Multicenter Phase Research Articles

PL05 Presentation Time: 2:30 PM: Long-Term Late Side-Effects after Breast Conserving Surgery and Whole Breast Irradiation versus Accelerated Partial Breast Irradiation Using Multicatheter Brachytherapy - 10-Year Update of the GEC-ESTRO Multicentric Phase 3 Trial

PL05 Presentation Time: 2:30 PM: Long-Term Late Side-Effects after Breast Conserving Surgery and Whole Breast Irradiation versus Accelerated Partial Breast Irradiation Using Multicatheter Brachytherapy - 10-Year Update of the GEC-ESTRO Multicentric Phase 3 Trial

Efficacy and safety of inclisiran in real-world clinical practice. Results from the CHOLINET Registry

Abstract Background/Introduction Inclisiran has been recently introduced in clinical practice. Thus, efficacy and safety data from real-world settings are limited. Purpose Cholinet (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry including 36 Italian centers, designed to assess efficacy, safety, adherence and persistence of inclisiran treatment, and clinician’s behavior on LLT in very high CV risk patients with atherosclerotic CV disease and/or familial hypercholesterolemia (FH). Methods From November 2022 through February 2024, the Cholinet registry enrolled patients receiving inclisiran according to standard clinical practice. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at subsequent follow-up. Results We enrolled 668 patients in treatment with inclisiran (15.1% with FH, 30.7% female, mean age 63 years), Data on follow-up at 3 months (booster time) were available for 495 of them. At the time of inclisiran first prescription median LDL-C was 102 mg/dl and reached 51 mg/dl at the time of 3 months observation (50% mean reduction, 51 mg/dl absolute median reduction). None of the 495 patients reaching 3 months follow up missed the reinjection dose administration. Of 668 patients enrolled, 553 patients (82.7%) were on LLT, of them 107 (19.3%) were on ezetimibe alone, 67 (12.1%) on statin alone and 379 (68.5%) on a statin and ezetimibe combination. Of the enrolled patients, 45 (6.7%) were previously treated with evolocumab and 34 (5%) with alirocumab. Among the patients evaluated at the 3-month follow-up, 307 patients (62%) achieved the LDL cholesterol target; of them, 450 (91%) were treated with inclisiran and statin±ezetimibe. Evaluating the distribution of the percentage reduction in LDL cholesterol values, a heterogeneity emerged that was partly explainable by the concomitant lipid-lowering therapy and partly by the previous exposure to PCSK9 inhibitors. Conclusions These preliminary data from the Cholinet Italian registry show that inclisiran effectively reduces (50%) LDL-C in real-world settings. The LDL-C target was achieved in 62% of patients; of them 91% were on lipid-lowering therapy, showing that combination therapy is necessary in most of these patients.

Effect of nelonemdaz for patients with out-of-hospital cardiac arrest: the AWAKE phase II randomised clinical trial

Abstract Background Hypoxic brain injury is a major hurdle that limits the survival of out-of-hospital cardiac arrest (OHCA). Nelonemdaz is a dual-target neuroprotectant, serving as a moderate NR2B-selective N-methyl-D-aspartate (NMDA) receptor antagonist while also exhibiting potent free radical scavenger properties. This dual neuroprotective action of nelonemdaz has the potential to reduce hypoxic brain injury in OHCA. We investigated the efficacy and safety of nelonemdaz for patients with OHCA. Methods AWAKE trial was a double-blind, placebo-controlled, randomised, multicentre phase II trial at 5 sites in South Korea. OHCA patients undergoing targeted temperature management were randomly assigned to high-dose (5250 mg), low-dose (3250 mg), and placebo groups at a 1:1:1 ratio. The primary outcome was the blood level of neuron-specific enolase (NSE) after 4th administration of drug. Secondary outcomes comprised blood biomarkers including neuron specific enolase (NSE) and S100beta, brain magnetic resonance imaging (MRI), and Cerebral Performance Category (CPC) and Modified Rankin Scale (mRS) up to day 90. Safety is assessed by serious adverse event. Findings: A total of 105 patients were enrolled between November 18, 2018 to February 23, 2023. Patients with a median age of 61 years and 82% male were assigned to the high-dose (N=37), low-dose (N=35), and placebo (N=33) groups. Primary outcome was evaluated in 93 patients. There was no difference of neuron specific enolase (NSE, ng/mL), which served as the primary endpoint, between high-dose (median and interquartile range; 23·7, 15·0–69·9) and placebo (17·5, 13·6–113·0) groups and also between low-dose (26·6, 16·2–83·4) versus placebo groups (all p>0·05). Among secondary outcomes, fractional anisotropy of brain MRI was significantly higher in high-dose group compared to placebo group (0·465, 0·449–0·485 versus 0·441, 0·431–0·464; p=0·028), and was not different between low-dose (0·462, 0·439–0·480) and placebo groups (p>0·05). At day 90, the common odds ratio (95% confidence interval) indicating a favourable 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 to placebo group (all p>0·05). No serious adverse events were reported. Interpretation: Nelonemdaz did not reduced blood NSE level of OHCA patients. However, patients treated with high-dose nelonemdaz showed better fractional anisotropy that suggests reduced cerebral white matter damage. Patients treated with nelonemdaz also showed a favourable tendency of neurological recovery at day 90 without significant adverse effects. These results justify the initiation of a large-scale phase III trial.Neurological function up to day 90

Preoperative chemo-CIRT in Re/BRe pancreatic cancer: Insights from a multicenter prospective phase II clinical study (NCT03822936).

There is debate about the optimal management of borderline resectable (bRe) and resectable (Re) pancreatic ductal adenocarcinoma (PDAC). Both preclinical and clinical evidence showed that carbon ion radiotherapy (CIRT) produces superior control on radioresistant histologies compared to conventional photon beam radiotherapy (RT). However, so far there is a lack of data concerning the integration of CIRT in a multimodal approach with chemotherapy and surgery for bRe/Re. We recently presented the first analysis of a multicenter prospective phase II clinical study aimed at assessing the feasibility and effectiveness of a neoadjuvant chemotherapy + short course of CIRT followed by surgery and adjuvant chemotherapy in the management of bRe/Re PDAC. The study was terminated early due to low patient enrollment.Herein, we reported a post-hoc analysis focusing on toxicity, dosimetry and translational assessment. In our experience, CIRT can be integrated into a multimodal treatment strategy for bRe/Re PDAC, alongside chemotherapy and surgery. A case of fatal liver failure occurring three months post-surgery has been documented, likely related to the combination approach. Although the treatment plans were satisfactory according to the Local Effect Model (LEM) model, recalculations using the modified Microdosimetric Kinetic Model (mMKM) revealed suboptimal target coverage. Additionally, we observed an increased expression of PD-L1 following CIRT. This multimodal approach was well tolerated; however, clinicians should carefully monitor for vascular disorders during follow-up and further investigate surgical techniques after CIRT. The increased PD-L1 expression supports the immunogenic effects of particle therapy and lays the groundwork for future studies. To enhance the therapeutic ratio of CIRT treatments, integrating dose-averaged LETd (LETd-based objectives into the plan optimization process should be considered. ClinicalTrials.gov Identifier: NCT03822936.

Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials

The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.

Stereotactic Radiotherapy Plus Nivolumab in Patients with Locally Advanced Pancreatic Cancer: Results from Phase 1/2 Clinical CA209-9KH Trial.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. Patients aged ≥ 18years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.

Prospective Multicenter Comprehensive Survey on Male Sexual Dysfunction following Laparoscopic, Robotic, and Transanal Approaches for Rectal Cancer (the LANDMARC Study).

To investigate the incidence of male sexual dysfunction (SD) including erectile dysfunction (ErD) and ejaculatory dysfunction (EjD) after minimally invasive rectal cancer surgery. Male SD significantly affects post-rectal cancer surgery quality of life (QOL). Current assessments using the International Index of Erectile Function-5 are unsuitable for patients with reduced postoperative sexual activity, because it assumes sexual intercourse. This study addresses this gap using the Erection Hardness Score (EHS) and custom ejaculatory questionnaires. This prospective multicenter open-label phase II trial enrolled 399 patients who underwent laparoscopic (Lap), robotic (Ro), or transanal (Ta) rectal cancer surgery. EHS and custom ejaculatory questionnaires assessed ErD, EjD, and potency impairment at 3, 6, and 12 months postoperatively. The rates were assessed in the full analysis set and compared between the Lap and Ro groups after propensity score matching. At 12 months, the overall incidences of ErD and EjD were 34.7% and 29.8%, respectively. The Ro group showed a significantly lower EjD rate (25.0%) than the Lap group (40.9%), with no significant difference in ErD. Potency impairment was lower in the Ro group at 6 months (32.7% vs. 22.3%) and 12 months (29.0% vs. 17.8%) postoperatively. The Ta group showed relatively high ErD and EjD at 3 months, with some recovery at 12 months. Minimally invasive rectal cancer surgery commonly results in ErD, EjD, and potency impairment. Robotic surgery provides lower EjD rates and less potency impairment. Comprehensive sexual function assessments are essential to inform patients and improve QOL outcomes.

Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation

BackgroundTP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483

Multicenter randomized phase III study of high-dose therapy with autologous stem cell transplantation versus observation for patients with newly diagnosed peripheral T-cell lymphoma who achieved complete metabolic response after induction therapy (JCOG2210, TRANSFER study).

Patients with peripheral T-cell lymphoma demonstrated a poor prognosis after obtaining a complete response with induction treatment compared to those with B-cell lymphoma. Once it relapsed, curative treatment is frequently limited to invasive treatments with significant treatment-related mortality, including allogeneic stem cell transplantation. The limitations of these treatment choices indicate the necessity for developing optimal consolidation therapies to prevent relapse. This multicenter randomized phase III trial aims to confirm the superiority of the high-dose therapy with autologous stem cell transplantation over observation alone in terms of progression-free survival for patients with newly diagnosed peripheral T-cell lymphoma who achieved complete metabolic response after induction therapy. A total of 140 patients from 52 hospitals will be enrolled in Japan over 5.5years. This trial is registered in the Japan Registry of Clinical Trials as jRCTs031240169 (https://jrct.niph.go.jp/latest-detail/jRCTs031240169).

Clinical development and proof of principle testing of new regenerative vascular endothelial growth factor-D therapy for refractory angina: rationale and design of the phase 2 ReGenHeart trial

BackgroundDespite tremendous therapeutic advancements, a significant proportion of coronary artery disease patients suffer from refractory angina pectoris, that is, quality-of-life-compromising angina that is non-manageable with established pharmacological and interventional treatment...

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

Trastuzumab Deruxtecan With Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study.

This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC). Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate (cORR) by independent central review. Seven patients with mBC were enrolled in part 1 and received T-DXd 3.2 mg/kg (4 patients) or 5.4 mg/kg (3 patients) plus nivolumab. The RDE for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously/3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of 3 administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and 4 with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the cORR (95% CI) for cohorts 1-4 was 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. Median treatment duration (range) with T-DXd in cohorts 1-4 was 8.9 (1-23), 6.9 (1-21), 3.9 (1-21) months, and not assessed; most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, 75.0%). Adjudicated drug-related ILD/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0% (1 grade 5 each, cohorts 1 and 3). T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T‑DXd. ILD/pneumonitis is an important risk and requires careful monitoring and prompt intervention.

A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT

AbstractBronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial, adult participants with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared with enrollment. The primary end point differed according to cohort (cohort A, improvement, defined as ≥10% increase in FEV1; cohort B, stabilization, defined as an absence of ≥10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting the criteria for BOS were enrolled and treated (cohort A, n = 36; cohort B, n = 13). The primary end point was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 National Institutes of Health Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response), with most responses occurring in mild or moderate disease. Noninfectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03674047.

A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor-Naïve EGFR-Mutant Metastatic Non-Small Cell Lung Cancer (RAMOSE trial).

Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS). The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis. At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug. Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR-mutant NSCLC. The combination is safe and well tolerated.

Role of 18F-FDG-PET/CT in the initial staging of very high-risk Ewing Sarcoma in a prospective multicentric Phase II Study: Is there still a place for bone marrow sampling?

The Ewing Sarcoma Family of Tumors (ESFT) constitutes a group of rare malignancies, wherein approximately one-third of cases exhibit metastatic spread, particularly impacting prognosis when bone and/or bone marrow (BM) are involved. Primary extra-pulmonary metastatic ESFT often necessitates intensified therapeutic approaches. Accurate staging plays a pivotal role in clinical decision-making, with fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) currently serving as a non-invasive modality for assessing ESFT's BM extent. In the French phase II COMBINAIR3 (NCT03011528) study, a comprehensive approach for patients with extra-pulmonary ESFT metastasis was evaluated. We prospectively compared the efficacy of PET/CT to BM aspiration and biopsy (BMAB) analysis in patients undergoing initial staging. Among the 42 patients analyzed (median age 14 y, 2:1 male/female ratio), 45% presented with pelvic primary tumors and 83% had bone/BM involvement at diagnosis. Our findings showed PET/CT had 100% specificity and 83.3% sensitivity in detecting initial BM involvement. Overall, PET/CT correctly classified 92.8% of patients, reaching 100% accuracy in patients identified with bone involvement, thus surpassing the standard BMAB. These results suggest that the conventional use of BMAB in the initial staging of high-risk ESFT patients can be omitted, promoting PET/CT as a non-invasive alternative, thus improving staging accuracy and treatment decisions in ESFT management.

Effect of extending the period from oral administration of 5-aminolevulinic acid hydrochloride to photodynamic diagnosis during transurethral resection for non-muscle invasive bladder cancer on diagnostic accuracy and safety: a single-arm multicenter phase III trial.

In Japan, the authorized period (2-4 h) between oral administration of 5-aminolevulinic acid hydrochloride (5-ALA) and transurethral resection for non-muscle invasive bladder cancer (NMIBC) may restrict photodynamic diagnosis (PDD) usage. Therefore, this prospective, single-arm, phase III study aimed to evaluate the diagnostic accuracy and safety of PDD at an extended administration period (4-8h). From January 2022 to May 2023, 161 patients with NMIBC were enrolled from eight hospitals. The primary endpoint was the blue light (BL) sensitivity of pathologically positive biopsies. The secondary endpoints were a comparison of the specificity and positive and negative prediction rates under BL and white light (WL) conditions. A total of 1242 specimens comprising 337 histological NMIBC specimens were analyzed. BL-sensitivity was 95.3%. Its lower limit of 95% confidence interval (92.4-97.3%) exceeded the threshold (70%) of non-inferiority to authorized usage. Sensitivity and specificity were significantly higher and lower for BL than those for WL (95.3% vs. 61.1%, P < 0.001; 52.7% vs. 95.2%, P < 0.001), respectively. The positive and negative predictive rates were significantly lower and higher for BL than those for WL (42.9% vs. 82.7%, P < 0.001; 96.8% vs. 86.8%, P < 0.001), respectively. Of the 145 patients receiving 5-ALA, 136 (93.8%) and 75 (51.7%) experienced 377 adverse events and 95 adverse reactions, respectively, most of which were grade 1 or 2. For extended period, the efficacy of PDD for NMIBC was similar to that of authorized period, in terms of higher sensitivity and lower specificity compared with WL, and the safety was acceptable.

6733 Bone Turnover Markers Predict Bone Mineral Density Increases With Abaloparatide In Men Similarly To Women: Results From ATOM

Abstract Disclosure: J.P. Brown: Advisory Board Member; Self; Amgen Inc. Consulting Fee; Self; Amgen Inc, Gilead, Paladin, Pfizer, Inc., Servier. Research Investigator; Self; Mereo BioPharma, Radius Health, Inc, Servier. Speaker; Self; Amgen Inc. Other; Self; Ultragenyx. R.A. Adler: Grant Recipient; Self; Radius Health, Inc. E.M. Lewiecki: Consulting Fee; Self; Amgen Inc, Radius Health, Inc, Kyowa Kirin, Angitia, Ascendis. Research Investigator; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Speaker; Self; Amgen Inc, Kyowa Kirin. N. Binkley: Consulting Fee; Self; Amgen Inc, Radius Health, Inc. Research Investigator; Self; Amgen Inc, Radius Health, Inc. E.S. Orwoll: Consulting Fee; Self; Amgen Inc, Angitia, Biocon, Radius Health, Inc, Ultragenyx. Y. Wang: Employee; Self; Radius Health, Inc. D.L. Kendler: Consulting Fee; Self; Amgen Inc, Radius Health, Inc. Grant Recipient; Self; Amgen Inc, Radius Health, Inc. Speaker; Self; Amgen Inc, Radius Health, Inc. B.H. Mitlak: Employee; Self; Radius Health, Inc. R. Eastell: Consulting Fee; Self; Immunodiagnostic Systems, Sandoz, Samsung, CL Bio, Biocon, Takeda, UCB. Grant Recipient; Self; Alexion Pharmaceuticals, Inc.. Speaker; Self; Pharmacosmos, Alexion Pharmaceuticals, Inc., UCB, Amgen Inc. Background: Early serum procollagen type I N-terminal propeptide (PINP) increases correlate with 18-month lumbar spine (LS) bone mineral density (BMD) increases in postmenopausal women; however, this relationship has not been assessed in men. The Abaloparatide for the Treatment of Men with Osteoporosis (ATOM; NCT03512262) study demonstrated that abaloparatide (ABL) treatment in men with osteoporosis rapidly increased BMD at the LS, total hip (TH), and femoral neck (FN) compared with placebo (PBO). Bone turnover markers (BTMs), PINP and serum carboxy-terminal cross-linked telopeptide of type I collagen (CTX), were measured during the study. In this analysis, the correlation of early increases in BTMs and increases in BMD at 12 months between the ABL and PBO groups were determined and the results in men were compared to 12-month results in women from the ACTIVE study. Methods: ATOM was a randomized, double-blind, placebo-controlled, multicenter phase 3 study. A total of 228 men aged 40 to 85 years with osteoporosis or osteoporosis associated with hypogonadism were randomized 2:1 to receive 80 µg subcutaneous daily ABL or PBO for 12 months (ABL, n=149; PBO, n=79). Blood samples were collected under fasting conditions at baseline and post-dose at 1, 3, 6, and 12 months, and PINP and CTX measured. The correlation of increase from baseline in PINP and CTX concentrations, measured by log ratio over baseline, was compared with percentage increase from baseline BMD at 12 months using Spearman’s rank correlation. To compare between men and women, Pearson correlation coefficients were assessed using the z score test after Fischer’s Z transformation. Results: In the ABL group, median PINP level was 48.2 ng/mL at baseline, peaked at month 1 (109.0 ng/mL) and was 85.7 ng/mL at month 12. Median CTX level was 0.327 ng/mL at baseline, peaked at month 6 (0.476 ng/mL) and was 0.448 ng/mL at month 12. The increase in BTMs relative to baseline were significantly greater at all time points compared to PBO (P&amp;lt;0.0001). Median levels of PINP and CTX in men and women were similar over 12 months. Early PINP increases and subsequent LS BMD increases were significantly correlated for ABL in men starting at month 1, with the strongest correlations observed between 3 and 6 months. The correlation at 3 months was considered more clinically relevant, and the correlation coefficient in men receiving ABL (r=0.6138; P&amp;lt;0.0001) and women receiving ABL (r=0.561; P&amp;lt;0.0001) at 3 months are similar. Additionally, there was a significant correlation between the 1-month log ratio of PINP and TH BMD in men receiving ABL (r=0.1903; P&amp;lt;0.05). Conclusion: In the ATOM study, there was a significant correlation between early increases of BTMs (1 and 3 months) and BMD increases at 12 months. The correlation between early increases in PINP and percentage increase in LS BMD after 12 months of treatment with ABL in men is similar to that reported in women. Presentation: 6/2/2024

Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.

Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.

Comprehensive combined analysis of physician-initiated phase II and III clinical trials on a cultured human corneal endothelial cell product for treating bullous keratopathy.

To evaluate the efficacy and safety of a cultured human corneal endothelial cell (cHCEC) product in eyes with bullous keratopathy (BK). Combined analysis of multicenter phase II and III clinical trials. This analysis involved 15 BK eyes in the phase II trial and 12 BK eyes in the phase III trial that underwent cHCEC transplant therapy. Safety was assessed in all the cases. Efficacy was assessed in 17 cases with exclusion of the low- and medium-dose groups in the phase II trial. The primary endpoint was a corneal endothelial cell density of 1000 cells/mm2 or more at 24 weeks post-transplant, which was attained in 94.1% of the eyes (16 of 17), with a 95% CI of 71.3-99.9%. Additionally, 82.4% of the eyes (14 of 17) met the secondary endpoint of reduction in corneal thickness to less than 630 µm without corneal epithelial edema within the same time frame, with a 95% CI of 56.6-96.2%. The mean decrease in corneal thickness from baseline to 24 weeks post-transplant was -187.4 µm (95% CI, -240.2 µm to -134.5 µm). Furthermore, all the eyes exhibited improvement in best-corrected visual acuity from baseline to 24 weeks post-transplant (95% CI, 80.5-100.0%). By 24 weeks post-transplant, 88.9% of the patients (24 of 27) had experienced adverse events, which were mostly local, mild, and transient. The cHCEC product of this study reconstitutes the corneal endothelial layer with high cellular density and restores corneal thickness and improves visual acuity.

Short-term results of a multicenter study based on a modified N7 induction regimen combined with arsenic trioxide in the treatment of children with high-risk neuroblastoma

Objective: To analyze the short-term clinical efficacy and safety of arsenic trioxide (ATO) combined with a modified N7 induction regimen in the treatment of children with high-risk neuroblastoma (NB). Methods: This study was a prospective, single-arm, multicenter phase Ⅱ clinical study. Sixty-seven high-risk NB children from eight units of Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Wuhan Children's Hospital of Tongji Medical College of Huazhong University of Science and Technology, First Affiliated Hospital of Guangxi Medical University, Hainan General Hospital, Affiliated Hospital of Guangdong Medical University, Kunming Children's Hospital, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, and Guangdong Provincial Agricultural Reclamation Center Hospital were enrolled from January 2019 to August 2023 and were treated with ATO combined with a modified N7 induction regimen. The efficacy and adverse effects at the end of induction chemotherapy were assessed and analyzed, and the differences in the clinical characteristics were further compared between the treatment-responsive and treatment-unresponsive groups by using the Fisher's exact test. Results: Among 67 high-risk NB children, there were 40 males (60%) and 27 females (40%), with the age of disease onset of 3.5 (2.6, 4.8) years. Primary NB sites were mostly in retroperitoneum (including adrenal gland) (56/67, 84%) and the common metastases sites at initial diagnosis were distant lymph node in 25 cases (37%),bone in 48 cases (72%),bone marrow in 56 cases (84%) and intracalvarium in 3 cases (4%). MYCN gene amplification were detected in 28 cases (42%). At the end of induction, 33 cases (49%) achieved complete remission, 29 cases (43%) achieved partial remission, 1 case (1%) with stable disease, and 4 cases (6%) were assessed as progressive disease (PD). The objective remission rate was 93% (62/67) and the disease control rate was 94% (63/67). The percentage of central system metastases at the initial diagnosis was higher in the treatment-unresponsive group than in the treatment-responsive group (2/5 vs. 2% (1/62), P=0.013), whereas the difference in MYCN gene amplification was not statistically significant between two groups (3/5 vs.40% (25/62), P=0.786). Grade Ⅲ or higher adverse reactions during the induction chemotherapy period were myelosuppression occurred in 60 cases (90%), gastrointestinal symptoms occurred in 33 cases (49%), infections occurred in 20 cases (30%), hepatotoxicity occurred in 4 cases (6%), and cardiovascular toxicity occurred in 1 case (2%). There were no chemotherapy-related deaths. Conclusion: ATO combined with N7-modified induction regimen had a superiority in efficacy and safety, which deserved further promotion in clinical practice.