Investigator-initiated Trial Research Articles

Prospective screening and proposed treatment algorithm for immune checkpoint inhibitor induced myositis in neoadjuvant-treated rectal cancer patients: data from the phase II CHINOREC trial

Abstract Background Myositis is an infrequent (<1%) but potentially life-threatening (case fatality rate 40-50%) immune-related adverse event (irAEs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) and nivolumab (NIVO). The true incidence is likely to be underestimated and may not be representative for curative neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently, the summary of product characteristics (SmPC) does not suggest any pre-emptive screening or surveillance. Methods The CHINOREC study is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with intermediate to locally advanced rectal cancer (LARC) receive either neoadjuvant CRT alone or in combination with a single dose of IPI and 3 cycles of NIVO, following surgical resection. Patients are monitored at baseline and throughout the whole study period for myotoxicity biomarkers, including cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Findings From 06/2020 to 11/2023, 80 patients have been enrolled of whom 50 patients were randomized to the CRT+IPI/NIVO arm. Six patients (12%) developed biopsy-verified myositis. Myositis treatment was promptly implemented using a pragmatic step-up approach. Patients received glucocorticoids (GC) with concomitant intravenous immunoglobulin (IVIG). If myotoxicity biomarkers did not improve, patients received infliximab (INFLIXI) and/or plasma exchange (PLEX). Although all patients had strikingly elevated cTnT (median peak 284 ng/L, 95% CI 39-3097), cTnI levels remained largely normal, correlating with a negative cardiac magnetic resonance (CMR). All patients underwent successful tumor surgery without any major surgical complication. As of today, all patients' creatine kinase (CK) and myoglobin (MB) levels have normalized and they are tumor free without any major sequela. Interpretation Longitudinal biomarker screening (cTnT/cTnI) for ICI-induced myotoxicities is pivotal in curative neoadjuvant-treated cancer patients to initiate an early counter treatment in a holistic step-up approach, without compromising oncological principles.

Safety and tolerability of a Muse cell-based product in neonatal hypoxic-ischemic encephalopathy with therapeutic hypothermia (SHIELD trial).

Hypoxic-ischemic encephalopathy (HIE), associated with high mortality and neurological sequelae, lacks established treatment except therapeutic hypothermia. Clinical-grade multilineage-differentiating stress-enduring (Muse) cells (CL2020) demonstrated safety and efficacy in nonclinical HIE rat models, thereby leading to an investigator-initiated clinical trial to evaluate CL2020 safety and tolerability in neonatal HIE as a single-center open-label dose-escalation study with 9 neonates with moderate-to-severe HIE who received therapeutic hypothermia. Each patient received a single intravenous injection of CL2020 cells between 5 and 14 days of age. The low-dose (3 patients) and high-dose (6 patients) groups received 1.5 × 106 and 1.5 × 107 cells/dose, respectively. The occurrence of any adverse event within 12 weeks following CL2020 administration was the primary endpoint of this trial. No significant changes in physiological signs including heart rate, blood pressure, and oxygen saturation were observed during or after administration. The only adverse event that may be related to cell administration was a mild γ-glutamyltransferase level elevation in one neonate, which spontaneously resolved without any treatment. All patients enrolled in the trial survived, and normal developmental quotients (≥ 85) in all 3 domains of the Kyoto Scale of Psychological Development 2001 were observed in 67% of the patients in this trial. CL2020 administration was demonstrated to be safe and tolerable for neonates with HIE. Considering the small number of patients, a randomized controlled confirmatory study is warranted to verify these preliminary findings and evaluate the efficacy of this therapy.

From the Beginning of the Korean Gynecologic Oncology Group to the Present and Next Steps.

The Korean Gynecologic Oncology Group (KGOG) was established in 2002 and is the only organization in Korea conducting multi-center clinical trials for gynecologic cancers. Since its re-establishment as a non-profit organization in 2021, KGOG has grown significantly, now including 207 gynecologic oncology specialists from 76 hospitals. This growth is a testament to the dedication and hard work of all those involved in the organization. KGOG is committed to maximizing the activation of multi-center clinical research through policies that support patients with rare diseases and gynecologic cancer research, focusing on strengthening institutional capacity, equalizing participation opportunities, and enhancing information sharing. A significant milestone for KGOG was becoming a member of the US Gynecologic Oncology Group (GOG) in 2005, allowing participation in GOG clinical trials. KGOG later joined the Gynecologic Cancer InterGroup (GCIG) and strengthened its capabilities by hosting the first Endometrial Cancer Consensus Conference-Clinical Research (ECCC-CR) in 2023. KGOG holds biannual meetings and symposia, as well as 224 operating committee meetings annually to review the discussions of the Tumor Site Committee. KGOG has conducted 156 investigator-initiated trial (IIT) or sponsor-initiated trial (SIT) studies as KGOG-led or participated in research. Currently, 18 studies are registered, and 10 are in preparation. To date, 68 papers have been published. KGOG conducts six national projects and collaborates with external organizations such as the NRG Oncology Foundation, Gynecologic Oncology Group Partners (GOG-P), GCIG, East Asian Gynecologic Oncology Trial group (EAGOT), and the Japanese Gynecologic Oncology Group (JGOG). Through collaboration with renowned international research institutions, KGOG has significantly expanded the scope of its research, achieving noteworthy clinical outcomes. This report not only introduces the history and recent status of KGOG but also presents the exciting future direction of the organization, filled with potential breakthroughs and advancements in gynecologic oncology research.

Retrospective Investigator-Initiated Trial on Tocopherol Acetate Vaginal Administration in Pre-and Postmenopausal Women.

Menopause, a natural phase in a woman's life, often adversely affects physical, mental, sexual, and emotional well-being due to low estrogen levels. This study examines the impact of vaginal ovules with tocopherol acetate (Filme Gyno-V® ovules, manufactured by Panin Srl and distributed by Hulka Srl, Italy), 500 mg per ovule, on vaginal health in pre- and menopausal women. Fifty women aged 50-70 were divided into menopausal (28) and premenopausal (22) cohorts and treated with the ovules for two weeks, with assessments before and after treatment. The findings showed that distressing symptoms of vaginal atrophy, such as dryness, itching, and pain during intercourse, were resolved post-treatment. A molecular analysis revealed a reduction in Escherichia coli in both cohorts and an increase in three species of Lactobacillus in premenopausal patients. This study concludes that Filme Gyno-V ovules may benefit vaginal health by alleviating atrophy symptoms and promoting healthy vaginal microbiota.

Renal Denervation Is Effective in Reducing Blood Pressure in Patients with CKD: Results of a Multicenter, Prospective, Randomized, Sham-Controlled, Blinded, Investigator-Initiated Trial

Renal Denervation Is Effective in Reducing Blood Pressure in Patients with CKD: Results of a Multicenter, Prospective, Randomized, Sham-Controlled, Blinded, Investigator-Initiated Trial

JS2-6 An investigator-initiated clinical trial aimed at improving outcomes of lung cancer immunotherapy

JS2-6 An investigator-initiated clinical trial aimed at improving outcomes of lung cancer immunotherapy

GnRH-a-based fertility-sparing treatment of atypical endometrial hyperplasia (AEH) and early endometrial carcinoma (EC) patients: a multicenter, open-label, randomized designed clinical trial protocol

BackgroundAround 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes.MethodsThis study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence.Ethics and disseminationThe protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association’s Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal.ConclusionsProspective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH.Trial registration numberChinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022.

Digital consults in heart failure care: a randomized controlled trial

Guideline-directed medical therapy (GDMT) has clear benefits on morbidity and mortality in patients with heart failure; however, GDMT use remains low. In the multicenter, open-label, investigator-initiated ADMINISTER trial, patients (n = 150) diagnosed with heart failure and reduced ejection fraction (HFrEF) were randomized (1:1) to receive usual care or a strategy using digital consults (DCs). DCs contained (1) digital data sharing from patient to clinician (pharmacotherapy use, home-measured vital signs and Kansas City Cardiomyopathy Questionnaires); (2) patient education via a text-based e-learning; and (3) guideline recommendations to all treating clinicians. All remotely gathered information was processed into a digital summary that was available to clinicians in the electronic health record before every consult. All patient interactions were standardly conducted remotely. The primary endpoint was change in GDMT score over 12 weeks (ΔGDMT); this GDMT score directly incorporated all non-conditional class 1 indications for HFrEF therapy with equal weights. The ADMINISTER trial met its primary outcome of achieving a higher GDMT in the DC group after a follow-up of 12 weeks (ΔGDMT score in the DC group: median 1.19, interquartile range (0.25, 2.3) arbitrary units versus 0.08 (0.00, 1.00) in usual care; P < 0.001). To our knowledge, this is the first multicenter randomized controlled trial that proves a DC strategy is effective to achieve GDMT optimization. ClinicalTrials.gov registration: NCT05413447.

A Randomized Trial on Hemodynamic Optimization of Cerebral Perfusion after Successful Endovascular Therapy in Patients with Acute Ischemic Stroke (HOPE)

Introduction: In patients with acute ischemic stroke (AIS) secondary to intracranial large vessel occlusion, optimal blood pressure (BP) management following endovascular treatment (EVT) has not yet been established. The randomized trial on Hemodynamic Optimization of Cerebral Perfusion after Successful Endovascular Therapy in Patients with Acute Ischemic Stroke (HOPE) (clinicaltrials.gov id: NCT04892511) aims to demonstrate whether hemodynamic optimization using different systolic BP targets following EVT according to the degree of final recanalization, is more effective than currently recommended BP management in improving functional outcomes of patients with AIS. Methods: HOPE is an investigator-initiated multicenter clinical trial with randomized allocation, open-label treatment, and blinded endpoint evaluation (PROBE). Patients with an anterior circulation AIS within 24 h of symptom onset, treated with EVT, and showing successful recanalization (mTICI ≥2b) at the end of the procedure, are equally allocated (1:1) to hemodynamic optimization according to the study protocol versus BP management according to current guidelines (≤180/105 mm Hg). The protocol includes two different targets of systolic BP depending on the recanalization status (mTICI = 2b: 140–160 mm Hg; mTICI = 2c/3: 100–140 mm Hg). The protocol is applied within the first 72 h and includes BP lowering as well as vasopressor therapies when needed. The primary outcome is the proportion of favorable outcome (modified Rankin Scale [mRS] 0–2) at 90 days. Secondary outcomes include the shift on the mRS score, neurological deterioration, symptomatic intracerebral hemorrhage, and mortality. Conclusion: The HOPE trial will provide new information on the safety and efficacy of different BP targets following EVT according to the degree of final recanalization in patients with AIS.

Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study

Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.

Response to "Randomized controlled trial of remimazolam compared with placebo in Japanese patients undergoing upper gastrointestinal endoscopy: Phase III investigator-initiated clinical trial".

Response to "Randomized controlled trial of remimazolam compared with placebo in Japanese patients undergoing upper gastrointestinal endoscopy: Phase III investigator-initiated clinical trial".

An investigator-initiated trial to evaluate safety and tolerability of YSCH-01 in patients with recurrent glioblastoma.

TPS33 Background: Glioblastoma (GBM), accounting for 55% of primary malignant brain tumors, is characterized by its highly aggressive nature, poor prognosis, and high recurrence rate. Surgical resection is the primary treatment, yet recurrence is common, and survival rates remain dismal. Recurrent GBM lacks established interventions and standardized therapies. YSCH-01 is an oncolytic adenovirus, developed based on cancer-targeting gene-viro-therapy strategy (1), that has been incorporated with an interferon-like immune anticancer gene (L-IFN). Our preclinical studies have demonstrated significant tumor inhibition by YSCH-01 in both cell-line derived xenograft and patient-derived xenograft models (2). This investigator-initiated trial aims to evaluate the safety and efficacy of YSCH-01 in subjects with recurrent GBM. Methods: Six subjects with recurrent GBM are planned to be enrolled, receiving intracranial injections of YSCH-01 via Ommaya reservoir at a dosage of 5.0×1010 VP, once every 3 weeks for a total of 5 administrations, with a dose-limiting toxicity (DLT) assessment period of 3 weeks. Ommaya reservoir implantation will precede drug administration by one day. Inclusion criteria specify pathology-confirmed recurrent GBM, age 18-75 years, expected survival ≥ 12 weeks, and Karnofsky Performance Status (KPS) score ≥ 50 points, with at least one enhanced lesion of ≥ 1 cm diameter. Safety will be evaluated based on DLT and adverse events (AEs) assessed using CTCAE 5.0. Efficacy will be assessed every 5 weeks using Response Assessment in Neuro-Oncology (RANO) criteria, with overall survival follow-up at 12 weeks for two years. Two of the planned six cases have been enrolled, completing the DLT period without DLTs. The trial is registered with Clinical Trial Registry under NCT05914935. Clinical trial information: NCT05914935 .

An exploratory investigator-initiated trial via intrathecal or intracerebroventricular delivery of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

23 Background: The MT027, developed by T-Maximum, is a B7-H3 (CD276)-directed genetically modified allogeneic T cell, targeting CD276-overexpressed tumor cells. Here, we reported a first-in-human, single-center, open-label investigator-initiated trial (IIT) via intrathecal or Intracerebroventricular delivery targeting recurrent high-grade glioma (ChiCTR2100047968). Methods: As of March 7, 2024, a total of 50 adult patients with recurrent high-grade glioma, B7H3+ expression, and KPS ≥40 were enrolled and administered at least one dose of MT027 (FAS), of whom, 32 received at least 3 doses (PPS1), 15 subjects with ≥3 doses and at least 1 efficacy visit (PPS2). 4 dose levels of 1.0, 1.5, 2.0, 2.5×107 cells per injection were administered once every 4 weeks. Results: The overall results demonstrated the favorable tolerability, safety, PK/PD characteristics, and preliminary efficacy. In FAS, the most common AE were fever and headache, without any CRS, ICANS, GvHD, or drug-related death. There were 4 cases (8%) of grade 3 AE or greater and 3 cases (6%) of SAEs. The copies of CAR in all groups reached 10000-100000 copy/ug, and persisted for &gt; 60 days after a single dose. After multiple doses, the MT027 CAR-T cell numbers maintained at a high level (median 8850 copies /μg (range: 200-385900)) and for a long time. The levels of IL6, TNF-α and IFN-γ in CSF increased significantly and maintained for a long time. The mOS was 13.54 m (95% CI: 7.45; 19.63) and 20.73 m (95% CI: 16.12; 25.34) in PPS1 and PPS2, respectively. The 12-month OS rate was 53.30% (95%CI: 37.5%-75.7%) and 84.60% (95%CI: 67.1%-100%) in PPS1 and PPS2, respectively (historical data: 14%). The objective response rate (ORR) was 33% and the disease control rate (DCR) was 80% in PPS2. Conclusions: In patients with relapsed high-grade glioma, the intrathecal or ICV administration of MT027 cell therapy was found to be safe and well-tolerated. The toxicity of grade 3 or above was 1/5 of similar products. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose treatments were stable. MT027 exhibited longer persistence in the body of the patients, and the cell numbers and cytokine responses induced in vivo were 1-2 orders of magnitude higher than those of similar products. MT027 cell therapy demonstrated the excellent efficacy in treating relapsed high-grade glioma, with significantly prolonged overall survival and higher objective response rate compared to the historical data and similar product data. Currently, we are preparing for the IND filing in US (expected in 2024) with the recurrent glioblastoma as the first indication. Clinical trial information: ChiCTR2100047968 .

Safety, tolerability, and immunogenicity of WGc-043 in subjects with EBV-positive cancers: Results from an investigator-initiated trial.

139 Background: The Epstein-Barr virus (EBV) persists and spreads after infection in humans, leading to the occurrence and metastasis of a variety of cancers, posing great challenges in the treatment of cancer.. Conventional cancer therapies tend to have limited success and significant side effects. Therefore, there is an urgent need to develop more safe and efficient treatments such as innovative mRNA vaccines, which provide a new approach to cancer immunotherapy. WGc-043, an mRNA vaccine targeting EBV-positive tumor associated antigens, was evaluated for safety, tolerability, and immunogenicity in a prospective, single-center, investigator-initiated study. Methods: The study included 12 patients aged ≥18 with EBV-positive recurrent or metastatic nasopharyngeal carcinoma. Eligibility criteria included at least one measurable lesion, ECOG performance status 0-1, expected survival greater than three months, and no autoimmune disease. Participants were divided into three dose cohorts (25 μg, 50 μg, 100 μg) and received five administrations followed by optional continued monthly treatment of WGc-043 by intramuscular injection. The study assessed safety by adverse event monitoring, immune response based on the peripheral blood and tumor tissue sample analysis and efficacy according to imaging guidelines and irRECIST version 1.1. Results: The study results demonstrated that WGc-043 had a favorable safety profile with only grade 1 or 2 adverse events and fever (4/12) reported as the most common adverse event. Notably, two patients achieved partial response (PR) and five patients had stable disease (SD), highlighting the potential clinical efficacy of WGc-043. In addition, most (91.7%) subjects showed a significant reduction in plasma EBV DNA levels after administration. Immunogenicity analysis using IFN-γ ELISpot showed that 8 (66.7%) of the 12 enrolled patients developed strong specific immune responses against EBV-associated antigens, indicating that WGc-043 is a potent immunotherapy. Conclusions: This exploratory study underscores the safety and potential efficacy of WGc-043 as an mRNA vaccine for EBV-associated cancers, demonstrating its ability to induce specific immune responses and achieve substantial disease control in a challenging patient population, although further studies in larger clinical trials are needed. These results not only support the advancement of WGc-043 as a candidate for immunotherapy in EBV-positive cancers, but also highlight the translational potential of mRNA vaccine technology in the oncology landscape. Clinical trial information: NCT05714748 . [Table: see text]

Investigator-initiated clinical trial of stabilizer device: A novel intracranial exchange guidewire for neuroendovascular treatments.

Neuroendovascular procedures, especially those involving significant vessel tortuosity, giant intracranial aneurysms, or distally located lesions, frequently necessitate exchange methods. However, exchange maneuvers pose a risk of inadvertent vessel injury. To address these challenges, a Stabilizer device was developed and evaluated for its efficacy and safety. This clinical trial aimed to assess the efficacy and safety of the Stabilizer device in facilitating the navigation of neuroendovascular devices to target lesions in cases where the exchange technique was necessary. This was a single-arm, prospective, open-label, multicenter clinical trial performed at nine different sites. It focused on investigating the use of the Stabilizer device for treating intracranial aneurysms and atherosclerosis. A total of 31 patients were enrolled across nine centers in Japan from July 21, 2022, to March 10, 2023. The study enrolled 24 (77.4%) patients with intracranial aneurysms and seven (22.6%) patients with intracranial artery stenosis. Majority of the target lesions were in the middle cerebral artery territory (83.9%). The Stabilizer device was used to exchange for 0.027-inch catheters, intermediate catheters, PTA balloons, and Wingspan stent system. The Stabilizer device demonstrated 100% technical success rate. While three complications related to the treatment were noted, there were no complications related to the device, including any vascular damage. This is the first multicenter clinical trial that investigated and demonstrated technical efficacy as well as overall safety profile of the Stabilizer device in neuroendovascular procedures where the use of an exchange method was necessary.

Radiofrequency ablation via catheter and transpapillary access in patients with cholangiocarcinoma (ACTICCA-2 trial) – a multicenter, randomized, controlled, open-label investigator-initiated trial

BackgroundDespite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy.Methods/DesignACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material.DiscussionACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment.Trial registrationThe study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024.Graphical

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.

The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling. Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. This investigator-initiated trial was funded by Merck.

Randomized controlled trial of remimazolam compared with placebo in Japanese patients undergoing colonoscopy: A phase III, investigator-initiated trial.

We conducted an investigator-initiated clinical trial in which remimazolam was used to achieve sedation in patients undergoing colonoscopy. This multicenter, double-blind, placebo-controlled, phase III investigator-initiated trial included patients who underwent colonoscopy under sedation achieved with remimazolam (initial dose: 3 mg; additional doses: 1 mg) or normal saline (placebo). The primary endpoint was the sedation success rate during colonoscopy, defined as successful sedation (modified observer's alertness/sedation [MOAA/S] score ≤4 prior to colonoscopy), the successful completion of the colonoscopy, and no more than five additional doses of remimazolam per 15 min during the procedure. The sedation success rate was 95.0% (38/40 patients) in the remimazolam group and 0.0% (0/11 patients) in the placebo group (p&lt;0.01). The time from the end of the procedure to awakening was 0.0 (interquartile range: 0.0-0.0) min in both groups. The time from the end of the procedure to ambulation was 5.0 min (interquartile range: 0.0-10.0 min) in the remimazolam group and 0.0 min (interquartile range: 0.0-0.0 min) in the placebo group (p=0.02). No serious adverse events occurred. The use of remimazolam to achieve sedation in Japanese patients undergoing colonoscopy was more effective than the use of a placebo. This study was registered in the Japan Registry of Clinical Trials (registration number: jRCT2031200360).

Plasma as endothelial rescue in septic shock: A randomized, phase 2a pilot trial.

Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer. We evaluated the efficacy and safety aspects of cell-free and pathogen inactivated pooled plasma (OctaplasLG®) as resuscitation in septic shock patients. This randomized, investigator-initiated phase IIa trial ran at a Danish single center intensive care unit, from 2017 to 2019. Patients were 18 years of age or older with septic shock and randomized to fluid optimization with OctaplasLG® or Ringer-acetate in the first 24 h. The primary endpoints were changes in biomarkers indicative of endothelial activation, damage, and microvascular perfusion from baseline to 24 h. Safety events and mortality were assessed during 90 days. Forty-four patients were randomized, 20 to OctaplasLG versus 24 to Ringer-acetate. The median age was 69, and 55% were men. Median Sequential Organ Failure Assessment score was 13. Baseline differences favoring the Ringer-acetate group were observed. The OctaplasLG® group was resuscitated with 740 mL plasma and the Ringer-acetate group with 841 mL crystalloids. There was no significant change in the microvascular perfusion or five biomarkers except VEGFR1 change, which was higher in patients receiving OctaplasLG® 0.12(SD 0.37) versus Ringer-acetate -0.24 (SD 0.39), with mean difference 0.36 (95% CI, 0.13-0.59, p = .003) in favor of Ringer-acetate. This study found that fluid resuscitation with OctaplasLG® in critically ill septic shock patients is feasible. Baseline confounding prevented assessment of the potential effect of OctaplasLG®.

Efficiency of eSource Direct Data Capture in Investigator-Initiated Clinical Trials in Oncology

BackgroundClinical trials have become larger and more complex. Thus, eSource should be used to enhance efficiency. This study aimed to evaluate the impact of the multisite implementation of eSource direct data capture (DDC), which we define as eCRFs for direct data entry in this study, on efficiency by analyzing data from a single investigator-initiated clinical trial in oncology.MethodsOperational data associated with the targeted study conducted in Japan was used to analyze time from data occurrence to data entry and data finalization, and number of visits to the site and time spent at the site by clinical research associates (CRAs). Additionally, simulations were performed on the change in hours at the clinical sites during the implementation of eSource DDC.ResultsNo difference in time from data occurrence to data entry was observed between the DDC and the transcribed data fields. However, the DDC fields could be finalized 4 days earlier than the non-DDC fields. Additionally, although no difference was observed in the number of visits for source data verification (SDV) by CRAs, a comparison among sites that introduced eSource DDC and those that did not showed that the time spent at the site for SDV was reduced. Furthermore, the simulation results indicated that even a small amount of data to be collected or a small percentage of DDC-capable items may lead to greater efficiency when the number of subjects per site is significant.ConclusionsThe implementation of eSource DDC may enhance efficiency depending on the study framework and type and number of items to be collected.