Single-dose Study Research Articles

TRLS-01. Trial in Progress: A Prospective, Multicenter Phase 2b Study to Establish Image Interpretation Criteria for 18F-Fluciclovine PET in Detecting Recurrent Brain Metastases after Radiation Therapy (PURSUE)

BackgroundBrain metastases are the most common intracranial tumor in adults, occurring in 10–40% of patients with cancer. Despite multimodal treatment approaches, the prognosis remains poor and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is recommended to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI has low specificity.Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging could help physicians identify patients for whom non-effective or unneeded treatments can be ceased in order to minimize treatment-associated morbidity, and to avoid erroneous premature cessation of potentially effective therapy.18F-Fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors.MethodsNCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across 8 US sites if they have a reference lesion considered equivocal on MRI for recurrent brain metastasis and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <28 days after the equivocal MRI and 2–21 days before planned craniotomy. Outcome measures comprise diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on application of the established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.

Apixaban Pharmacokinetics and Pharmacodynamics in Subjects with Mild or Moderate Hepatic Impairment.

BackgroundHepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production.ObjectiveThis study evaluated the effect of mild or moderate (Child–Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety.MethodsThis open-label, parallel-group, single-dose study included eight mildly and eight moderately hepatically impaired subjects, and 16 healthy subjects. Subjects received a single oral apixaban 5-mg dose (day 1). Pharmacokinetic, pharmacodynamic, and safety assessments were completed at prespecified time points. Apixaban maximum plasma concentration and area under the concentration–time curve to infinity were compared between subjects with hepatic impairment and healthy subjects.ResultsApixaban area under the concentration–time curve to infinity point estimates and 90% confidence intervals were 1.03 (0.80–1.32) and 1.09 (0.85–1.41) for subjects with mild and moderate hepatic impairment vs healthy subjects. Maximum plasma concentration results were similar. Mean (standard deviation) apixaban unbound fraction was 6.8% (1.4), 7.9% (1.8), and 7.1% (1.3) in subjects with mild or moderate hepatic impairment and in healthy subjects. Mean change from baseline in international normalized ratio (3 h post-dose) was 14.7%, 12.7%, and 10.7% for subjects with mild or moderate hepatic impairment and healthy subjects, respectively. A direct relationship was observed between apixaban anti-factor Xa activity and plasma concentration across groups. No serious adverse events or discontinuations due to adverse events occurred.ConclusionsMild or moderate hepatic impairment had no clinically relevant impact on apixaban pharmacokinetic or pharmacodynamic measures, suggesting that dose adjustment may not be required.

Hypoglycemic Activity of Methanol Fraction of Tectona grandis (Linn) Bark in Experimental Rat Models

Diabetes mellitus (DM) is a now a major global health problem and its incidence is increasing day by day in whole world. There are various medicinal plants in India those possess antidiabetic property which are traditionally used in management of diabetes. Tectona grandis Linn. (TG) plant belonging to family Verbenaceae is medicinally reported and claims to cure various diseases in Indian traditional system of medicine (Ayurveda) and also in folklore. The purpose of this present study is to examine the hypoglycemic potential of methanol fractions (50, 100 and 200mg/kg body weight) of Tectona grandis bark (MFTG) from defatted hydro-alcoholic extract in normoglycemic, streptozotocin induced (45mg.kg‒1) diabetic and glucose loaded hyperglycemic rats by single and multiple oral administration in comparison to standard drug Glibenclamide (2.5 mg/kg body weight). Initially acute oral toxicity study of MFTG was carried out in rats to estimate the dose for animal study. The study report showed that the MFTG (200mg/kg) significantly (p&lt;0.05 to p&lt;0.01) reduces blood glucose level both in normoglycemic and diabetic rats induced by Streptozotocin and oral glucose loaded methods till the end of 8 hour and 3hour respectively during the single dose study and from the 15th day to 30th day in multi dose study. Hence the present study reveals that MFTG possess significant hypoglycemic activity which inspires the traditional use of the plant for the treatment of diabetes mellitus.

A randomized, double-blind, single-dose study (LAVENDER) to assess the safety, tolerability, pharmacokinetics, and immunogenicity of a combined infusion of ABP 980 and pertuzumab in healthy subjects

PurposeABP 980 (KANJINTI™) is a biosimilar to reference product HERCEPTIN® (trastuzumab RP). The goal of this study was to characterize the safety, tolerability, and immunogenicity of ABP 980 plus pertuzumab (PERJETA®) when co-administered in a single infusion bag in healthy subjects.MethodsThis randomized, double-blind, single-dose, 2-arm, parallel-group study (LAVENDER Study) evaluated an intravenous (IV) infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag relative to an IV infusion of trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag given over 60 min. The subjects were followed for 92 days post dosing.ResultsA total of 42 subjects were enrolled in the study and treated with investigational product. Due to an operational issue during dosing, the first 6 subjects enrolled in the study were replaced. A total of 36 randomized subjects, n = 18 for ABP 980 plus pertuzumab and n = 18 for trastuzumab RP plus pertuzumab, were treated. Resulting serum concentrations of ABP 980 and trastuzumab RP were similar. There were no serious adverse events, no deaths, and no cardiac disorders during the study. No subject developed anti-drug antibodies throughout the study.ConclusionsThis study demonstrated the safety and tolerability of ABP 980 and pertuzumab admixture in a single infusion bag. The safety profiles and pharmacokinetic parameters of ABP 980 and pertuzumab were consistent with what is known for trastuzumab RP and pertuzumab.Clinical trial listingEudraCT 2018-002903-33.

Safety and Systemic Exposure of Triamcinolone Acetonide Following Ultrasound-Guided Intra-Articular Injection of Triamcinolone Extended-Release or Standard Triamcinolone Acetonide in Patients with Shoulder Osteoarthritis: An Open-Label, Randomized Study.

Background and ObjectivesOsteoarthritis (OA) is a major public health burden. While knee and hip joints are most commonly affected, the glenohumoral (shoulder) joint is also frequently involved. We evaluated the pharmacokinetics and safety/tolerability of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide crystalline suspension (TAcs) in patients with shoulder OA.MethodsIn this phase 2, randomized, open-label, single-dose study (NCT03382262), adults with moderately-to-severely symptomatic shoulder OA for ≥ 6 months randomly received a single ultrasound-guided intra-articular (IA) injection of TA-ER 32 mg or TAcs 40 mg. Safety was evaluated throughout 12 weeks post-injection; blood samples for pharmacokinetic evaluations were collected pre-injection and through Day 85 post-injection.ResultsAmong 25 randomized patients, 12 received TA-ER and 13 received TAcs. Most patients were female (60%), and all had moderate (72%) or severe (28%) shoulder OA. Adverse events (AEs) were reported by four (33%) patients following TA-ER and three (23%) following TAcs injection. No AE was serious or led to study discontinuation. Systemic exposure following TAcs was approximately 1.5-fold higher than that following TA-ER injection (geometric mean [GM] AUC0–last 873,543 vs 557,602 h × pg/mL). GM Cmax was also higher in TAcs- than TA-ER-treated patients (2034 vs 1283 pg/mL). Bioequivalence testing confirmed lower systemic TA exposure following TA-ER than TAcs IA injection.ConclusionThese pharmacokinetic data confirm protracted release of TA from TA-ER following IA injection in patients with shoulder OA. Lower peak and systemic TA exposure following TA-ER suggests TA-ER could potentially confer an improved systemic safety profile over TAcs.Trial Registration NumberNCT03382262 (December 22, 2017 retrospectively registered).

Selected Articles from This Issue

In this First Disclosure, Smith and colleagues describe ASN004, a Dolaflexin-containing antibody drug conjugate targeting the 5T4 oncofetal antigen expressed on a wide range of tumors. ASN004 contains a scFv-Fc antibody and a Auristatin F Hydroxypropylamide payload with a drug-to-antibody ratio of 10-12. In a single dose study, 1 mg/kg achieved complete tumor regression in a cervical cancer model. ASN004 was also shown to have greater activity than the HER2-targeted trastuzumab-DM1 in a gastric model with high HER2 expression despite low 5T4 expression. Pharmacokinetics revealed low free payload drug and dose-dependent exposure. Their results support the continued clinical development of ASN004.In this First Disclosure, Duranti and colleagues outline a single-chain diabody targeting the hERG1 potassium channel and the β1 subunit of integrin receptors (scDb-hERG1-β1). The diabody bound with high affinity to the two proteins only when they were linked together and spared normal cells. The scDb-hERG1-β1 was antiproliferative against tumor spheroids through inhibition of AKT and HIF-1α signaling. The diabody also showed a favorable pharmacokinetic and toxicologic profile when injected into mice. Taken together, the disclosure provides evidence for the continued clinical development of scDb-hERG1-β1.VEGF inhibitors and immune therapies have continued to create favorable outcomes for renal cell carcinoma (RCC) patients. For those who don't respond to these therap. options, Yang and colleagues hypothesized mTOR inhibition will remain a salvage option either by itself or in combined therapy. A recent clinical trial demonstrated mTOR inhibition combined with the vascular agent BNC105P failed to show increased efficacy compared to mTOR inhibition alone. In this study, they demonstrate the transcriptomic gene signatures of patients from that clinical study that correlated with benefit with mTOR inhibition. Their findings were then validated using the phase III CheckMate 025 study.There remains an urgent need for new drug discovery in pediatric cancer with an added goal of reducing long-term toxicity. In this article, Vassal and colleagues underline the outcome of a pediatric cancer international multistakeholder meeting to develop a consensus set of requirements for preclinical drug development in pediatric cancers. The recommendations include the use of cell-based and mouse models as well as proof-of-concept data packages for clinical development. They are designed to represent the minimum guidelines necessary for the international development of drugs for pediatric cancer within the new regulatory environment set up by the RACE act.

Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics.

Simple SummaryWith the incorporation of immune-modulating therapies into the standard management of triple-negative breast cancer, there is increased interest in the non-invasive imaging of the tumor immune microenvironment. Ferumoxytol is FDA-approved as an iron replacement therapy for iron-deficiency anemia and is also a superparamagnetic iron oxide nanoparticle (SPION) resulting in negative enhancement on T2-weighted MR imaging. It has previously been established that ferumoxytol is taken up by macrophages. In the current study, we used ferumoxytol-contrasted MRI to quantitatively image the iron concentration, and, by extension, the tumor-associated macrophage infiltration within the tumor microenvironment of a highly inflammatory model of triple-negative breast cancer.Tumor-associated macrophages (TAMs) in breast cancer regulate inflammation, immunosuppression, angiogenesis, and metastasis. However, TAM imaging remains a clinical challenge. Ferumoxytol has long been an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used as an intravenous (IV) treatment for iron-deficiency anemia. Given its high transverse relaxivity, ferumoxytol produces a negative image contrast upon cellular uptake in T2-weighted magnetic resonance imaging (MRI) studies. Here we evaluated ferumoxytol as a contrast agent to image/quantify TAMs in an aggressive mouse model of breast cancer: We developed [Fe]MRI to measure the 5-dimensional function c(x,y,z,t), where c is the concentration of nanoparticle iron and {x,y,z,t} is the 4-dimensional set of tumor space-time coordinates. Ferumoxytol SPIONs are readily phagocytosed (~104/cell) by the F4/80+CD11b+ TAMs within breast tumors. Quantitative [Fe]MRIs served to determine both the spatial and the temporal distribution of the SPION iron, and hence to measure [Fe] = c(x,y,z,t), a surrogate for TAM density. In single-dose pharmacokinetic studies, after an IV dose of 5 mg/Kg iron, [Fe]MRI measurements showed that c(x,y,z,t) within breast tumors peaked around [Fe] = 70 μM at 42 h post-administration, and decayed below the [Fe]MRI detection limit (~2 μM) by day 7. There was no SPION uptake in control organs (muscle and adipose tissue). Optical microscopy of tissue sections confirmed that F4/80+CD11b+ TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients.

Bioequivalence study of different brands of vildagliptin in healthy human subjects

BackgroundVildagliptin is a dipeptidyl peptidase-4 inhibitor used to treat diabetes mellitus. No bioequivalence study data have been published for the Indian population comparing bioequivalence of vildagliptin brands Galvus, Zomelis, and Jalra. This study aimed to evaluate the bioequivalence between three brands of vildagliptin 50 mg tablet (test 1, Zomelis; test 2, Jalra; and reference, Galvus) and to compare these test formulations with the reference formulation to meet the regulatory requirements of bioequivalence of CDSCO, India. The study was conducted in the clinical research center of the college after enrolling 12 healthy volunteers. This study was a single-dose, randomized, open-label, balanced, three treatment, three period, under fasting condition in 12 adult healthy volunteers. After overnight fasting, the subjects received a single dose of either of any three brands of the vildagliptin tablet (T1—test 1; T2—test 2; and R—reference). The washout period was 7 days. Randomization was in the way of T1T2R in the first period, T2T1R in the second period, and RT1T2 in the third period. Blood samples were collected, after that drug concentration in the plasma was measured with the help of HPLC. Outcome measures 90% confidence interval of the geometric mean ratios (test/reference) for the LnCmax, LnAUC0-t, and LnAUC0-∞ was calculated.ResultsThe AUC0-t was 1390.03, 1401.50, and 1409.37 ng h/ml for the T1, T2, and R, respectively. Cmax was 287.89, 287.41, and 285.17 ng/ml for the T1, T2, and R, respectively. AUC0-∞ was 1452.03, 1467.59, and 1473.53 ng h/ml for the T1, T2, and R, respectively. No significant difference was observed in the pharmacokinetic parameters between the T1, T2, and R. The geometric mean ratios for T1/R for LnCmax, LnAUC0-t, and LnAUC0-∞ were 1.0014 (90% CI, 1.0002–1.0026), 0.9992 (90% CI, 0.9971–1.0013), and 0.9994 (90% CI, 0.9973–1.0016), respectively. For the T2/R, geometric mean ratios for LnCmax, LnAUC0-t, and LnAUC0-∞ were 1.0003 (90% CI, 0.9992–1.0013), 0.9988 (90% CI, 0.9969–1.0008), and 0.9985 (90% CI, 0.9961–1.0010), respectively.ConclusionIn this single-dose study involving Indian healthy volunteers under fasting conditions, the three brands of vildagliptin (Zomelis, Jalra, and Galvus) were bioequivalent as per the bioequivalence criterion of CDSCO, India.

Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies.

Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested. ZB716 was metabolized primarily by CYP2D6 and CYP3A. In human liver microsomes, ZB716 demonstrated relatively low inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (when testosterone was used as the substrate), and no inhibition of CYP2B6 and 3A4 (when midazolam was used as the substrate). In assays for enzyme activity, ZB716 induced CYP1A2, 2B6, and 3A4 in a concentration-dependent manner. Single-dose and repeated-dose pharmacokinetic studies in rats and dogs showed oral bioavailability, dose-proportional drug exposure, and drug accumulation as measured by maximum concentration and area under the concentration–time curve (AUC).

A randomized, single-dose, pharmacokinetic equivalence study comparing MB02 (proposed biosimilar) and reference bevacizumab in healthy Japanese male volunteers

PurposeMB02 is a biosimilar to bevacizumab that has demonstrated similar physicochemical and functional properties in in vitro studies to the reference bevacizumab (Avastin®). This study aims to assess the pharmacokinetic (PK) similarity of MB02 to the reference bevacizumab in Japanese population.MethodsThis double-blind, randomized, parallel-group, single-dose PK study, was performed in healthy Japanese male volunteers. Subjects were equally randomized (1:1) to receive a single (3 mg/kg) IV dose of MB02 or reference bevacizumab. PK assessments were done up to 70 days post-dose. Non-compartmental parameters were calculated. PK similarity was determined using predefined equivalence range (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC0–∞). Immunogenicity samples were taken pre-dose and up to day 70. Safety was assessed throughout the study.ResultsIn total, 48 subjects (24 in each treatment group) were dosed. Consequently to the observed similar PK profile, the 90% confidence interval for the geometric means ratio for the primary PK endpoint, AUC0–∞, was within the predefined equivalence range (0.981–1.11). Forty-seven treatment-emergent adverse events (TEAEs) were reported in 20 subjects (41.7%) with comparable incidence among MB02 and reference bevacizumab groups (22 and 25, respectively), none of them was severe or serious. Anti-drug antibodies incidence was low and similar between treatment groups.ConclusionsPharmacokinetic similarity of MB02 to reference bevacizumab was evidenced in Japanese healthy subjects, with comparable safety and immunogenicity profile between treatments. This study supports the biosimilarity of MB02 to reference bevacizumab in Japanese population. ClinicalTrials.gov identifier: NCT04238650.

Pharmacokinetics, Urinary Excretion, and Pharmaco-Metabolomic Study of Tebipenem Pivoxil Granules After Single Escalating Oral Dose in Healthy Chinese Volunteers.

Tebipenem pivoxil (TBPM-PI), an oral carbapenem antibiotic, has shown special advantages in pediatric infections and was in urgent need in China. Although pharmacokinetics, urinary excretion, and metabolite information of its active form tebipenem (TBPM) has been reported, ethnic differences may exist among the Chinese and Japanese population. By now, no systematic pharmacokinetics, urinary excretion, metabolites, or safety information has been revealed to the Chinese population. The purpose of the present work was to investigate abovementioned information of TBPM-PI granules after oral single ascending doses of 100, 200, and 400 mg in Chinese volunteers. Based on the pharmacokinetic study, the urine pharmaco-metabolomic analysis was conducted to reveal metabolomic interruptions and metabolite information. The study design was a single-center, open-label, randomized, single-dose pharmacokinetic study of 36 healthy volunteers (with half of them being male and the other half female). Time to maximum concentration (T max) was reached at 0.50, 0.50, or 0.67 h for 100, 200, or 400 mg, respectively. The linear pharmacokinetic characteristic of maximum plasma concentration (C max) was detected over 100–200 mg. The area under the concentration time curve (AUC) was proportional to the dose in the range of 100–400 mg. The maximum urinary excretion rate was detected at 0–1 or 1–2 h for dose of 100 or 200–400 mg. Cumulative amount of TBPM excreted in urine by 24 h accounted up to 90, 95, and 80% of dose administered for three groups, respectively. The pharmaco-metabolomic analysis revealed urine metabolic trajectory of deviation at 0–1 or 1–2 h and gradually regressing back to the pre-dose group at the following time periods. Urine metabolites from M1 to M4 were identified, indicating ethnic difference in metabolites among the Chinese or Japanese population. The current work proved safety and tolerance of single-dose administration of oral TBPM-PI in Chinese healthy volunteers over doses of 100–400 mg. All these results provide pharmacokinetics, urine excretion, urine metabolomics, urine metabolites, and safety information in healthy Chinese volunteers after oral single ascending doses of TBPM-PI, benefitting further development and clinical utilities.

Hypoglycemic and anti-lipidemic Evaluation of Fruit Extract and Solvent Fractions of Ziziphus oenoplia in Streptozotocin-Induced Diabetic Rats

Stem Bark, Root and fruit of Ziziphus oenoplia (Rhamnaceae) has been used in traditional health systems to treat diabetes and many more disorders in southern Asia as India, Sri Lanka and Burma. However hypoglycemic and hypo-lipidemic potential of fruit of this valuable plant is not scientifically validated till date. The aim of present study is to evaluate hypoglycemic and hypo-lipidemic effect of ethanol extracts and solvent fractions of Ziziphus oenoplia fruit. The ethanol extracts and solvent fractions in different dose concentration 100, 200, 400 mg/kg of Ziziphus oenoplia fruit were evaluated for hypo-glycemic effect in single dose and multiple dose study for 21 days as well as for hypo-lipidemic potential in streptozotocin induced diabetic rats. The outcome of present study indicates, crude extract and solvent fractions significantly reduce blood glucose level on normoglycemic and diabetic rats.The acute oral toxicity study of Z. oenoplia fruit extract did not show mortality in the animals at the limit dose of 2g/kg. In STZ induced diabetic rat, maximum BGL lowering effect produced by EEZO400 followed by CF400 after 21 days of treatment. Total cholesterol, triglycerides and low-density lipoprotein was also significantly decreased. The observed result may be due to active principles present in extract and fractions. The result showed the potential effects of Z.oenoplia fruit extract and fractions as hypoglycemic and anti hyper-lipidemic in dose dependant manner compare to glibenclemide as standard drug. The claimed traditional use as anti-diabetic has scientific back ground.&#x0D;

Abstract 56: A novel B7-H6/CD3 bispecific IgG-like T cell engaging antibody for the treatment of colorectal cancer

Abstract Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related deaths worldwide with only a minority of patients responding to immune checkpoint targeting therapies. To effectively treat mCRC, we have developed a novel B7-H6/CD3 IgG-like T cell Engager (ITE) that mediates cytolytic synapse formation between T cells and tumor cells, re-directs their cytolytic activity selectively to B7-H6 (B7 homolog 6, NCR3LG1) expressing CRC cells, and increases infiltration of immune cells into the tumor tissue. B7-H6 is a member of the B7 family of immune receptors. We have identified B7-H6 as a novel antigen which is expressed in several solid tumor indications. In CRC tissues B7-H6 is expressed in &amp;gt;95 % of cases, while no to very little expression could be detected in normal tissues, thus making B7-H6 a promising antigen to re-direct cytolytic T cells to B7-H6-expressing CRC cells. The bispecific monovalent B7-H6/CD3 ITE is designed to bind simultaneously to CD3 on T cells and B7-H6 on CRC cells resulting in formation of a cytolytic synapse without interfering with the natural function of B7-H6 and has sustained serum exposure. In vitro, unstimulated T cells were co-cultured with B7-H6 expressing CRC cell lines and increasing concentrations of the B7-H6/CD3 ITE. The B7-H6/CD3 ITE induced dose-dependent lysis of CRC cell lines with EC50 values ranging from 0.9 to 25 ng/mL, whereas viability of B7-H6-negative cells was not affected, demonstrating the selectivity of the B7-H6/CD3 ITE for the B7-H6 antigen. In addition, the B7-H6/CD3 ITE induced B7-H6-dependent activation and proliferation of T cells, and granzyme B and cytokine secretion. In vivo, the B7-H6/CD3 ITE induced dose-dependent anti-tumor activity in subcutaneous CRC (NCI-H716, HCT-15, HT-29) xenograft tumor bearing immunodeficient mice which were reconstituted with human PBMCs or T cells. Tumor regressions were observed with single doses of &amp;lt; 0.5 mg/kg of B7-H6/CD3 ITE administered as i.v. injection, and anti-tumor activity could be further enhanced by q7d dosing. Consistent with the mode-of-action, the B7-H6/CD3 ITE led to a profound infiltration of both CD4+ and CD8+ T cell subsets into the tumor, which correlated with cleaved caspase 3 expression on tumor cells and tumor shrinkage. The inflammatory tumor microenvironment that was created by treatment with the B7-H6/CD3 ITE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells. The B7-H6/CD3 ITE shows cross-reactivity to both B7-H6 and CD3 of human and non-human primate origin respectively, and demonstrates antibody-like pharmacokinetic properties in a single dose study in cynomolgus monkeys. Our pre-clinical data demonstrate that the B7-H6/CD3 ITE is a highly B7-H6-selective and efficacious T cell engaging antibody with the ability to convert a non-inflamed into an inflamed tumor environment which supports clinical development. Citation Format: Susanne Hipp, Wei Zhang, Xiaoyun Liao, Aurelie Auguste, Annika Osswald, Kathrin Bauer, Christian Walterskirchen, Farzaneh H. Sayedian, Manuela Kellner, Craig Giragossian, Vladimir Voynov, Andrew E. Nixon, Paul J. Adam. A novel B7-H6/CD3 bispecific IgG-like T cell engaging antibody for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 56.

Pharmacokinetics and Bioequivalence of Isavuconazole Administered as Isavuconazonium Sulfate Intravenous Solution via Nasogastric Tube or Orally in Healthy Subjects.

ABSTRACTFor critically ill patients with invasive fungal infections, a nasogastric (NG) tube can be an alternative route for administration of isavuconazonium sulfate (ISAVUSULF). This was a randomized, open-label, 2-period, 2-sequence single-dose crossover study comparing single doses of 372 mg ISAVUSULF intravenous (i.v.) solution via NG tube (test formulation) to 372-mg ISAVUSULF capsules for oral administration (reference formulation) in healthy male and female subjects. A single dose of ISAVUSULF was administered under fasting conditions on day 1 of each period, with a washout of 30 days between periods. Pharmacokinetic (PK) samples were collected predose through day 21. Standard safety and tolerability assessments were conducted in each period. The analysis of variance estimate of the study population demonstrates that the isavuconazole i.v. NG tube administration geometric least-squares (LS) mean values of the observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUClast), AUC to time infinity (AUCinf), and AUC from start of dosing to 72 h (AUC72) were 105.3%, 97.6%, 99.3%, and 97.8%, respectively, of the corresponding oral-administration values. The geometric LS mean ratio and 90% confidence intervals for the PK parameters were completely contained within the prespecified limits of 80% to 125%. There were no deaths or serious adverse events that led to the withdrawal of treatment during the study. The study met its primary endpoint of bioequivalence between the two routes of administration. Both routes of administration were well tolerated.

Phase I Trial Results of a Solid Dispersion Formulation of Deferasirox with Enhanced Bioavailability Relative to Exjade® and JadenuTM

Chronic iron overload (CIO) is associated with anemias such as thalassemia that require blood transfusions as a chronic therapy. It is a serious and difficult to treat condition that is associated with multiple organ toxicities including of the liver, heart and endocrine glands. Untreated, CIO can lead to organ failure and death.In 2005, the first oral iron chelator, deferasirox (DFX) in the form of a tablet for oral suspension (Exjade®), was approved in the United States for treating CIO. In 2015, a film-coated tablet (JadenuTM) was introduced as a more convenient formulation for patients.Chirnomas, et al at Children's Hospital Boston (Blood, 2009) have previously published on a subgroup of transfusion dependent thalassemia patients in whom failure to achieve negative iron balance is linked to poor absorption of DFX into systemic circulation as compared to a control group that did respond to DFX.DFX is a drug molecule with poor water solubility and large sensitivity to pH. It is practically insoluble in gastric fluid and very slightly soluble in intestinal fluid. These molecular traits of DFX likely contribute to its food effect and more importantly could lead to poor absorption of the drug in some patients (e.g., patients with more acidic GI tracts and/or on high doses).Solid dispersion technology has been successfully used to address drug solubility challenges in a number of cases (e.g., ritonavir, etravirine, everolimus, ivacaftor). However, DFX as a molecule has a high melting temperature and poor solubility in organic solvents which together have precluded the use of traditional solid dispersion technology. A solid dispersion tablet formulation of deferasirox (DST-0509) was developed using a novel solid dispersion technology (KinetiSol®) that is able to process DFX.DST-0509 was tested in 2 phase I studies, Study 101 and 102. Study 101, a single dose study in healthy volunteers, demonstrated improvements in the bioavailability of DST-0509 compared to Jadenu™ at a dose of 14 mg/kg. Furthermore, DST-0509 is the first deferasirox formulation to show no differences in total absorption between high-fat fed and fasted states.Study 102 was a randomized, single dose, 3-period, 3-sequence crossover, oral bioavailability study of DST-0509 compared to Exjade® and Jadenu™ in fasted healthy volunteers at higher doses (25 - 33 mg/kg). The results showed less variability in Cmax and AUC with DST-0509 versus Exjade®, and meaningfully enhanced absorption versus Exjade® and Jadenu™. See Figure 1., “Comparative Bioavailability of DST-0509 to Exjade® and Jadenu™ in healthy subjects at high doses”.Future studies are planned to see if the enhanced bioavailability seen in these studies translates into superior iron control in patients not achieving target iron control on current deferasirox treatments. [Display omitted] DisclosuresKeen:DisperSol Technologies: Employment, Equity Ownership. Miller:DisperSol Technologies: Employment, Equity Ownership, Patents & Royalties. Tulloch:DisperSol Technologies: Consultancy; Capital Biopharma Consulting: Consultancy, Employment; Faraday Pharmaceuticals: Employment, Equity Ownership.

Bion-1301, a First-in-Class APRIL Neutralizing Antibody for the Treatment of Multiple Myeloma: Preclinical Safety, and Analysis of Pharmacokinetics — Pharmacodynamics Relationship

BION-1301 is a first-in-class humanized antibody targeting APRIL (TNFSF13). We demonstrated that BION-1301 inhibits proliferation and survival of tumor cells and alleviates both APRIL-mediated drug resistance and immune suppression in preclinical multiple myeloma (MM) models1. BION-1301 inhibits ligand dependent activation of both receptors TACI and BCMA, and as such differentiates from BCMA (TNFSF17) targeting cytotoxic approaches. Here, we report on the preclinical safety, Pharmacokinetics (PK)/ Pharmacodynamics (PD) relationship and pharmacometric analysis of BION-1301.A single-dose non-human primate study administering intravenous BION-1301 at 0.3, 3 and 30 mg/kg dose levels, yielded PK parameters typical for IgG4 class antibodies and absence of tolerability issues. PD analysis showed a statistically significant reduction in total IgA and IgM in a dose-dependent fashion. Another measure of target modulation by BION-1301 was provided by co-injection of the hapten TNP-Ficoll (T-cell independent antigen) in different dose groups. Consistent with our observations in hAPRIL transgenic mice and in a dose-dependent fashion, BION-1301 reduced TNP-specific IgA and IgM2. Using a weekly dosing regimen, a 4-week repeat-dose toxicity study was executed at 10, 30 and 100 mg/kg, demonstrating that BION-1301 had no effect on vital organs, ECG's, blood pressure, neurobehavioral examinations, and other factors examined, at any dose level at up to 100mg/kg. Chronic exposure to BION-1301 led to significantly reduced levels of IgA, IgG and IgM observed at all dose levels.To determine target engagement of BION-1301, quantitative assays were developed to detect free APRIL and BION-1301. BION-1301 reduced free APRIL levels in serum in a dose-dependent manner following single and multiple dose administrations. Using a MABEL approach, PK/PD pharmacometric modeling informed a proposed human starting dose of 50 mg.We anticipate initiation of a clinical trial to characterize safety and PK/PD relationship of BION-1301 in heavily pretreated patients with MM. Eligible patients need to have received at least 3 prior treatment lines, including IMiDs, PIs, and monoclonal antibodies. Following identification of a recommended Phase 2 dose, an expanded cohort will investigate clinical activity of single-agent BION-1301. The clinical activity of BION-1301 in combination with other MM therapies as informed by our preclinical experiments will be investigated in additional clinical trials.In summary, BION-1301 was well tolerated and binding of APRIL in non-human primates resulted in decreased IgA, IgG and IgM production. PK and target engagement biomarkers predict the first in human dose using PK/PD modeling. BION-1301, which was shown preclinically to inhibit MM proliferation, survival, drug resistance and reversed an immune suppressive phenotype1, is expected to enter clinical trials in 2017.

AVID200: A Novel TGF-β Inhibitor for the Treatment of Anemia Associated with Myelodysplastic Syndromes

AVID200 is an engineered TGF-β ligand trap comprised of TGF-β receptor ectodomains fused to a human Fc domain. AVID200 has antibody-like properties and is 1,000 times more selective for neutralizing TGF-β1 and TGF-β3 (pM potency), compared to TGF-b2. Since TGF-β1 and TGF-β3 are negative regulators of hematopoiesis, while TGF-b2 is a positive regulator of hematopoiesis, the unique isoform selectivity profile of AVID200 makes it an attractive agent for the treatment of Myelodysplastic syndrome (MDS) associated anemia. As TGF-β2 is implicated in normal cardiovascular function and tumor cell dormancy, the specificity profile of AVID200 also minimizes the potential for cardiotoxicity and promotion of metastasis, which have been observed with pan-neutralizing TGF- β agents.MDS consist of a group of disorders that lead to cytopenia through ineffective hematopoiesis. One critical factor that is commonly associated with the occurrence of these disorders is the pathological overproduction of TGF-β. Increased TGF-β results in the arrest of myeloprogenitor cells preventing hematopoiesis. This disruption of the differentiation program and resulting cytopenia can lead to development of acute myeloid leukemia (AML) in one-third of MDS patients.A critical feature of MDS is an increased level of non-homologous end-joining (NHEJ) activity, a low fidelity form of DNA damage repair, as compared to high-fidelity homologous recombination (HR) repair. The increased level of NHEJ repair in MDS cells results in a hypersensitivity to DNA damaging agents such as mitomycin C (MMC). Previously, in a model of MDS, treatment with TGF-β inhibitors was shown to restore the ratio of NHEJ:HR repair to normal, resulting in more accurate DNA repair. Therefore, the effect of increased TGF-β in patients with MDS is deleterious in two ways. First, elevated levels of TGF-β suppress erythropoiesis leading to anemia. Second, the shift from HR to NHEJ allows for less precise DNA repair and the development of mutations which could result in AML formation.Using a TGF-β responsive AML line, we have shown that AVID200 prevents the growth inhibition induced by TGF-β1. Additionally, AVID200 reversed the hypersensitivity to MMC, implying an improvement in DNA damage repair. Currently, we are investigating the effectiveness of treating two MDS cell lines (MDS-92 and MDS-L) with AVID200 to determine its ability to not only prevent the growth inhibition associated with TGF-β1, but also to enhance DNA damage repair.The safety of AVID200 has been evaluated in several preclinical models. In a chick embryo model of metastasis, AVID200 did not promote the growth of metastatic foci, whereas a pan-neutralizing TGF-β inhibitor did. This result is important since a significant percentage of patients with MDS go on to develop AML and other cancers. The cardiac safety of AVID200 was evaluated in a single-dose pilot non-human primate study. No adverse cardiovascular events were observed at doses of up to 30 mg/kg, the highest dose tested.These results indicate that AVID200 is a promising new agent for the safe and effective treatment for MDS associated anemia.(MJT is a Mitacs Accelerate Program Postdoctoral Fellow) DisclosuresThwaites:Formation Biologics: Employment, Research Funding. Koropatnick:Formation Biologics, Inc.: Research Funding. Tremblay:Formation Biologics: Employment. O'Connor-McCourt:Formation Biologics: Employment.

Excretion and Distribution of the 60-kDa PEG Moiety Used in BAY 94-9027 in Male Wistar Rats

Introduction: PEGylation is a widely used method to prolong the half-life of therapeutic proteins. Long-acting factor VIII (FVIII) products developed through PEGylation may potentially reduce the burden associated with prophylaxis in patients with hemophilia A. BAY 94-9027 is a prolonged-half-life FVIII product modified through site-specific addition of a 60-kDa (2 × 30-kDa branched) PEG via a maleimide linker to a cysteine amino acid. BAY 1025662 is the 60-kDa PEG moiety used for PEGylation including linker and cysteine (PEG-60-Mal-Cys). In toxicology studies, BAY 94-9027 and BAY 1025662 were not associated with any adverse events or PEG-related cellular vacuolation (Ivens et al. Haemophilia. 2013;19:11-20). The rate-limiting clearance of the PEG part of PEGylated proteins after metabolism is expected to be similar to that when the corresponding PEG is administered alone (Baumann et al. Drug Discov Today . 2014;19:1623-1631). The study objective was to investigate the pharmacokinetics and mass balance of total radioactivity in male Wistar rats after a single intravenous (IV) administration of [14C]-labeled BAY 1025662, including size exclusion chromatography profiles of urine at selected time points.Methods: Radiolabeled BAY 1025662 ([prop-14C]BAY 1025662) was synthesized using a 2-step process resulting in a maleimide linker bearing the [14C] label at the propionic acid moiety. Radioactivity following a single IV dose of 11 mg/kg (the estimated maximal human PEG dose over ~30 years' treatment with BAY 94-9027) was determined in body fluids, organs and tissues, and in excreta by liquid scintillation counting after appropriate sample preparation and by quantitative whole-body autoradiography during and at the end of the study.Results: Single-dose mass balance studies using [prop-14C]BAY 1025662 showed that 30.4% of administered radioactivity was excreted within 1 week (23.7% in urine and 6.3% in feces); cumulative excretion at day 168 via urine and feces was 82.6% of the administered dose (68.4% via urine, 13.8% via feces). High-performance liquid chromatography profiling analysis of rat urine suggested that BAY 1025662 is excreted nearly unchanged (74% of total radioactivity, corresponding to 17.6% of dose, present unchanged in urine in the 0- to 168-hour interval). Radioactivity was continuously, albeit slowly, eliminated throughout the study; elimination half-life was 23 and 24 days in blood and plasma, respectively. The corresponding elimination half-lives of radioactivity were 33, 31, 39, 54, and 68 days in the liver, skin, carcass, testes, and kidneys, respectively. Elimination was almost complete at the end of experiment, with a total recovery of radioactivity (cumulative excretion plus residues in animals) of 89% on day 168. Following [prop-14C]BAY 1025662 administration, radioactivity was slowly distributed from blood to peripheral organs, reaching maximum concentration 2 hours postdose; highest maximum concentration was observed in blood, followed by lung and liver. At day 168, only ~4% of the administered radioactive dose was still present in the animal body, partially localized in endocrine/exocrine glands and lymphatic organs. No residual radioactivity was observed in the brain, indicating no crossing of the blood-brain barrier.Conclusions: Following single-dose administration of [prop-14C]BAY 1025662, elimination was almost complete by the end of the experiment on day 168. These results suggest that there are excretion processes in place for high-molecular-weight PEGs such as the PEG 60 moiety used in BAY 94-9027. Two clearance processes are proposed for large PEGs (>30 kDa), as indicated by a faster initial excretion over the first 1-2 weeks, followed by a nonspecific uptake into cells by pinocytosis leading to a longer elimination half-life. The PEG moiety can be recycled from inside the cells back to the plasma, possibly by exocytosis, to then undergo further (mainly renal) excretion (Baumann et al. Drug Discov Today . 2014;19:1623-1631). DisclosuresBaumann:Bayer AG: Employment. Schwarz:Bayer AG: Employment. Hucke:Bayer AG: Employment. Piel:Bayer AG: Employment. Sandmann:Bayer AG: Employment.

IMI2-PainCare-BioPain-RCT3: a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by electroencephalography (EEG)

BackgroundIMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.MethodsThis is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.DiscussionLEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.Trial registrationThis trial was registered 25/06/2019 in EudraCT (2019%2D%2D001204-37).

A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects.

Objective: This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects. Methods: A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞, were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed. Results: A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were 91.81–103.64%, 85.19–95.39% and 85.04–95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody. Conclusion: HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20181610.