First Clinical Trials In Humans Research Articles

A radiolabeled mAb 3BNC117 with copper-64: First round in favor for studying clearance of HIV reservoirs

The article published by McMahon and colleagues [1] reports the first clinical trial in humans using a monoclonal neutralizing antibody (mAb) attached to a detection system with radioisotopes and measured by positron-emission tomography (PET) to assess the neutralizing effect of the mAb among the potential reservoirs of human immunodeficiency virus (HIV) in volunteers with and without HIV infection. The series of experiments implemented by the team shows the effort invested to obtain all measurements with the highest accuracy and precision crucial for this sort of studies.

The Memory-Modifying Potential of Optogenetics and the Need for Neuroethics

Optogenetics is an invasive neuromodulation technology involving the use of light to control the activity of individual neurons. Even though optogenetics is a relatively new neuromodulation tool whose various implications have not yet been scrutinized, it has already been approved for its first clinical trials in humans. As optogenetics is being intensively investigated in animal models with the aim of developing novel brain stimulation treatments for various neurological and psychiatric disorders, it appears crucial to consider both the opportunities and dangers such therapies may offer. In this review, we focus on the memory-modifying potential of optogenetics, investigating what it is capable of and how it differs from other memory modification technologies (MMTs). We then outline the safety challenges that need to be addressed before optogenetics can be used in humans. Finally, we re-examine crucial neuroethical concerns expressed in regard to other MMTs in the light of optogenetics and address those that appear to be unique to the memory-modifying potential of optogenetic technology.

Abstract A10: Treatment of squamous cell carcinoma by alpha radiation-based brachytherapy (Alpha DaRT)

Abstract Objective: The first clinical trial in humans with skin and oral cavity squamous cell carcinoma (SCC) was performed in order to evaluate the effect of a unique intratumoral alpha radiation-based tumor ablation treatment termed Diffusing Alpha-emitters Radiation Therapy (DaRT). Methods: Radium-224 loaded sources (DaRT seeds) were inserted into solid tumors and released by recoil short-lived alpha-emitting atoms (Rn-220, Po-216, Pb-212, Bi-212, Po-212, Tl-208). These atoms disperse in the tumor and spray it with highly destructive alpha radiation. The decay products diffuse in the tumor mass to a distance of at least 5 mm. Results: A feasibility and safety clinical study is ongoing and currently 28 patients were treated at the Rabin Medical Center (Israel) and IRST (Italy). Patients with histopathologic confirmed skin or head and neck SCC, and tumor size ≤5 centimeters in the largest diameter, were enrolled. Treatment was delivered based on a CT-simulation pretreatment plan. The seeds (1 cm long and 0.7 mm in diameter), each carrying a dose of 2 μCi, were placed up to 5 millimeters from each other. CT was used in order to confirm the position of the radioactive seeds. Two weeks after implantation the seeds were removed, and six weeks after treatment a CT scan was performed to assess the effect of treatment. Study results are available for 18 cases that were treated per protocol and reached the 30-day follow-up period. Age of the patients ranged from 60 to 102 years (median 80 years). Ten patients had oral cavity SCC and 18 were diagnosed with cutaneous SCC. Thirteen subjects were treated within prior radiation failure fields (radiation dosage >60Gy). All tumors responded to the treatment; 13 tumors exhibited a complete response and five tumors showed partial response. No major toxicity was noted. Conclusions: In this first feasibility and safety human study we demonstrated that alpha-based treatment (DaRT) resulted in enhanced radiobiologic potential. Furthermore, the treatment was effective against radioresistant SCC tumors without any major side effects. Citation Format: Aviram Mizrachi, Aron Popovtzer, Eli Rosenfeld, Ran Ben-Hur, Itzhak Kelson, Yona Keisari. Treatment of squamous cell carcinoma by alpha radiation-based brachytherapy (Alpha DaRT) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A10.

The effect of melatonin on cisplatin-induced nephrotoxicity: A pilot, randomized, double-blinded, placebo-controlled clinical trial

IntroductionCisplatin-induced nephrotoxicity (CIN) is a major dose-limiting factor in cisplatin use for the management of human cancers. This study was designed to evaluate the effect of melatonin on CIN as the first clinical trial in humans. MethodsThis pilot, randomized, double-blinded, placebo-controlled clinical trial was conducted with cancer patients. Participants were randomly assigned to receive either 20 mg/day oral melatonin or placebo from 24 to 48 hours before cisplatin therapy. Urine samples were collected at 0, 6 and 24 h following cisplatin infusion to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and creatinine. Serum creatinine (SCr) levels were assessed at baseline and 72 h after cisplatin administration. ResultsFifty-five patients were randomly assigned to receive either melatonin (n = 25) or placebo (n = 30), where 3 (7.5 %) versus 9 (21.4 %) acute kidney injury (AKI) episodes were reported in each group respectively. Although urinary biomarkers increased in both groups, the magnitude of the increase was smaller in the melatonin group compared to placebo. In addition, differences of urine KIM-1/creatinine ratio at 6 h and 24 h from baseline were significantly lower in the melatonin group (2.37(−71.16 to 63.70) ng/mg and −1.45(−80.28 to 48.76) ng/mg) compared to placebo (3.83(−11.19 to 37.05) ng/mg and 0.38(−5.42 to 70.00) ng/mg). ConclusionsThis study showed that the number of AKI episodes in patients who received melatonin was lower compared to the placebo group, although it was not found to be statistically significant due to the small sample size. Moreover, melatonin administration in cisplatin recipients reduced tubular kidney injury, evidenced by less increase in KIM-1/creatinine and NGAL/creatinine ratios.

A New Radiation Concept, Treatment of Squamous Cell Carcinoma by Alpha-radiation Based Brachytherapy (Alpha DaRT)

The first clinical trial in humans with skin and oral cavity squamous cell carcinoma was performed in order to evaluate the effect of a unique intra-tumoral alpha radiation based tumor ablation treatment termed Diffusing Alpha emitters Radiation Therapy (DaRT). DaRT relies on alpha particles and thus, effective against hypoxic tumors. DaRT seeds can be produced with various intensities, sizes and shapes and enable custom designed seeds .In our prior animal studies, we demonstrated the effectiveness of the treatment in mice for many tumors. In this first Human study we evaluated its role for Skin and oral Cavity Squamous cell Carcinoma. A Radium-224 loaded sources (DaRT seeds) were inserted into solid tumors and released by recoil short-lived alpha-emitting atoms (Rn-220, Po-216, Pb-212, Bi-212, Po-212, Tl-208). These atoms disperse in the tumor, and spray it with highly destructive alpha radiation. The decay products diffuse in the tumor mass to a distance of at least 5 mm. Thus, a sizable fraction of the tumor is irradiated by alpha particles, and because of their short half-life, only small amounts of the isotopes disperse in the body. A feasibility and safety clinical study is ongoing and currently were treated 13 patients at the Rabin Medical Center (Israel) . Patients with gamma radiation resistant recurrent histopathological confirmed skin or head and neck SCC, and tumor size ≤ 5 centimeters in the longest diameter, were enrolled. Treatment was delivered based on a CT-simulation pre-treatment plan. The Ra-224 Alpha DaRT Seeds were inserted under local anesthesia using a specially designed Alpha DaRT Applicator. The seeds (1 cm long and 0.7 mm in diameter) each carrying a dose of 2 μCi were placed 6 millimeters from each other. CT was used to check the position of the radioactive seeds. Two to four weeks after implantation the seeds were removed, and six weeks after treatment CT was performed to assess the effect of treatment. Blood tests and urinalysis were performed during the treatment. The Age of the patients ranged between 70 to 94 (median 81). Six patients had recurrent oral cavity SCC and seven diagnosed with aggressive skin SCC. All were treated within radiation failure fields(Radiation dosage >60 Gy).With a median follow up of 5 month, All tumors responded to the treatment; 9 tumors had a complete response, three tumors showed a partial response, and one tumor is still under observation. No major toxicity was noted. The areas around the treated tumors were not necrotic and no radionecrosis developed. In this feasibility and safety human study we demonstrated that alpha particles based DaRT exhibit enhanced radiobiological potential. The treatment was effective against radio-resistant SCC tumors without major toxicity.

PCP9 - GENE THERAPY CRISIS: HOW WILL THE CURRENT PRODUCT PIPELINE AFFECT THE PHARMACEUTICAL INDUSTRY AND HEALTHCARE SYSTEMS?

Since the first clinical trial in humans (1989), there have been approximately 2,500 registered clinical trials in gene therapy. Considered as a disruptive new technology, gene therapies provide a radical new approach that targets the cause of the illness rather than the symptoms, and have potential in a number of therapeutic areas. Gene therapies have the benefit of potentially producing significant cost offsets by replacing long-term treatments, reducing in-patient care / hospitalizations and further exacerbations or adverse events. The caveat, however, is the elevated upfront costs that gene therapies incur. Through a targeted review of current literature (e.g. PubMed) and databases (e.g. Datamonitor/EMA), this paper aims to map the current gene therapy landscape (i.e. current pipeline products and developing policies) and highlight the evolving hurdles and solutions of access for gene therapies. The final goal is to encourage a debate on the potential impact that gene therapy could have on the pharmaceutical industry and the healthcare systems/budgets. Alternative financing models should consider the following features and benefits that gene therapy can offer: Development of innovative fee-for-service payer models to potentially high upfront-costs leading to more cooperative and combined stakeholder approaches that may transcend sectors Transition from symptom management to cure (e.g. impact on chronic diseases) Impact on in-patient pathways and care Long-term potential to shift treatment costs from traditional treatments Possibility to cure previously untreatable/incurable diseases (e.g. genetic mutations, viruses, oncology, etc.) Payers and policymakers must consider more innovative and collaborative solutions in any future financial models to facilitate access of valuable new therapies to treat diseases with high burden and significant unmet needs, whilst balancing ever-restricted healthcare budgets. This paper intends to explore the potential options available along with pros and cons for each.

Alpha-Particle Based Brachytherapy Treatment of Patients with Squamous Cell Carcinoma, a New Effective Concept

The first clinical trial in humans with skin and oral cavity squamous cell carcinoma was performed in order to evaluate the effect of a unique intra-tumoral alpha radiation based tumor ablation treatment termed Diffusing Alpha emitters Radiation Therapy (DaRT). DaRT is currently the only efficient brachytherapy for treatment of the entire volume of solid tumors by alpha radiation. DaRT relies on alpha particles and thus, effective against hypoxic tumors. DaRT seeds can be produced with various intensities, sizes and shapes and enable custom designed seeds for individual patients to deliver a more effective and conformal treatment to unresectable tumors and metastatic lesions.

Erectile dysfunction treated with intracavernous stem cells: A promising new therapy?

In the past decades, great interest has been shown in the development of new therapies for erectile dysfunction. Stem cell therapy has generated promising results in numerous preclinical trials in animal models, which is why has led to the development of the first clinical trials in humans. The main cause involved in the pathophysiology of erectile dysfunction is vascular damage related to endothelial and neuronal injury. The interest in stem cell therapy is justified by their capability to differentiate into specific damaged tissues, including endothelium and nervous tissue, and induction of the host own cell proliferation. Despite the great effort of the many studies carried out to date, knowledge about biological effects, therapeutic efficacy and safety of stem cells therapy for erectile dysfunction is still very limited.

Historical perspective of cell transplantation in Parkinson's disease.

Cell grafting has been considered a therapeutic approach for Parkinson’s disease (PD) since the 1980s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of cell-transplantation for PD consists in grafting dopamine-producing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.

Stem cell therapy for white matter disorders: don't forget the microenvironment!

White matter disorders (WMDs) are a major source of handicap at all ages. They often lead to progressive neurological dysfunction and early death. Although causes are highly diverse, WMDs share the property that glia (astrocytes and oligodendrocytes) are among the cells primarily affected, and that myelin is either not formed or lost. Many WMDs might benefit from cell replacement therapies. Successful preclinical studies in rodent models have already led to the first clinical trials in humans using glial or oligodendrocyte progenitor cells aiming at (re)myelination. However, myelin is usually not the only affected structure. Neurons, microglia, and astrocytes are often also affected and are all important partners in creating the right conditions for proper white matter repair. Composition of the extracellular environment is another factor to be considered. Cell transplantation therapies might therefore require inclusion of non-oligodendroglial cell types and target more than only myelin repair. WMD patients would likely benefit from multimodal therapy approaches involving stem cell transplantation and microenvironment-targeting strategies to alter the local environment to a more favorable state for cell replacement. Furthermore most proof-of-concept studies have been performed with human cells in rodent disease models. Since human glial cells show a larger regenerative capacity than their mouse counterparts in the host mouse brain, microenvironmental factors affecting white matter recovery might be overlooked in rodent studies. We would like to stress that cell replacement therapy is a highly promising therapeutic option for WMDs, but a receptive microenvironment is crucial.

Passive and active immunization strategies against Clostridium difficile infections: State of the art

The pathophysiology of Clostridium difficile infections (CDI) could be considered as a three-step process that takes place after disruption of the digestive microbiota by antibiotics: 1) germination of spores; 2) multiplication and persistence of C. difficile in the colonic niche thanks to colonization factors; 3) production of the two toxins TcdA and TcdB and for some strains an additional toxin, the binary toxin CDT. Different immunization strategies against C. difficile have been developed, first regarding the toxins. Immunization assays with colonization factors have followed, and allowed accumulation of new data concerning theirs functions and immunogenicity. Here, we present the toxins, the colonization factors and their use in passive and active immunizations to treat and/or to prevent C. difficile infections. The various experiments performed in animal models and the first clinical trials in humans are reported.

The Future of Capsule Endoscopy

Small-bowel capsule endoscopy (SBCE) was introduced 11 years ago by Given Imaging and is becoming the gold standard for small-bowel examination. This major step in the field of digestive medicine has opened the possibility of promising non-invasive explorations of the esophagus, stomach, and colon. SBCE can be used to overcome the inherent limitations of enteroscopy, especially in the West, where the capsule has been available since 2001. Obscure gastrointestinal (GI) bleeding with normal findings on upper and lower endoscopy remains the most important indication, and suspected Crohn's disease is also a well-accepted indication. Findings from a capsule investigation may warrant therapeutic endoscopy, but in many cases, SBCE avoids this useful but time-consuming endoscopic procedure. The use of a colon capsule for colorectal cancer screening when traditional colonoscopy is contraindicated or impossible is undergoing clinical trials. Early results seem promising, but control of colonic motility is still cumbersome, and patient preparation remains the most important drawback. We performed the first clinical trial in humans of a magnetically guided gastric capsule that offers the possibility of investigation with a capsule that can be controlled spatially. To date, we have carried out procedures in more than 400 patients and volunteers, with impressive results compared with high-definition gastroscopy. Even though endoscopy remains the most important tool in the GI field, capsules offer promising new possibilities.

Spheramine for Treatment of Parkinson’s Disease

Spheramine (Bayer Schering Pharma AG, Berlin, Germany) is currently being tested as a new approach for the treatment of Parkinson's disease (PD). It consists of an active component of cultured human retinal pigment epithelial (hRPE) cells, attached to an excipient part of cross-linked porcine gelatin microcarrriers. Spheramine is administered by stereotactic implantation into the striatum of PD patients and the use of immunosuppression is not required. Current pharmacologic therapies of PD are oriented to the administration of dopaminergic medications. Human RPE cells produce levodopa, and this constitutes the rationale to use Spheramine for the treatment of PD. The preclinical development of Spheramine included extensive biologic, pharmacologic, and toxicologic studies in vitro and in animal models of PD. The first clinical trial in humans evaluated the safety and efficacy of Spheramine implanted in the postcommissural putamen contralateral to the most affected side in six patients with advanced PD. This open-label study demonstrated good tolerability and showed sustained motor clinical improvement. A phase II double-blind, randomized, multicenter, placebo-controlled (sham surgery) study is underway to evaluate safety, tolerability, and efficacy of Spheramine implanted bilaterally into the postcommissural putamen of patients with advanced PD. Spheramine represents a treatment approach with the potential of supplying a more continuous delivery of levodopa to the striatum in advanced PD than can be achieved with oral therapy alone.

A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development

Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose. A European initiative including 18 companies has undertaken an evidence-based review of acute toxicity studies and assessed the value of the data generated. Preclinical and clinical information was shared on 74 compounds. The analysis indicated acute toxicity data was not used to (i) terminate drugs from development (ii) support dose selection for repeat dose studies in animals or (iii) to set doses in the first clinical trials in humans. The conclusion of the working group is that acute toxicity studies are not needed prior to first clinical trials in humans. Instead, information can be obtained from other studies, which are performed at more relevant doses for humans and are already an integral part of drug development. The conclusions have been discussed and agreed with representatives of regulatory bodies from the US, Japan and Europe.

Don’t Give Up on Erythropoietin as a Neuroprotective Agent

To the Editor .— Ohls et al1 recently reported in Pediatrics that recombinant erythropoietin (rEpo), given in a randomized, controlled clinical trial to reduce transfusions in extremely low birth weight (ELBW) infants, did not significantly influence the neurodevelopmental outcome at 18 to 22 months’ corrected age. The question of the neurodevelopmental outcome of rEpo-treated ELBW infants became of highest interest since animal studies using a variety of models for hypoxic-ischemic brain injury (see refs 2 and 3 for review) as well as the first clinical trial in humans with stroke provided substantial evidence for significant neuroprotective effects of rEpo.4 It is indeed neither unexpected nor disappointing that ELBW infants who received rEpo (400 U/kg body weight 3 times weekly, given intravenously[ iv] or subcutaneously [sc]) from 96 hours of age and until the 35th postmenstrual week did not show a benefit in the neurodevelopmental outcome. This needs additional explanation, because specific aspects of the biology of Epo and its receptor (Epo-R) in the central nervous system (CNS) need to be considered for future strategies in using rEpo as a neuroprotective agent in neonates. Such aspects concern (1) Epo-R expression, (2) endogenous Epo production, and (3) time and dosage of rEpo treatment, particularly regarding its transport across …