Cleveland

Researchers are investigating the drug bezuclastinib in an open-label, two-part Phase 2 study for patients with Advanced Systemic Mastocytosis (AdvSM), including Aggressive Systemic Mastocytosis (ASM), Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN), and Mast Cell Leukemia (MCL). The study aims to evaluate the safety, effectiveness, and how the drug behaves in the body for these serious conditions. Bezuclastinib is given orally as tablets taken continuously in 28-day cycles. The study has two parts: Part I focuses on identifying safe and tolerable doses of bezuclastinib over 18 months, while Part II evaluates its effectiveness by measuring the objective response rate and confirming the relationship between drug exposure and response during another 18-month period. Participants will undergo assessments including clinical evaluations, laboratory tests, and monitoring of their disease status to determine treatment effects and safety. Researchers will track the drug's impact on the disease and patient health throughout the study, which involves continuous treatment and follow-up over the specified time frames.

Researchers are evaluating the effect of starting Airsupra inhaler treatment in the emergency department (ED) on acute asthma recurrence over 3 months. This phase 4, multicenter, randomized controlled trial focuses on adults aged 18 to 54 who visit the ED for acute asthma exacerbations and are discharged with a plan for short-course systemic corticosteroids. The study aims to see if Airsupra, which combines albuterol and budesonide, can reduce asthma relapses and improve asthma control compared to usual care. The trial will also explore outcomes in key subgroups based on demographics and prior asthma history. Participants at intervention sites will receive Airsupra as a rescue inhaler, with dosing up to 6 doses per day (2 inhalations per dose), alongside a short course of systemic corticosteroids. Usual care sites will manage patients per standard practice without Airsupra. All patients receive brief asthma education. Enrollment will last 4-5 months at 30 sites across the US, and patients will be followed for 3 months after their ED visit. During the study, patients will complete structured interviews and chart reviews at enrollment. Follow-up assessments by phone or text will occur around 3, 6, and 12 weeks post-ED visit to track asthma relapse, control using the AirQ questionnaire, medication use, and any side effects. Medical records for the year before and 3 months after enrollment will be reviewed to identify asthma outcomes. The main measure is asthma recurrence within 3 months, including urgent visits for worsening symptoms. Safety and asthma control will also be evaluated throughout the study period.

Researchers are evaluating 4D-710, an investigational gene therapy, in adults with cystic fibrosis (CF) lung disease who cannot use or tolerate CFTR modulator therapy. This Phase 1/2, multicenter, open-label trial also includes a sub-study assessing 4D-710 in adults with advanced CF lung disease or frequent lung flare-ups despite using CFTR modulators. The study aims to assess the safety, tolerability, and early effectiveness of this gene therapy in these populations. The trial involves a single dose of 4D-710, which is a gene therapy using a specialized virus to deliver a modified CFTR gene. Participants receive this treatment once, and those in the sub-study must be on a stable CFTR modulator regimen for at least 60 days before screening and continue it during a 24-month observation period. The study monitors participants with CF lung disease ranging from moderate to advanced stages. During the study, participants undergo regular evaluations including lung function tests, oxygen level checks, and monitoring for adverse effects. Researchers track the occurrence and severity of any side effects over a 60-month period. The study also includes assessments of lung health, medication adherence, and clinical status to understand the therapy's impact and safety over time.

Researchers are exploring a new treatment approach for myelodysplastic syndromes (MDS) and related myeloid malignancies, conditions where the bone marrow fails to produce enough healthy blood cells. This trial studies a combination therapy using low doses of two drugs, 5-azacitidine and decitabine, given alternately to overcome resistance mechanisms seen when these drugs are used alone. This is a single-arm, open-label early phase 1 pilot study aiming to evaluate the overall response rate of this alternating regimen in participants with MDS or MDS/myeloproliferative overlap disorders who have shown potential sensitivity to hypomethylating agent therapy. Participants will receive 5-azacitidine at 50 mg/m² on Day 1 each week and decitabine at 5 mg/m² on Day 4 each week, with or without granulocyte-colony stimulating factor (G-CSF). Treatment will continue for at least 24 weeks unless the disease clearly progresses. Those who respond to the treatment may continue until relapse or progression that does not improve with dose escalation as defined by the study protocol. During the study, participants will be closely monitored for their response, including complete and partial responses and hematologic improvements. Safety will be assessed by tracking significant adverse events. Additional laboratory studies will explore correlations between drug effects and biological markers. The primary outcome is the overall response rate up to six months after treatment ends. The study includes ongoing assessments of disease status, side effects, and biological markers over the treatment period and beyond.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, with more than 900,000 newly diagnosed cases and approximately 830,000 deaths in 2020. Surgical resection and liver transplantation are potential curative options for patients with early-stage HCC. However, most patients present with metastatic and/or unresectable disease and systemic treatment is the only therapeutic option for these patients. Although several ICI-based combination therapies have recently extended survival for many patients with HCC, biomarker-directed strategies are limited for this disease. Prostate Specific Membrane Antigen (PSMA) is a protein that is expressed in prostate cells and overexpressed in prostate cancer and is accepted as a valuable theragnostic (combined diagnostic and therapeutic) target in metastatic castration-resistant prostate cancer. 68Ga-PSMA-11 PET (PSMA PET) is now utilized to select patients with metastatic prostate cancer for PSMA-directed therapy with 177Lu-PSMA-617. PSMA is now known to be expressed in a variety of solid tumors, including HCC, specifically in the neovasculature associated with solid tumors. However, there is a lack of data exploring whether there is a role for PSMA-directed therapy in non-prostate solid tumors. Investigator performed PSMA IHC on 148 HCCs from surgical resection or liver explant specimens from patients at the Mayo Clinic, and 90% of HCCs showed PSMA immunostaining localized to the tumor endothelium. More than 50% of HCCs showed 31-100% PSMA immunostaining by area. In several cases, the normal liver background did show faint canalicular staining, highlighting the need to distinguish between normal tissue and tumor-associated expression. In a similar study using immunohistochemistry (IHC) to evaluate PSMA expression in HCC, 79.2% of tumors showed high levels of PSMA expression at any location, with the majority of this expression occurring in a neovascular staining pattern (89.9%). One patient underwent imaging with PSMA PET which demonstrated intense and heterogeneous PSMA uptake in the HCC tumor. Several additional reports have demonstrated that PSMA expression in HCC can be detected noninvasively by PSMA PET.20,21 Our group at Mayo Clinic prospectively evaluated PSMA uptake using Ga-PSMA PET in patients with treatment-naïve HCC. In 31 patients, 39 lesions were identified. In this study, 64% had high PSMA uptake (grade 3 or 4) and 36% had low PSMA uptake (grade 1 or 2). It is expected that PSMA uptake will be much higher in patients with advanced HCC. PSMA PET has been compared with MRI for detection of HCC and had similar efficacy to MRI in a cohort of 19 patients. Similarly, a meta-analysis of 6 studies including 126 patients imaged with PET/CT or PET/MRI with PSMA-targeting radiopharmaceuticals in patients with newly diagnosed or recurrent HCC showed a detection rate of greater than 85%.These studies clearly suggest that targeting PSMA could be an attractive target in patients with advanced HCC. The VISION study was a phase 3 trial investigating the efficacy and safety of 177Lu-PSMA-617 (Lu-177 vipivotide tetraxetan) with standard of care in patients with previously treated metastatic castration-resistant prostate cancer who were identified as PSMA PET-positive. Similarly, the phase III PSMAfore study of Lu-177 vipivotide tetraxetan demonstrated improvement in radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer after prior treatment. In HCC, a recent preclinical study demonstrated that radioligand therapy using \[177Lu\]Lu-PSMA-617 and \[177Lu\]Lu-EB-PSMA-617 effectively suppressed tumor growth and prolonged survival time in PSMA-positive HCC xenograft mice. However, this strategy has not been prospectively utilized in patients with HCC after first-line therapy. There is limited clinical data examining the role of PSMA radioligand therapy in HCC. One study included 2 patients with no other systemic therapy options available and demonstrated insufficient tumor radiation dosing by intratherapeutic SPECT/CT-based dosimetry after only a single cycle of therapy. This data is limited by the short treatment course of only 1 cycle, which was inadequate to induce a response, small sample size, and heavy pre-treatment. Although the pattern of PSMA expression in HCC is distinct from that in prostate cancer, there is evidence from tyrosine kinase inhibitor (TKI) efficacy that targeting the neovasculature via inhibition of angiogenesis in the local tumor environment can limit tumor growth and improve survival.

This research aims to evaluate the effects of litifilimab (BIIB059), a monoclonal antibody, in adults with active subacute or chronic cutaneous lupus erythematosus (CLE), with or without systemic lupus erythematosus (SLE). Participants have active skin symptoms of CLE that have not improved with antimalarial therapy or had difficulties continuing that treatment. The study focuses on reducing skin disease activity using several scores including CLA-IGA-R and CLASI, while also assessing safety, immune response, and quality of life. Participants will be randomly assigned to receive either litifilimab or a placebo injection under the skin every four weeks during a 24-week double-blind period where neither participants nor researchers know which treatment is given. After this, all participants will receive litifilimab injections every four weeks for an additional 28 weeks. Those who complete the treatment may join a long-term extension study or enter a follow-up safety period lasting up to 24 weeks. Total participation may last up to 80 weeks. Throughout the study, researchers will monitor skin disease activity using the CLA-IGA-R erythema score and the CLASI-A activity score to see how many participants improve. They will also assess safety, tolerability, immune system effects, and participants' quality of life using questionnaires. These evaluations occur regularly during both treatment periods and follow-up to understand the impact of litifilimab on CLE symptoms and overall health.

Researchers are evaluating the safety, how the body processes, and effects on body weight of the investigational drug CRB-913 in participants with obesity. This Phase 1b study includes two parts: Part 1 focuses on healthy adults to measure drug levels in the blood after a single dose, while Part 2 involves obese participants to assess safety and weight effects using different doses compared to placebo. Part 2 is blinded so that participants, doctors, and the sponsor do not know who receives the drug or placebo. In Part 1, healthy adults receive a single dose of CRB-913 tablets to study how much of the drug enters the bloodstream and how long it stays. In Part 2, obese participants take one of three doses of CRB-913 or placebo once daily for 12 weeks. After treatment ends, participants are monitored for 28 days. The study includes a randomized, double-blind, placebo-controlled design for Part 2. Participants will attend study visits for drug administration, safety assessments, and blood tests to measure drug levels and effects on body weight. Researchers will monitor for side effects and adverse events from the first dose through 28 days after final dosing. The total participation time includes the 12-week treatment period plus the 28-day follow-up phase to evaluate safety and drug behavior in the body.

Researchers are evaluating the safety and effectiveness of rilzabrutinib compared to placebo in adults with active Immunoglobulin G4 Related Disease (IgG4-RD). This Phase 3, randomized, double-blind study aims to measure the time until the first IgG4-RD clinical disease flare during a 52-week treatment period. Additional goals include assessing disease control, flare-free rates, use of glucocorticoid rescue, and monitoring safety through adverse events, laboratory tests, and electrocardiograms. Participants will be randomly assigned to receive either oral rilzabrutinib tablets or placebo for 52 weeks. Glucocorticoids may be used as rescue medication if needed. The study includes a screening period lasting 4 to 6 weeks before treatment begins, followed by the 52-week double-blind treatment phase, and a 2-week follow-up after treatment. An optional open-label extension lasting up to 108 weeks is also available for participants. During the study, participants will attend 16 visits for assessments, which may include clinical evaluations, imaging tests such as CT, MRI, PET, or ultrasound to monitor disease activity, and laboratory tests. Researchers will track time to disease flare and collect data on flare-free rates, safety parameters, and medication use. Participants' vaccination status and contraceptive use will be monitored according to local guidelines, and overall study participation could last up to 60 weeks or longer if joining the extension phase.

Researchers are evaluating the quality of life in adults aged 18 to 70 who have hypertrophic cardiomyopathy, thoracic aortic dilatation, or radiation-induced heart disease. These patients are being studied to understand how these cardiac conditions affect various aspects of life, including physical, emotional, social, and spiritual well-being. The study is prospective, longitudinal, and observational without comparison or randomization, aiming to fill gaps in knowledge about the impact of these diseases on daily living and overall health satisfaction. Participants complete the Cardiac Quality of Life Survey electronically at three time points: baseline, 3 months, and 9 months after the first visit. This survey covers five key domains: global, physical, emotional, social, and spiritual health. It also assesses self-efficacy and resilience, which relate to the patient's confidence in managing their health and their ability to cope with challenges. Patients included are those newly seen at the Cleveland Clinic for these cardiac conditions and not scheduled for surgery during the study period. Throughout the study, participants' quality of life is monitored using survey measures that capture changes over time in various health domains. Researchers compare survey results at 3 and 9 months to the baseline to assess improvements or declines in well-being. The study also evaluates the impact of hereditary cardiac disease and radiation-induced heart disease. Participant involvement includes completing online questionnaires from home, with assessments focused on physical symptoms, emotional health, social support, spiritual outlook, and overall health satisfaction, helping clinicians better manage long-term effects of these cardiac diseases.

Researchers are looking for ways to treat germinal center B-cell-like diffuse large B-cell lymphoma (GCB DLBCL). DLBCL is a fast-growing blood cancer that affects B-cells. GCB is a type of DLBCL that affects young B-cells that are still maturing. The goal of this study is to learn if more people who receive zilovertamab vedotin (MK-2140) and R-CHP have the cancer respond (go away) than those who receive polatuzumab vedotin and R-CHP.