRDE) was determined as 8.4 mg/kg. Grade ≥ 3 treatment-related adverse events rate was 28.1% (9/32) and platelet count decreased (4/32, 12.5%) was the most common one. No drug-related death was observed. Objective response rate and disease control rate of 15 evaluable patients in 7.2 mg/kg and 8.4 mg/kg cohorts were 40.0% (6/15) and 60.0% (9/15). Pharmacokinetics analysis showed low exposure and accumulation of free DM1 in circulation.ConclusionGQ1001 is well tolerated and shows promising efficacy in previously treated HER2-positive advanced solid tumors. DRDE was determined as 8.4 mg/kg for following trials.Trial registration NCT, NCT04450732, Registered 23 June 2020, https://clinicaltrials.gov/study/NCT04450732

Phase 2 study of serplulimab with the bevacizumab biosimilar HLX04 in the first-line treatment of advanced hepatocellular carcinoma

IntroductionThis study aimed to evaluate the safety and preliminary efficacy of serplulimab, a novel programmed death-1 inhibitor, with or without bevacizumab biosimilar HLX04 as first-line treatment in patients with advanced hepatocellular carcinoma.MethodsThis open-label, multicenter phase 2 study (clinicaltrials.gov identifier NCT03973112) was conducted in China and consisted of four treatment groups: group A (serplulimab 3 mg/kg plus HLX04 5 mg/kg, subsequent-line), group B (serplulimab 3 mg/kg plus HLX04 10 mg/kg, subsequent-line), group C (serplulimab 3 mg/kg, subsequent-line) and group D (serplulimab 3 mg/kg plus HLX04 10 mg/kg, first-line). Group D was the only group in which participants received the study treatment in the first-line setting. The primary endpoint was safety.ResultsFollowing previous report on groups A and B, results of group D are herein presented. As of February 7, 2023, 61 patients were enrolled and were followed up for a median of 25.5 months. Grade ≥ 3 treatment-emergent adverse events were reported by 29 (47.5%) patients. One patient died from adverse events that were considered related to study treatment. Among the patients with at least one post-baseline tumor assessment (n = 58), the objective response rate was 29.3% (95% CI: 18.1–42.7) as assessed by an independent radiological review committee (IRRC) per RECIST v1.1. IRRC-assessed median progression-free survival was 7.3 months (95% CI: 2.8–11.0), and median overall survival was 20.4 months (95% CI: 15.0–NE), respectively.ConclusionSerplulimab combination therapy with HLX04 showed a manageable safety profile as well as preliminary efficacy in patients with advanced HCC in the first-line setting.

Efficacy and safety of SHR8554 on postoperative pain in subjects with moderate to severe acute pain following orthopedic surgery: A multicenter, randomized, double-blind, dose-explored, active-controlled, phase II/III clinical trial.

Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID24). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID24 compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and -19.8 (p < 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery. TRIAL REGISTRATION: Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.

Longitudinal circulating tumor DNA monitoring in predicting response to short-course radiotherapy followed by neoadjuvant chemotherapy and camrelizumab in locally advanced rectal cancer: data from a Phase Ⅲ clinical trial (UNION).

This study, conducted as part of a multicenter phase III clinical trial, aimed to assess the utility of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) in comparing the efficacy of short-course and long-course chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). A total of 244 plasma samples from 79 LARC patients undergoing neoadjuvant therapy (NAT) before surgery were collected at various time points. Targeted deep sequencing using a novel MRD panel was performed. During NAT, ctDNA levels declined significantly. Baseline ctDNA-MRD status did not correlate significantly with treatment response. Notably, compared to long-course radiotherapy, microsatellite instability increased significantly after short-course radiotherapy (shortRT). Additionally, ctDNA negativity or lower levels were significantly associated with pathological complete response (pCR). Clearance of ctDNA and MRD after shortRT correlated significantly with pCR. A predictive model based on ctDNA-MRD, combined with carcinoembryonic antigen (CEA), outperformed models using only MRD or only CEA in predicting pCR/non-pCR. These findings provide insights into NAT for LARC and highlight ctDNA-based MRD assessment's potential in tailoring treatment strategies, emphasizing the need for personalized approaches.

Hydroxychloroquine in combination with platinum doublet chemotherapy as first-line treatment for extensive-stage small cell lung cancer (Study 15): A randomised phase II multicentre trial.

Most patients with small-cell lung cancer (SCLC) present with extensive-stage (ES) disease and have a poor prognosis despite achieving high initial response rates to platinum-based doublet chemotherapy. This study evaluated whether adding hydroxychloroquine (HCQ) to chemotherapy could improve outcomes. This was a randomised multicentre phase II trial. Eligible patients had untreated ES-SCLC, a performance status 0-2 and measurable disease. Patients were randomly assigned (1:1 ratio) to HCQ (400mg orally twice daily) plus carboplatin-gemcitabine or carboplatin-etoposide alone. Chemotherapy was administered for up to six cycles, with HCQ given concurrently and then as single agent for up to 30 months. Primary endpoint was PFS, aiming for a hazard ratio (HR) of 0.70. 72 patients were randomised (36 HCQ+chemotherapy and 36 chemotherapy alone). Median HCQ treatment duration was 4.4 months. HCQ did not improve PFS (HR 1·12 95%CI 0·69-1.84; p=0·64), with a median of 5.7 months (HCQ+chemotherapy) versus 6.2 months (chemotherapy). The corresponding median OS were 8.9 and 10.2 months (HR 0.83, 95%CI 0.48-1.45, p=0.52). Fewer patients in the HCQ arm completed four cycles of chemotherapy due to adverse events (64% vs. 81%). Grade ≥3 adverse events were higher in the HCQ+chemotherapy arm (83.3% vs. 27.8%), primarily anaemia, neutropenia, and thrombocytopenia, partly due to the initially higher gemcitabine dose used CONCLUSIONS: Combining HCQ with platinum doublet chemotherapy did not improve PFS or OS outcomes for ES-SCLC, resulting in more patients stopping chemotherapy due to increased adverse events. When considered alongside other randomised studies of HCQ in cancer, the evidence collectively indicates a limited role for HCQ as a therapeutic option.

Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: 3-year survival update and multi-omics analysis.

Atezolizumab plus bevacizumab has shown promising efficacy in advanced mucosal melanoma in the multi-centre phase II study. This report updates 3-year survival outcomes and multi-omics analysis to identify potential response biomarkers. Forty-three intention-to-treat (ITT) patients received intravenous administration of atezolizumab and bevacizumab every 3 weeks. Available samples underwent whole exome sequencing, transcriptome sequencing and targeted bisulphite sequencing to assess correlations with clinical outcomes. With a median follow-up of 40.3 months, the median overall survival (mOS) was 23.7 months (95% confidence interval [CI], 15.1-34), and the 3-year OS rate was 28.7% (95% CI, 17.6%-46.8%). Patients with upper site melanoma exhibited longer progression-free survival (PFS), higher tumour neoantigen burden (TNB) and greater copy number variations (CNVs) burden compared to those with lower site melanoma. NRAS mutations were associated with enhanced angiogenesis, with five of six patients achieving partial response. Inflammatory cell infiltration, angiogenic status and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators. This 3-year updated analysis confirms the sustained efficacy of atezolizumab in combination of bevacizumab in patients with advanced mucosal melanoma. Inflammatory cell infiltration and angiogenic status were associated with therapeutic response. Furthermore, mucosal melanoma of upper site and NRAS mutation appear to be good predictors of response to immune checkpoint inhibitor and anti-angiogenic combination treatment. Targeting SMAD2 and p38 MAPK pathways may further improve the outcome of mucosal melanoma. 3-year follow-up study confirmed the therapeutic efficacy of atezolizumab combined with bevacizumab Tumors in the upper site and NRAS mutations are more sensitive to treatment Inflammatory cell infiltration, angiogenic status, and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators.

Clinical Efficacy and Safety of Ibutilide in Cardioversion of Atrial Fibrillation or Flutter in Indian Patients: A Multicenter Study.

To assess the efficacy and safety of Ibutilide infusion for cardioversion of atrial fibrillation (AF) or flutter (AFL) to sinus rhythm. This open-label, multicenter phase IV study was conducted at six sites across India. The study enrolled 120 patients (108 with AF, 12 with AFL), each receiving up to two, 10-minute intravenous doses of 1.0 mg Ibutilide. The primary endpoints were the proportion of patients achieving cardioversion and the mean time taken to achieve cardioversion. Secondary endpoints included the proportion of patients maintaining sinus rhythm at 24 hours and the incidence of adverse events. The cardioversion rate at 4 hours post-Ibutilide infusion among 120 patients was 65.83% (n = 79), with an average conversion time of 35.12 ± 36.71 minutes. At 24 hours, 85 patients (70.8%) had successful cardioversion, with a mean time of 107.24 minutes. The majority of patients (71.76%) had achieved cardioversion within 30 minutes. Of the 85 patients who achieved successful conversion, 82 (68.3%) maintained sinus rhythm at 24 hours. A total of 66 patients (55%) achieved cardioversion with the first bolus whereas 19 (15.8%) needed a second bolus. Atrial fibrillation patients had a higher conversion rate (75%) compared to AFL patients (33%). A total of 10 adverse events were recorded in eight patients (6.67%), including nausea, headache, palpitations, and bradycardia. Three severe cardiac events, one case of ventricular tachycardia, and two of tachycardia necessitated discontinuation of Ibutilide. No fatalities or serious adverse events (SAE) were reported. Ibutilide was found to be effective and well-tolerated for rapid restoration of sinus rhythm in patients with AF or AFL. CTRI/2018/01/011248. Dewan B, Navale S, Shinde S, Chaudhary J. Clinical Efficacy and Safety of Ibutilide in Cardioversion of Atrial Fibrillation or Flutter in Indian Patients: A Multicenter Study. Indian J Crit Care Med 2025;29(1):45-51.

Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings.

Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy. This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery. Major pathological response (MPR, primary endpoint) was previously reported; here, we report 3-year disease-free survival (DFS), OS, and clinical characteristics of patients developing brain metastases (BM) with integrated data from tumor genomics, gene expression, and quantitative immunofluorescent measurement of immune markers. Of 30 enrolled patients, 29 were taken to the operating room. 26 underwent R0 resection, with 17 experiencing MPR (10 pCR). With a median follow-up of 39.5 months, the median OS was 55.8 months, and the median DFS was 34.5 months. Landmark OS at 36 months was 77%. Among 14 patients with recurrent disease, 6 patients had BM. Patients whose tumors had mutations in STK11 and KEAP1 did not have a significantly higher incidence of BM. Reduced copy number of STK11 and KEAP1, both residing on chromosome 19p, was observed in ~1/3 of tumors. Reduced CN of STK11 was significantly associated with worse pathological response and incidence of BM. Consistent with recent phase III studies, 3-year OS data with neoadjuvant atezolizumab+chemotherapy was associated with prolonged PFS and OS. Establishing associations between STK11 and KEAP1 genomic alterations and key clinical outcomes in early-stage NSCLC requires further study.

Effect of oral nintedanib vs placebo on epistaxis in hereditary hemorrhagic telangiectasia: the EPICURE multicenter randomized double-blind trial.

Epistaxis greatly affects patients with hereditary hemorrhagic telangiectasia (HHT). Although few systemic treatment exist, nintedanib, is a good candidate thanks to its anti-angiogenic activity. Our main objective was to evaluate the efficacy of oral nintedanib on epistaxis duration in HHT patients with moderate to severe epistaxis. This multicenter phase 2 randomized, placebo-controlled, double-blind trial was conducted between June 2020 and February 2023. Inclusion criteria were being over 18years old and having a confirmed HHT diagnosis with an epistaxis severity score greater than 4. Sixty patients were randomized to receive either nintedanib or placebo for 12weeks with a 12week follow-up. The primary endpoint was the proportion of patients achieving a reduction of at least 50% in mean monthly epistaxis duration comparing the 8weeks before treatment to the last 8weeks of treatment. Main secondary outcomes included monthly duration and frequency of epistaxis and hemoglobin levels. Of the 60 randomized patients, 56 completed the trial. Thirteen patients (43%) in the nintedanib group vs 8 (27%) in the placebo group met the primary endpoint (p = 0.28). We observed a significant decrease in median epistaxis (57% vs 27%, p = 0.013) and a significant increase in median hemoglobin levels (+ 18 vs - 1g/L, p = 0.02) in the nintedanib vs the placebo group. Although we did not achieve our primary outcome, we observed a significant reduction in epistaxis duration and a significant increase in hemoglobin levels in patients treated with nintedanib. This supports the efficacy of nintedanib, and further studies are needed.

Study protocol for Adaptive ChemoTherapy for Ovarian cancer (ACTOv): a multicentre phase II randomised controlled trial to evaluate the efficacy of adaptive therapy (AT) with carboplatin, based on changes in CA125, in patients with relapsed platinum-sensitive high-grade serous or high-grade endometrioid ovarian cancer

IntroductionAdaptive ChemoTherapy for Ovarian cancer (ACTOv) is a phase II, multicentre, randomised controlled trial, evaluating an adaptive therapy (AT) regimen with carboplatin in women with relapsed, platinum-sensitive high-grade serous or...

A phase II double-blind multicentre, placebo-controlled trial to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP): the SESAM study protocol

IntroductionThe megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function PIK3CA variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a...

Stereotactic Body Radiotherapy vs Sorafenib Alone in Hepatocellular Carcinoma

Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy. To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone. This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023. Personalized SBRT, 27.5 to 50 Gy in 5 fractions. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life. Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively. In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone. ClinicalTrials.gov Identifier: NCT01730937.

CPX-351 plus gemtuzumab ozogamicin for relapsed/refractory acute myelogenous leukemia: a University of California Hematologic Malignancies Consortium trial

In this multicenter phase Ib trial, we investigated the combination of CPX-351 and gemtuzumab ozogamicin (GO) in relapsed/refractory acute myeloid leukemia (AML). Cohort A received CPX-351 plus a single dose of GO, while cohort B received two doses of GO. Thirteen participants received investigational treatment. Dose-limiting toxicities (DLTs) occurred in one participant in each cohort, with manageable adverse events. No cases of hepatic sinusoidal obstructive syndrome occurred. Out of 12 evaluable participants, four achieved complete remission (CR), three of whom were negative for measurable residual disease. The median time to recovery of hematopoiesis for responders was 37 days. CPX-351 with GO was feasible with acceptable toxicity and marrow recovery kinetics. Further evaluation in a larger patient cohort is necessary to assess the efficacy of this regimen in relapsed/refractory AML.

Efficacy and safety of the combination of envafolimab and lenvatinib in unresectable hepatocellular carcinoma: a single-arm, multicentre, exploratory phase II clinical study.

Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECISTcriteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.

Efficacy and safety of Ranquilon® in the therapy of patients with anxiety associated with neurasthenia and adjustment disorder: results of the double-blind, randomized, placebo-controlled, multicenter phase 3 clinical trial

Objective: to evaluate the efficacy and safety of Ranquilon® (INN amide N-(6-phenylhexanoyl) glycyl-L-tryptophan)) tablets 1 mg2 at a dose of 6 mg per day (JSC “Valenta Pharm”, Russia) compared with placebo in the treatment of patients with anxiety in neurasthenia and adjustment disorder. Materialand methods. The clinical trial (CT) included a total of 220 patients with anxiety due to neurasthenia or adjustment disorder (adaptive reaction disorder) and a score on the Hamilton Anxiety Rating Scale (HARS) from 18 to 24 inclusive, the severity of asthenia on the self-assessment scale of asthenia (Multidimensional Fatigue Inventory, MFI-20) is more than 50 points, as well as at least 4 points on the severity subscale of the clinical global impression scale (Clinical Global Impression—Severity, CGI-S), who were randomly assigned to two groups and received double-blind treatment. Patients of group 1 (n=110) received Ranquilon® , 1 mg tablets, at a dose of 6 mg/day (2 tablets 3 times) for 28 days. Patients of group 2 (n=110) received PL in the same dosage regimen. The primary outcome measure for the clinical trial was the assessment of patient response rate (proportion of responders) as a ≥50% reduction in the mean total Hamilton Anxiety Rating Scale (HARS) score at Visit 3 (Day 29±1) compared to baseline at Visit 0 (days from -7 to -1). Secondary efficacy criteria included assessment of various parameters over time at visits 2 and 3 compared to the baseline (visit 0), in particular: on the HARS scale—the proportion of patients with a decrease in anxiety level (in the mean total score) by ≥50% and the proportion with ≤17 points, average anxiety score; for the CGI-I subscale—the proportion of patients with significant and pronounced improvement, on the CGI-S subscale—the proportion of patients with a score of 1 or 2 points, the mean total score of the change in the severity of the condition; on the MFI-20 scale—change in mean total score, the proportion of patients with a decrease in mean total score by 25%, by 50% and to ≤30 points, the mean total score for all subscale items; on the Spielberger-Hanin scale—change in the mean total score of personal anxiety and situational anxiety. To assess safety monitoring of adverse events (AEs), serious adverse events (SAEs), clinically significant deviations in vital signs, laboratory parameters, ECG parameters, etc. was analyzed. Results. The proportion of responders with a ≥50% reduction in HARS mean total score at Visit 3 (Day 29±1) compared to baseline (Visit 0) was statistically significantly higher (p&lt;0.0001) in in group 1 (Ranquilon® ) compared with group 2 (PL), respectively, was 70.0% (n=77) and 24.5% (n=27) (difference—45.5% (n =50)). Evaluation of all secondary efficacy criteria also showed a statistically significant benefit of therapy in Group 1 compared to Group 2 (p&gt;&lt;0.05). A total of 64 AEs were recorded in 44 (20.0%) patients: 43 AEs in 28 patients (25.5%) in Group 1 and 21 AEs in 16 (14.6%) patients in Group 2. There was no significant difference between treatment groups in the number of patients with AEs (p=0.063). In both groups, mild AEs were recorded; there were no patients with serious AEs (SAEs), SAEs with fatal outcome, or AEs that led to discontinuation of study therapy. No clinically significant abnormalities observed in vital signs, laboratory parameters, or ECG parameters. Conclusion. The superiority of Ranquilon® tablets 1 mg at a dose of 6 mg per day therapy over placebo in reducing anxiety in patients with conditions due to neurasthenia and adaptation disorder was confirmed. The drug demonstrated a favorable safety profile similar to that established for PL.&gt;&lt;0.0001) in in group 1 (Ranquilon® ) compared with group 2 (PL), respectively, was 70.0% (n=77) and 24.5% (n=27) (difference—45.5% (n =50)). Evaluation of all secondary efficacy criteria also showed a statistically significant benefit of therapy in Group 1 compared to Group 2 (p&lt;0.05).A total of 64 AEs were recorded in 44 (20.0%) patients: 43 AEs in 28 patients (25.5%) in Group 1 and 21 AEs in 16 (14.6%) patients in Group 2. There was no significant difference between treatment groups in the number of patients with AEs (p=0.063). In both groups, mild AEs were recorded; there were no patients with serious AEs (SAEs), SAEs with fatal outcome, or AEs that led to discontinuation of study therapy. No clinically significant abnormalities observed in vital signs, laboratory parameters, or ECG parameters. Conclusion. The superiority of Ranquilon® tablets 1 mg at a dose of 6 mg per day therapy over placebo in reducing anxiety in patients with conditions due to neurasthenia and adaptation disorder was confirmed. The drug demonstrated a favorable safety profile similar to that established for PL.

Accuracy of photodynamic diagnosis for non-muscle-invasive bladder cancer: Exploratory analysis of anatomical locations and tumor types using data from a prospective, single-arm, multicenter phase III trial.

Accuracy of photodynamic diagnosis for non-muscle-invasive bladder cancer: Exploratory analysis of anatomical locations and tumor types using data from a prospective, single-arm, multicenter phase III trial.

Phase 1/2 trial of XPO1 inhibitor selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer.

Patients with KRAS mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated advanced KRAS mutant NSCLC. The primary outcome of this multi-center phase 1/2 dose escalation trial of selinexor plus docetaxel was safety and tolerability. Selinexor was started one week before docetaxel to permit monotherapy pharmacodynamic assessment. Among 40 enrolled patients, median age was 66 years, 55% were female, and 85% were white. Maximum tolerated dose was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every three weeks. The most common adverse events were nausea (73%, 8% Gr ≥3), fatigue (70%, 5% Gr ≥3), neutropenia (65%, 60% Gr ≥3), and diarrhea (58%, 10% Gr ≥3). Of 32 efficacy evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild type TP53 (42%), including disease control and response rates (27% and 80%, vs. 9% and 27%, respectively; P=0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% CI, 0.07-0.67; P=0.003). Post-selinexor / pre-docetaxel, serum LDH levels increased an average 51 U/L in TP53 altered and decreased an average 48 U/L in TP53 wild type cases (P=0.06). Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.