First Study In Humans Research Articles

A Framework Proposal to Follow-Up on Preclinical Convulsive Signals of a New Molecular Entity in First-in-Human Studies Using Electroencephalographic Monitoring.

Traditionally, in dose‐escalating first‐in‐human (FiH) studies, a dose cap with a 10‐fold safety margin to the no observed effect level in animals is implemented if convulsive events are observed in animals. However, the convulsive risk seen in animals does not generally translate to humans. Several lines of evidence are summarized indicating that in a dose‐escalating setting, electroencephalographic epileptiform abnormalities occur at lower doses than clinical convulsive events. Therefore, we propose to consider the occurrence of epileptiform abnormalities in toxicology studies as premonitory signals for convulsions in dose‐escalating FiH studies. Compared with the traditional dose‐cap approach, this may allow the exploration of higher doses in FiH and, subsequently, phase II studies without compromising human safety. Similarly, the presence or absence of electroencephalographic epileptiform abnormalities may also aid the assessment of proconvulsive risk in situations of increased perpetrator burden as potentially present in pharmacokinetic and/or pharmacodynamic drug–drug interactions.

The next era of renal radionuclide imaging: novel PET radiotracers

Although single-photon-emitting radiotracers have long been the standard for renal functional molecular imaging, recent years have seen the development of positron emission tomography (PET) agents for this application. We provide an overview of renal radionuclide PET radiotracers, in particular focusing on novel 18F-labelled and 68Ga-labelled agents. Several reported PET imaging probes allow assessment of glomerular filtration rate, such as [68Ga]ethylenediaminetetraacetic acid ([68Ga]EDTA), [68Ga]IRDye800-tilmanocept and 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS)). The diagnostic performance of [68Ga]EDTA has already been demonstrated in a clinical trial. [68Ga]IRDye800-tilmanocept shows receptor-mediated binding to glomerular mesangial cells, which in turn may allow the monitoring of progression of diabetic nephropathy. [18F]FDS shows excellent kidney extraction and excretion in rats and, as has been shown in the first study in humans. Further, due to its simple one-step radiosynthesis via the most frequently used PET radiotracer 2-deoxy-2-[18F]fluoro-d-glucose, [18F]FDS could be available at nearly every PET centre. A new PET radiotracer has also been introduced for the effective assessment of plasma flow in the kidneys: Re(CO)3-N-([18F]fluoroethyl)iminodiacetic acid (Re(CO)3([18F]FEDA)). This compound demonstrates similar pharmacokinetic properties to its 99mTc-labelled analogue [99mTc](CO)3(FEDA). Thus, if there is a shortage of molybdenum-99, Re(CO)3([18F]FEDA would allow direct comparison with previous studies with 99mTc. The PET radiotracers for renal imaging reviewed here allow thorough evaluation of kidney function, with the tremendous advantage of precise anatomical coregistration with simultaneously acquired CT images and rapid three-dimensional imaging capability.

Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study.

8007 Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.

First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors.

5544 Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). We report preliminary results from a FIH Ph1 study of MORAb-202 in pts with FRA-positive solid tumors. Methods: This open-label, ongoing, FIH study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and/or the recommended dose of MORAb-202 (Part 1: Dose finding part with accelerated modified toxicity probability interval design; Part 2: Expansion part). Eligible pts had FRA-positive solid tumors who failed standard therapy and an ECOG PS of ≤1. MORAb-202 was administered by intravenous injection once every 3 weeks and dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle. Efficacy endpoints were assessed with RECIST v1.1 by investigator assessment. Results: As of Nov 16, 2018, 16 pts with confirmed FRA-positive tumors were enrolled and treated with MORAb-202 across 4 dose levels in Part 1 (0.3mg/kg: n = 3 [2 endometrial and 1 ovarian], 0.45mg/kg: n = 3 [3 ovarian], 0.68mg/kg: n = 3 [1 NSCLC, 1 ovarian, and 1 TNBC], 0.9mg/kg: n = 7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC]); all completed > 1 cycle. One pt in the 0.9mg/kg cohort experienced DLTs of alanine aminotransferase increased (grade 3) and gamma-glutamyl transferase increased (grade 3). Treatment-emergent adverse events (TEAEs) occurred in 15 pts (93.8%). The most common TEAEs were leukopenia and neutropenia (50% each). The objective response rate based on RECIST v1.1 was 37.5% (6/16 pts) in Part 1 with 1 complete response (ovarian) at 0.9mg/kg and 5 partial responses including 2 pts (both ovarian) at 0.9mg/kg, 1 pt (endometrial) at 0.3mg/kg, and 2 pts (1 TNBC and 1 NSCLC) at 0.68mg/kg. The disease control rate was 75% (12/16 pts). Exposure to MORAb-202 was dose proportional across the dose range investigated. Conclusions: MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942.

Duodenal mucosal resurfacing: proof-of-concept, procedural development, and initial implementation in the clinical setting

We aimed to develop duodenal mucosal resurfacing (DMR), a minimally invasive upper endoscopic hydrothermal ablation procedure, to treat insulin-resistant metabolic diseases. We completed a sham-controlled, rodent proof-of-concept study and longitudinal safety study in pigs to demonstrate feasibility to test DMR in humans. Subsequently, the DMR procedure was implemented in an open-label first-in-human (FIH) study of safety and efficacy in patients with type 2 diabetes (T2D). In rats, duodenal abrasion reduced hyperglycemia by 59 mg/dL on average, compared with no change from baseline in the sham treatment arm (P< .05). In pigs, the balloon catheter successfully and safely delivered hydrothermal ablation to the duodenal mucosa and superficial submucosa. Complete mucosal healing was demonstrated by week 6. In the FIH study, hydrothermal ablation was successfully administered with no evidence of perforation, pancreatitis, or hemorrhage. Duodenal biopsy specimens obtained 3 months postprocedure demonstrated full mucosal regrowth. No inflammation was observed, and there was minimal-to-mild collagen banding deposition observed in a proportion of ablation site biopsy specimens with no evidence of fibrotic scarring. Glycemic and hepatic measures improved through 6 months of follow-up. DMR shows potential as an endoscopic intervention that improves glycemic and hepatic parameters in patients with T2D. Further mechanistic and clinical studies are underway to further explore DMR as a treatment for metabolic disease.

Treatment with AMG 420, an Anti-B-Cell Maturation Antigen (BCMA) Bispecific T-Cell Engager (BiTE®) Antibody Construct, Induces Minimal Residual Disease (MRD) Negative Complete Responses in Relapsed and/or Refractory (R/R) Multiple Myeloma (MM) Patients: Results of a First-in-Human (FIH) Phase I Dose Escalation Study

Treatment with AMG 420, an Anti-B-Cell Maturation Antigen (BCMA) Bispecific T-Cell Engager (BiTE®) Antibody Construct, Induces Minimal Residual Disease (MRD) Negative Complete Responses in Relapsed and/or Refractory (R/R) Multiple Myeloma (MM) Patients: Results of a First-in-Human (FIH) Phase I Dose Escalation Study

Maternal Gestational Immune Response and Autism Spectrum Disorder Phenotypes at 7 Years of Age in the Seychelles Child Development Study.

Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers' serum at 28weeks' gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to pro-inflammatory cytokines) was associated with fewer ASD symptoms (B = - 0.40; 95% CI = - 0.72, - 0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = - 0.18; 95% CI = - 0.35, - 0.01), but only after removal of outliers. No associations were observed for other markers. These findings suggest that a shift in the maternal immune balance during pregnancy may be associated with ASD symptomatology. While the use of well-established measures that capture ASD phenotypic variability is a strength of the study, measurement of peripheral immune markers only once during gestation is a limitation. Our results should be confirmed using maternal immune markers measured throughout gestation.

Brain vasopressin signaling modulates aspects of maternal behavior in lactating rats.

The brain vasopressin system mediates various social behaviors as has been studied mostly in males. Only recently, advances in social neuroscience revealed that central vasopressin signaling via its V1a and V1b receptors also facilitates female social behavior, including maternal behavior. In this review, we show how maternal care, maternal motivation and maternal aggression of lactating rat mothers are modulated in a V1 receptor subtype- and brain region-specific manner. Measuring local release pattern of vasopressin via intracerebral microdialysis in the behaving rat mother as well as using pharmacological approaches to activate or block vasopressin receptors with subsequent behavioral observation provide detailed insight into the functional role of the vasopressin system in maternal behavior. In this context, the complementary rat animal model of high (HAB) and low anxiety-related behavior (LAB) is particularly helpful due to the genetically determined high activity of the vasopressin gene in HAB rats, which also underlies their high levels of maternal behavior. Furthermore, first studies in humans indicate that the vasopressin system in general and the V1a receptor in more particular might mediate mothering.

Maternal gestational immune response and autism spectrum disorder phenotypes at 7 years of age in the Seychelles Child Development Study

Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers’ serum at 28 weeks’ gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7 years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to pro-inflammatory cytokines) was associated with fewer ASD symptoms (B = − 0.40; 95% CI = − 0.72, − 0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = − 0.18; 95% CI = − 0.35, − 0.01), but only after removal of outliers. No associations were observed for other markers. These findings suggest that a shift in the maternal immune balance during pregnancy may be associated with ASD symptomatology. While the use of well-established measures that capture ASD phenotypic variability is a strength of the study, measurement of peripheral immune markers only once during gestation is a limitation. Our results should be confirmed using maternal immune markers measured throughout gestation.

Abstract CT051: Preliminary correlative and clinical data from a first-in-human (FIH) study of the intratumoral (IT) oncolytic virotherapy, Voyager-V1, in patients with solid tumors

Abstract Introduction Voyager-V1TM is derived from VSV, a bullet-shaped negative sense RNA virus with very low human seroprevalence; it is engineered to selectively replicate in and kill human cancer cells. Voyager-V1 encodes the human IFNβ gene to boost antitumoral immune responses and the thyroidal sodium iodide symporter NIS gene to permit noninvasive imaging of virus spread. FIH studies are underway via both IV and IT routes. Here we report safety and preliminary correlative data from the FIH IT study. Methods and objectives This is a classical 3+3 phase 1 design, using escalating single IT viral doses from 3 x 106 to 3 x 109 TCID50 into one target lesion. The primary objective is safety and tolerability, monitored by committee. Other objectives include PK by RT-PCR for viral genomes, serum IFNβ levels, Tc-99m SPECT/CT imaging to monitor virus infection in injected lesions, peripheral blood immunophenotyping with 11-color flow cytometry for activation markers on T cells, T-regs, NK cells, and MDSCs, and serial biopsies to assess the tumor microenvironment (TME). IHC was performed on tumor biopsies for CD3, CD8, CD4, FoxP3, CD68, PD-1 and PDL-1 pre and post treatment in non-injected and injected lesions. CD45 staining is ongoing. Results Dose level 3 is ongoing (n=8+). No DLTs have been observed to date. Most patients were male (75%), white (100%), with ECOG PS1 (75%) and a median of &amp;gt;6 lines of prior systemic therapy. AEs (in 63% patients) reported as related to study drug were mild-moderate, short-lived, and consisted of G1 fever, chills, hot flashes, nausea, vomiting, hyperhidrosis and G2 fatigue. Most patients had some mild AEs (pain, bruising, subclinical pneumothorax) related to biopsy and IT injection procedures and one had an SAE related to biopsy (G2 pneumothorax). There was no difference in incidence, intensity or duration of related AEs between dose levels so far. In patients analyzed to date, at the first three dose levels of 3 x 106, 1 x 107 and 3 x 107 TCID50 (n=7), viremia and serum IFNβ were below levels of detection after IT injection. There is evidence in all patients of an increase in PD-1 expression on CD4 and CD8 T cells, suggesting T cell activation post- single virus injection. One patient at dose level 2 had increased CD4 and CD8 T cells in the peripheral blood. TME analysis revealed increased infiltration of CD3 and CD8 cells in tumors of some patients. In addition, there are changes in numbers of FoxP3 and CD68 positive cells in the injected lesions compared to the pre-treatment and non-injected lesion. Two patients at dose level 3, one with an injected adrenal metastasis of colorectal cancer and another with a chest wall lesion from a head of pancreas primary, have positive SPECT/CTs on days 3-15 showing viral replication in tumor plus concomitant lymphocyte/neutrophil trafficking in the periphery. Conclusions IT injection of a single dose of the novel oncolytic virotherapy Voyager-V1 has proven safe at doses up to 3 x 107 TCID50. There was evidence of T cell activation with increased PD-1 expression in peripheral blood lymphocytes after a single IT injection. Tumor biopsies indicate increased lymphocyte infiltration. Two patients at the highest dose tested show signs of viral replication in the injected lesion plus evidence of systemic impact on leukocyte populations. Citation Format: Steven Powell, Manish R. Patel, Jaime R. Merchan, Timothy P. Cripe, James Strauss, Rosa M. Diaz, Nandakumar Packiriswamy, Bethany A. Brunton, Deepak Upreti, Rehan Khan, Lukkana Suksanpaisan, Rianna Vandergaast, Stephen J. Russell, Alice S. Bexon, Kah Whye Peng. Preliminary correlative and clinical data from a first-in-human (FIH) study of the intratumoral (IT) oncolytic virotherapy, Voyager-V1, in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT051.

Impact of transcranial direct current stimulation on structural plasticity of the somatosensory system.

While there is a growing body of evidence regarding the behavioral and neurofunctional changes in response to the longitudinal delivery of transcranial direct current stimulation (tDCS), there is limited evidence regarding its structural effects. Therefore, the present study was intended to investigate the effect of repeatedly applied anodal tDCS over the primary somatosensory cortex on the gray matter (GM) and white matter (WM) compartment of the brain. Structural tDCS effects were, moreover, related to effects evidenced by functional imaging and behavioral assessment. tDCS was applied over the course of 5 days in 25 subjects with concomitant assessment of tactile acuity of the right and left index finger as well as imaging at baseline, after the last delivery of tDCS and at follow-up 4 weeks thereafter. Irrespective of the stimulation condition (anodal vs. sham), voxel-based morphometry revealed a behaviorally relevant decrease of GM in the precuneus co-localized with a functional change of its activity. Moreover, there was a decrease in GM of the bilateral lingual gyrus and the right cerebellum. Diffusion tensor imaging analysis showed an increase of fractional anisotropy exclusively in the tDCSanodal condition in the left frontal cortex affecting the final stretch of a somatosensory decision making network comprising the middle and superior frontal gyrus as well as regions adjacent to the genu of the corpus callosum. Thus, this is the first study in humans to identify structural plasticity in the GM compartment and tDCS-specific changes in the WM compartment in response to somatosensory learning.

Medial frontal theta dissociates unsuccessful from successful avoidance and is modulated by lack of perseverance

Medial frontal activity in the EEG is enhanced following negative feedback and varies in relation to dimensions of impulsivity. In 22 undergraduate students (Mage = 18.92 years, range 18–22 years), we employed a probabilistic negative reinforcement learning paradigm in which choices to avoid were followed by cues indicating successful or unsuccessful avoidance of an impending aversive noise. Our results showed that medial frontal theta power was enhanced following a cue that signaled avoidance was unsuccessful. In addition, self-reported lack of perseverance, a dimension of impulsivity characterized by an inability to maintain focus and determination during a challenging task, was negatively correlated with medial frontal theta elicited to an unsuccessful avoidance cue. We also observed robust differences in alpha attenuation and beta modulation following unsuccessful avoidance cue presentation. To our knowledge, this is the first study in humans to show a functional relation between medial frontal theta modulation and avoidance success. We discuss our findings in the context of frontal theta and self-regulation, negative reinforcement, and anxiety.

Inhibition of Na+/K+‐ATPase and KIR channels abolishes hypoxic hyperaemia in resting but not contracting skeletal muscle of humans

Increasing blood flow (hyperaemia) to exercising muscle helps match oxygen delivery and metabolic demand. During exercise in hypoxia, there is a compensatory increase in muscle hyperaemia that maintains oxygen delivery and tissue oxygen consumption. Nitric oxide (NO) and prostaglandins (PGs) contribute to around half of the augmented hyperaemia during hypoxic exercise, although the contributors to the remaining response are unknown. In the present study, inhibiting NO, PGs, Na+ /K+ -ATPase and inwardly rectifying potassium (KIR ) channels did not blunt augmented hyperaemia during hypoxic exercise beyond previous observations with NO/PG block alone. Furthermore, although inhibition of only Na+ /K+ -ATPase and KIR channels abolished hyperaemia during hypoxia at rest, it had no effect on augmented hyperaemia during hypoxic exercise. This is the first study in humans to demonstrate that Na+ /K+ -ATPase and KIR channel activation is required for augmented muscle hyperaemia during hypoxia at rest but not during hypoxic exercise, thus providing new insight into vascular control. Exercise hyperaemia in hypoxia is augmented relative to the same exercise intensity in normoxia. During moderate-intensity handgrip exercise, endothelium-derived nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute to ∼50% of the augmented forearm blood flow (FBF) response to hypoxic exercise (HypEx), although the mechanism(s) underlying the remaining response are unclear. We hypothesized that combined inhibition of NO, PGs, Na+ /K+ -ATPase and inwardly rectifying potassium (KIR ) channels would abolish the augmented hyperaemic response in HypEx. In healthy young adults, FBF responses were measured (Doppler ultrasound) and forearm vascular conductance was calculated during 5min of rhythmic handgrip exercise at 20% maximum voluntary contraction under regional sympathoadrenal inhibition in normoxia and isocapnic HypEx (O2 saturation ∼80%). Compared to control, combined inhibition of NO, PGs, Na+ /K+ -ATPase and KIR channels (l-NMMA+ketorolac+ouabain+BaCl2; Protocol 1; n=10) blunted the compensatory increase in FBF during HypEx by ∼50% (29±6mLmin-1 vs. 62±8mLmin-1 , respectively, P<0.05). By contrast, ouabain+BaCl2 alone (Protocol 2; n=10) did not affect this augmented hyperaemic response (50±11mLmin-1 vs. 60±13mLmin-1 , respectively, P>0.05). However, the blocked condition in both protocols abolished the hyperaemic response to hypoxia at rest (P<0.05). We conclude that activation of Na+ /K+ -ATPase and KIR channels is involved in the hyperaemic response to hypoxia at rest, although it does not contribute to the augmented exercise hyperaemia during hypoxia in humans.

Protective Effect of Punica granatum Extract in Head and Neck Cancer Patients Undergoing Radiotherapy.

In India, head and neck cancers account for 30-40% cancers of all sites. Due to lack of screening program, wide variation in the availability of infrastructures and expertise, patients present at an advanced stage. The main stay of management of the head and neck tumours is surgery and chemoradiation. Radiation dermatitis and mucositis is one of the most common side effect encountered during the radiotherapy. Aim of our study was to study protective role of pomegranate extract on radiation induced dermatitis and mucositis in head and neck cancer patients. It was a prospective, clinical, double blind, case control study. 60 patients (30 active and controls) undergoing radiotherapy for head and neck cancer were studied for 12months. Patients in study group were given whole fruit pomegranate extract. Each capsule contained 300mg of whole fruit extract, each capsule contains 40% polyphenols and 27% punicalagin. Each patient were given 2 capsules every day for a period of 6-7weeks. The skin and mucosal changes was graded according to the acute radiation morbidity scoring criteria (RTOG) for skin and mucous membrane. The results were statistically significant. Pomegranate extract proved to be radioprotective. Our study is one of the first study in humans to demonstrate the effectiveness of pomegranate extract in preventing radiation dermatitis and mucositis.

Safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).

447 Background: BTC are aggressive tumors with limited treatment options and poor overall survival. Aberrant FGFR signaling has been implicated in BTC carcinogenesis. Debio 1347 is an orally available selective FGFRi with potent antitumor effect in preclinical model bearing FGFR alterations. Debio 1347 showed encouraging preliminary clinical activity and manageable treatment-emergent adverse events (TEAE) in its first-in-human (FIH) ph1 study (NCT1948297) dose-escalating part. Here we report only results from the BTC pts of this study. Methods: This FIH study enrolled pts with advanced solid malignancies harboring defined activating alterations of FGFR 1, 2, or 3: amplifications (amp), mutations (mut) and translocations (trans). Pharmacokinetics (PK) and pharmacodynamics were serially evaluated in blood, skin and/or tumor tissue. A confirmatory post-hoc analysis was performed centrally for all available biopsies. Results: Eight pts, six with intrahepatic cholangiocarcinoma (iCCA) and two with gallbladder cancer (GBC), were treated with Debio 1347 at doses between 60 and 150 mg orally daily in 28-day cycles. Among the iCCA pts, one had an FGFR2mut, one had an FGFR2 activating deletion (del), and one had an FGFR3mut; the other three had FGFR2trans. One of the two GBC pts had an FGFR3trans, the other one an FGFR2mut. All pts had prior systemic therapy (mostly 2 or 3 lines). The most common TEAEs were hyperphosphatemia (8/8), nail changes (5/8), nausea (5/8), dry mouth (4/8) and stomatitis (3/8). No grade ≥ 3 related TEAE were reported except grade 3 hyperphosphatemia (4/8). PK was comparable to that in pts with other solid malignancies.A partial response lasting up to 48 weeks was observed in an iCCA pt (FGFR2 del exon 5); three additional iCCA pts (FGFR2trans: ROCK1; KIAA1217; DDX21) and one GBC pt (FGFR3-TACC3 trans) had target lesions regression &lt; 30% and stayed on trial between 24 – 37 weeks. Overall disease control was 62.5%. Conclusions: These results suggest that BTC pts with genomic events leading to activation of FGFR2/3 may benefit from treatment with Debio 1347. Further study is ongoing in the expansion cohort of this trial. Clinical trial information: NCT1948297.

Histotripsy Treatment of Benign Prostatic Enlargement Using the Vortx Rx System: Initial Human Safety and Efficacy Outcomes

To assess clinical safety (primary) and efficacy (secondary) of histotripsy for treatment of symptomatic benign prostatic enlargement in a first-in human study. Twenty-five male subjects with moderate to severe lower urinary tract symptoms, prostate size between 30 and 80 g, and no evidence of prostate cancer were enrolled at 2 sites in a prospective, single-arm study. Treatment consisted of acoustic energy delivery through the perineum with integrated real-time transrectal ultrasound monitoring using the Vortx Rx system. Follow-up evaluations were performed on postoperative day 1 and 1, 3, and 6 months. Twenty-five men underwent histotripsy treatment with no serious intraoperative adverse events. Postoperatively, 3 cases of transient urinary retention (<3 days), 1 case of urinary retention (8 days in duration, defined as serious), a minor anal abrasion, and microscopic hematuria were considered device-related adverse events. Debulking of targeted prostate tissue was not observed with transrectal ultrasound imaging or with endoscopic visualization, and clinically meaningful improvement in uroflow or postvoid residual urine (PVR) did not occur. However, International Prostate Symptom Score improvement at 1 month was 12.5 (52.4%) ± 6.6 points (n = 25), at 3 months was 11.9 (50.8%) ± 7.6 points (n = 24), and at 6 months was 10.4 (44.0%) ± 7.6 points (n = 24) (P <.001). Prostate histotripsy was safe and well tolerated in this pilot human trial with improvement in lower urinary tract symptoms.

Drug development challenges in liver disease clinical trials

Drug development process faces many challenges, including those encountered in clinical trials for liver diseases. Drug development is a lengthy and highly costly process. Only 10% of compounds entering first study in humans (phase 1) make it to the market after an average of 14 years with a cost of

Amg 592 Is an Investigational IL-2 Mutein That Induces Highly Selective Expansion of Regulatory T Cells

Background: Low-dose interleukin-2 (IL-2) therapy expands regulatory T cells (Tregs) and provides clinical benefit for inflammatory diseases; however, concomitant increases in conventional effector T cells (Tcon) and natural killer (NK) cells may result in toxicity. AMG 592 is an investigational IL-2 mutein designed for greater Treg selectivity and longer half-life compared with recombinant IL-2 (aldesleukin). In preclinical studies and a phase 1, double-blind, placebo (PBO)-controlled first-in-human (FIH) study, we investigated the safety and tolerability of AMG 592 and its effects on expansion of Treg, Tcon, and NK-cells.Methods: AMG 592 activity was assessed as in vitro phosphorylated STAT5 (pSTAT5) in primary human peripheral blood mononuclear cells (PBMC). Treg, Tcon, and NK-cell expansion and cytokine production were assessed after culture of pre-stimulated human PBMC with increasing doses of AMG 592 or aldesleukin. The in vivo effects of AMG 592 on body temperature, C-reactive protein (CRP), and peripheral blood Treg, Tcon, and NK numbers were evaluated in cynomolgus monkeys after escalating single SC doses of AMG 592 or 5 consecutive daily SC doses of aldesleukin. In the FIH study, healthy volunteers in 8 dose cohorts received a single SC ascending dose of AMG 592 (n=6 per dose) or placebo (n=2 per dose) and were evaluated for safety and tolerability, pharmacokinetics (PK), pharmacodynamics, and cytokine production for 28 days.Results: In human PBMC cultures, AMG 592 caused more selective Treg response (pSTAT5 and proliferation) and lower production of pro-inflammatory cytokines than aldesleukin. Dose-dependent expansion of FoxP3+ Tregs in aldesleukin-treated cynomolgus monkeys was accompanied by increased body temperature and CRP; however, AMG 592 caused Treg expansion without significant effects on body temperature or CRP. In the ongoing FIH study, AMG 592 was well tolerated, with no serious adverse events (AEs). The most common AE across treatment arms was grade 1 painless erythema at or near the injection site that resolved without treatment. Preliminary PK results indicate dose-related increases in AMG 592 serum exposure. AMG 592 caused a robust, dose-dependent expansion of Tregs relative to Tcon in all treated individuals. Expanded Tregs had increased levels of CD25 and Foxp3, and were enriched for recent thymic emigrants. At the highest dose, the increase in the Treg:Tcon ratio peaked at day 8 (~4-fold vs baseline) and remained elevated up to day 29. Treg expansion by AMG 592 was highly selective, with no directional change in NK-cell numbers and minimal increase in Tcon. Moreover, there were no increases in the serum pro-inflammatory cytokines IL-6, TNFα, or IFN-γ above the limits of detection.Conclusion: AMG 592 caused a dose-dependent, selective expansion of Tregs in healthy volunteers. The lack of pro-inflammatory cytokines and reduced markers of inflammation by AMG 592 compared with aldesleukin suggests a wider therapeutic margin. The sustained Treg elevation compared with aldesleukin suggests less frequent dosing may be feasible. Further investigation of the ability of AMG 592 to restore immune homeostasis by Tregs in inflammatory and autoimmune diseases is warranted. DisclosuresTchao:Amgen Inc.: Employment, Equity Ownership. Gorski:Amgen Inc.: Employment, Equity Ownership. Yuraszeck:Amgen Inc.: Employment, Equity Ownership. Sohn:Amgen Inc.: Employment, Equity Ownership. Ishida:Amgen Inc.: Employment, Equity Ownership. Wong:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership.

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans.

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 μg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ∼30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF’s development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Abstract 4251: DNA methylation of mitochondrial biogenesis regulating genes: A possible link between telomeres, mitochondria, and cancer incidence

Abstract Background: PGC1A and PGC1B encode transcriptional factors that regulate mitochondrial biogenesis and have been implicated as a link between telomeric and mitochondrial functions. Telomere dysfunction is associated with impaired mitochondrial biogenesis and increased generation of reactive oxygen species. Animal studies have also shown that loss of PGC1A protects against cancer as mitochondrial function is required for transformation and tumor growth. No human studies have examined the role of these genes in relation to cancer incidence. Our objective was to examine associations between PGC1A and PGC1B methylation in relation to cancer incidence. Methods: We studied 491 Normative Aging Study participants who had blood drawn 1-4 times from 1999 through 2012. After median 10.2-year follow-up, there were 125 incident cancers including 36 prostate. PGC1A and PGC1B methylation was measured at 30 and 27 sites, respectively, using the HumanMethylation450k assay. We used Cox proportional hazards models to examine associations between CpG methylation and cancer incidence measured at first blood draw as well as in time-dependent associations. All models adjusted for age, race, smoking status and pack-years, alcohol consumption, blood cell composition, and processing batch. Results: In single-site adjusted time-dependent models, we identified 13 instances of 11 individual loci (10 from PGC1A and 1 from PGC1B) significantly associated with all-cancer and prostate cancer incidence. In multi-site adjusted models, we showed cg0677257 from the 3’ UTR of PGC1A was inversely associated with first-visit (HR: 0.41; 95% CI: 0.21, 0.79) and time-dependent all-cancer incidence (HR: 0.42; 95% CI: 0.22, 0.81). Similarly, we showed cg0942771 and cg03281309 from the gene body of PGC1A were inversely associated with time-dependent all-cancer incidence (HR: 0.51; 95% CI: 0.30, 0.88; HR: 0.74; 95% CI: 0.56, 0.98, respectively). Finally, we found that cg1521939 from the 5’ UTR region of PGC1B was positively associated with time-dependent all-cancer incidence (HR: 3.27; 95% CI: 1.55, 6.90). Conclusion: This is the first study in humans to show site-specific PGC1A and PGC1B methylation is a significant predictor of cancer incidence. These findings point to a possible interplay between telomere and mitochondrial dysfunction, and epigenetics in carcinogenesis. Additional studies should also examine these associations in larger cohorts with greater racial/ethnic, gender, and socioeconomic diversity to validate these findings. Citation Format: Jacob K. Kresovich, Tao Gao, Brian T. Joyce, Pantel Vokonas, Joel Schwartz, Andrea A. Baccarelli, Lifang Hou. DNA methylation of mitochondrial biogenesis regulating genes: A possible link between telomeres, mitochondria, and cancer incidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4251. doi:10.1158/1538-7445.AM2017-4251