Single Intravenous Infusion Research Articles

Perioperative omega-3 fatty acids fail to confer protection in liver surgery: Results of a multicentric, double-blind, randomized controlled trial

In a variety of animal models, omega-3 polyunsaturated fatty acids (Ω3-FAs) conferred strong protective effects, alleviating hepatic ischemia/reperfusion injury and steatosis, as well as enhancing regeneration after major tissue loss. Given these benefits along with its safety profile, we hypothesized that perioperative administration of Ω3-FAs in patients undergoing liver surgery may ameliorate the postoperative course. The aim of this study was to investigate the perioperative use of Ω3-FAs to reduce postoperative complications after liver surgery. Between July 2013 and July 2018, we carried out a multicentric, double-blind, randomized, placebo-controlled trial designed to test whether 2 single intravenous infusions of Omegaven® (Ω3-FAs) vs. placebo may decrease morbidity. The primary endpoints were postoperative complications by severity (Clavien-Dindo classification) integrated within the comprehensive complication index (CCI). A total of 261 patients (132 in the Omegaven and 129 in the placebo groups) from 3 centers were included in the trial. Most cases (87%, n=227) underwent open liver surgery and 56% (n=105) were major resections (≥3 segments). In an intention-to-treat analysis including the dropout cases, the mortality rate was 4% and 2% in the Omegaven and placebo groups (odds ratio0.40;95% CI 0.04-2.51; p=0.447), respectively. Any complications and major complications (Clavien-Dindo≥3b) occurred in 46% vs. 43% (p=0.709) and 12% vs. 10% (p=0.69) in the Omegaven and placebo groups, respectively. The mean CCI was 17 (±23) vs.14 (±20) (p=0.417). An analysis excluding the dropouts provided similar results. The routine perioperative use of 2 single doses of intravenous Ω3-FAs (100ml Omegaven) cannot be recommended in patients undergoing liver surgery (Grade A recommendation). Despite strong evidence of omega-3 fatty acids having liver-directed, anti-inflammatory and pro-regenerative action in various rodent models, 2 single omega-3 fatty acid infusions given to patients before and during liver surgery failed to reduce complications. Because single omega-3 fatty acid infusions failed to confer liver protection in this trial, they cannot currently be recommended. ClinicalTrial.gov: ID: NCT01884948; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215.

652 Ustekinumab Intravenous Reinduction Therapy Is Effective at Recapturing Response in Patients With Crohn's Disease

INTRODUCTION: Ustekinumab is a monoclonal antibody used in the treatment of Crohn's Disease that acts as an antagonist to interleukin-12 and interleukin-23. It is administered as a single intravenous infusion followed by subcutaneous maintenance dosing. There is paucity of literature evaluating the efficacy of repeating an intravenous infusion to recapture response among patients experiencing secondary loss of response to ustekinumab. We report on a cohort of patients who received a second intravenous ustekinumab loading dose after secondary loss of response at a large, academic IBD center. METHODS: We performed a retrospective cohort study of patients, who lost response to ustekinumab after initial intravenous standard induction followed by subcutaneous maintenance therapy and received a second intravenous ustekinumab loading dose following the standard weight-based dosing recommendations. We analyzed clinical and demographic characteristics of this patient population, including phenotype, prior therapies, and the efficacy of ustekinumab after the second infusion, including the subsequent maintenance dose after the second infusion. Response was defined as resolution or improvement of clinical symptoms that led to a second intravenous infusion. RESULTS: Among 372 patients treated with ustekinumab between 2016 and 2019, 18 (5%) patients received a second intravenous loading dose after experiencing secondary loss of response to their initial standard intravenous regimen. These patients had all failed prior biologic therapy and were placed on ustekinumab as second line (22%), third line (27%), fourth line (33%), fifth line (6%), or sixth line therapy (11%). After the second intravenous re-induction clinical response was observed in 15 patients (83%), whereas 3 (17%) patients did not respond and ustekinumab was stopped. Clinical and demographic characteristics of patients receiving a second loading dose are shown in Table 1. Among the 15 patients remaining on ustekinumab, 5 (33%) continued every 8-week dosing, 6 (40%) utilized every 6-week dosing, and 4 (27%) required every 4-week dosing regimens. CONCLUSION: A second intravenous ustekinumab loading dose is an effective strategy to recapture the therapeutic efficacy of ustekinumab after secondary loss of response. In addition, our data suggests that escalation in dosing frequency of maintenance subcutaneous therapy after a second intravenous loading dose should be considered for an ongoing durable response to ustekinumab.

689 Early Improvement After Intravenous Ustekinumab Induction in Patients With Ulcerative Colitis: Results From the UNIFI Induction Trial

INTRODUCTION: The UNIFI induction study evaluated the efficacy and safety of ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) after a single intravenous infusion. In this analysis, we evaluated the rapidity of the onset of the treatment effect. METHODS: Eligible patients were randomly assigned to placebo (PBO) or UST 130 mg or ∼6 mg/kg. Patients recorded stool frequency and categorized rectal bleeding daily for the 7 days before each visit. Partial Mayo scores were calculated at baseline and Week 2 using the average of the stool frequency and rectal bleeding scores from the most recent consecutive 3-day period before the visit and the physician's global assessment score recorded at the visit. C-reactive protein (CRP) and fecal biomarkers were measured at baseline and Day 14. RESULTS: At baseline, the mean 3-day average daily stool frequency was 7.0 in the PBO group, 6.9 in the UST 130-mg group, and 7.0 in the UST ∼6-mg/kg group. Patients receiving UST showed greater reductions in the daily number of stools compared with PBO as soon as the first assessment time point at Day 7. Mean changes from baseline in daily stool frequency were -0.7 for PBO, -1.0 for UST 130-mg (P = 0.098), and -1.2 for UST ∼6-mg/kg group (P = 0.018) by Day 7, respectively, and -0.9, -1.6 (P < 0.001), and -1.9 (P < 0.001) by Day 13, respectively (Figure 1). Rectal bleeding scores at baseline and Week 2 are summarized in Figure 2. Patients receiving UST showed significantly greater improvement from baseline to Day 14 in partial Mayo score and CRP (Table, P < 0.001 for all comparisons of UST vs PBO). Differences between the UST and PBO treatment groups in mean changes from baseline to Day 14 in fecal calprotectin did not reach significance (PBO -33.96 mg/kg, UST 130 mg 79.12 mg/kg [P = 0.875], UST ∼6 mg/kg -412.68 mg/kg [P = 0.152]). However, patients receiving UST showed significantly greater improvement in fecal calprotectin at Week 4 (mean changes from baseline: PBO -226.78 mg/kg, UST 130 mg -881.22 mg/kg [P = 0.013], UST ∼6 mg/kg -802.75 mg/kg [P < 0.001]). Similar results were observed for fecal lactoferrin. CONCLUSION: The effect of UST began rapidly after induction, with symptomatic improvement and reduction of systemic inflammation seen as early as the first assessments at Days 7 and 14, respectively.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Human Monoclonal Antibody Targeting the G Glycoprotein of Henipaviruses in Healthy Adults: A Randomised, First-in-Human Phase 1 Study

Background: The henipaviruses, Hendra virus and Nipah virus, are emerging zoonotic pathogens of bat origins that have been associated with poor clinical outcomes in humans. The monoclonal antibody (mAb) m102∙4 is a potent fully human antibody that neutralizes Hendra and Nipah viruses in vitro and in vivo. Clinical trials in humans represent the next stage in the utilization of this antibody in the prophylactic treatment and prevention of deaths from henipavirus infections. Methods: We performed a randomised, double-blind, placebo-controlled, singlecentre, dose escalation phase 1 study using the human monoclonal antibody m102∙4. Healthy adults aged 18-50 years with a body-mass index of 18.0 to ≤35.0 kg/m2 were assigned to one of five cohorts. A sentinel pair for each cohort was randomised in a 1:1 ratio to receive either active treatment or placebo. The remaining participants in each cohort were randomised 5:1 to receive m102∙4 or placebo. Cohorts 1 to 4 received a single intravenous infusion of m102∙4 at doses of 1, 3, 10, and 20 mg/kg respectively, and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg, 72 hours apart, with monitoring for 123 days. The primary objective was to assess the safety and tolerability of single and multiple IV doses of m102∙4 mAb. We also assessed pharmacokinetics, immunogenicity, and virus neutralisation. Analyses were completed according to protocol. Findings: Between April 15, 2015 and June 16, 2016, 77 healthy adults were screened and 40 participants were enrolled in the study; eight were assigned to each cohort (six randomised to receive m102∙4, and two randomised to receive placebo per cohort). A total of 86 treatment-emergent adverse events were reported by the 40 participants with similar rates between placebo and active treatment groups. Thirty-one events reported in 20 participants (50%) receiving m102∙4 were considered treatment-related, and six events were reported in five participants (50%) receiving placebo. A possible trend of treatment-related headaches with m102∙4 was noted; this was reported in 66.7% of participants administered singledose m102∙4 compared with 10% of those administered placebo. There was no increase in treatment-related headaches among those with repeat dosing. There were no deaths or severe adverse events leading to withdrawals or premature discontinuations during the study. Pharmacokinetics based on those receiving active treatment (n=30) were linear, with the mean halflife ranging from 16.5 to 27.6 days across Cohorts 1-4. There was small to moderate accumulation of monoclonal antibody in those receiving a repeat dose (Cohort 5), with elimination kinetics that were comparable to those receiving a single dose. Anti-m102∙4 antibodies were not detected at any time-point during the study. All serum samples at all time points exhibited virus-neutralisation activity when tested in vitro for both HeV and NiV. Interpretation: m102∙4 single and repeated dosing of up to two doses separated by 3 days appears to be safe and well tolerated when administered to healthy adult volunteers. A standard pharmacokinetic profile was observed with linear elimination kinetics. There was no evidence of an immunogenic response to m102∙4. Exploratory virus neutralisation studies confirmed that m102∙4 remained active for at least 8 days following administration of a clinically relevant dose. This study will inform future dosing regimens for m102∙4 to achieve prolonged exposure for systemic efficacy against henipaviruses. Trial Registration: The study was registered on the Australian New Zealand Clinical Trials Registry, registration number ACTRN12615000395538. Funding Statement: Queensland Department of Health, the National Health and Medical Research Council and the National Hendra Virus Research Program. Declaration of Interests: CCB is a US federal employee; and CCB and DSD are co-inventors on US patent Nos. 7,988,971 and 8,313,746 “Human monoclonal antibodies against Hendra and Nipah viruses”; assignees are The United States of America as represented by the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. (Bethesda, MD). All other authors declare no competing interests. Ethics Approval Statement: Ethics approval was obtained from the study site’s Human Research Ethics Committee at the QIMR Berghofer Medical Research Institute before participant enrolment commenced. The study was conducted under the Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme (CTN) and in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the National Health and Medical Research (NHMRC) statement on ethical conduct in human research.

Zoledronate in the prevention of Paget’s (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget’s disease of bone

IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in...

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial.

Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or two additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine-bone mineral density (LS-BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean ± SD) 4.82% ± 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)-BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. © 2019 American Society for Bone and Mineral Research.

Ravulizumab in paroxysmal nocturnal hemoglobinuria: a profile of its use

Ravulizumab (Ultomiris™) is a humanized monoclonal antibody that inhibits terminal complement C5, thereby reducing hemolysis, inflammation, and thrombosis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Ravulizumab was developed by re-engineering eculizumab to create a longer-acting antibody, which allows an 8-weekly administration schedule instead of the 2-weekly schedule required with eculizumab. A single intravenous infusion of ravulizumab provides immediate and complete inhibition of serum free C5. With continued ravulizumab treatment, breakthrough hemolysis rates decrease as a result of eliminating free C5-associated breakthrough hemolysis. The efficacy of ravulizumab is noninferior to that of eculizumab, as determined in complement-inhibitor naive patients and those previously treated with eculizumab. Ravulizumab was generally well tolerated, with a generally comparable tolerability profile to that of eculizumab.

A High-dose Pharmacokinetic Study of a New IgG4 Monoclonal Antibody Temelimab/GNbAC1 Antagonist of an Endogenous Retroviral Protein pHERV-W Env

PurposeTemelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS. MethodsThis randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially. FindingsTemelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36–110 mg/kg, mean temelimab Cmax increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses. ImplicationsThe favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.

Host cell in vivo production of the synthetic drug anti-CD25/IL-10 using minicircle vector.

Synthetic biologic drugs are highly successful for induction therapy in transplantation, but the development of novel biologics is limited because of the high cost of synthesis and purification. In this study, we developed a novel strategy for the production of synthetic protein drugs in vivo by the host itself. We utilized minicircle (MC) technology, which can robustly express a target molecule and secrete it from cells, as an indirect method to produce a protein of interest in vivo. We designed an MC vector containing the sequences of basiliximab (anti-CD25 mAb) and IL-10. We verified the substantial production of the anti-CD25/IL-10 protein from the MC in vitro and in vivo. The therapeutic effect of MC-derived anti-CD25/IL-10 was evaluated in a skin allograft mouse model by single intravenous infusion. Mice treated with the MC encoding anti-CD25/IL-10 exhibited prolonged skin allograft survival times accompanied by improved histologic changes and immunologic regulation. These findings indicate that the anti-CD25/IL-10 protein drug obtained by MC technology is functionally active and relevant for reducing allograft rejection. This self-reproducible strategy for synthetic protein drugs using MCs is a promising tool for transplantation.-Lim, S. W., Shin, Y. J., Luo, K., Quan, Y., Ko, E. J., Chung, B. H., Yang, C. W. Host cell in vivo production of the synthetic drug anti-CD25/IL-10 using minicircle vector.

Abstract CT225: A Phase Ib/IIa randomized pilot study to investigate the safety and tolerability of autologous T-cells with enhanced T-cell receptors specific to NY-ESO-1/LAGE-1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non-small cell lung cancer

Abstract Introduction: There is a high unmet medical need for patients with advanced non-small cell lung cancer (NSCLC) who have failed platinum-based chemotherapy and checkpoint inhibitors. Only 10% of such patients receive any benefit from current therapies, and novel therapies are needed to improve outcomes. Preclinical data support the efficacy, specificity and possible safety of NYESO1/LAGE1a T-cell receptor-engineered patient Tcells (GSK3377794) in NSCLC. Pembrolizumab (PEM) is a monoclonal antibody, which specifically blocks PD1/PDL1 interaction, thereby increasing the antitumor function of Tcells. Thus, the combination of GSK3377794 and PEM may work synergistically due to the inhibition of PD1/PD-L1 signaling on GSK3377794 and other T-cells, potentially further improving the therapeutic effect. Methods: This is a Phase Ib/IIa randomized, multiarm, openlabel pilot study (NCT03709706) in human leukocyte antigen (HLA)A*02:01, HLAA*02:05 and/or HLAA*02:06 adult patients (aged &amp;gt;18 years) whose tumors express NYESO1 and/or LAGE1a. This study aims to enroll up to 44 patients with unresectable Stage IIIb or Stage IV NSCLC who were either ineligible for definitive chemoradiotherapy, have recurrent disease which has progressed during or after platinumbased chemotherapy with or without anti-PD-1 agents, have terminated prior treatment due to intolerable side effects, or have refused standard approved treatment. Patients will be randomized (1:1) to two treatment arms. Arm A will receive GSK3377794 as monotherapy, administered as a single intravenous (IV) infusion; Arm B will receive GSK3377794 as a single IV infusion on Day 1 followed by PEM 200 mg initiated on Day 22 and continued for up to 35 cycles or until disease progression. Patients in Arm A who progress after receiving GSK3377794 monotherapy will be offered antiPD1 therapy at the same dose and duration as Arm B. The study will use a Bayesian adaptive design, wherein enrollment can be halted in either arm for futility. The patient journey will consist of 3 parts: patients will undergo eligibility screening (Part 1), followed by leukapheresis (Part 2), after which patients will enter the Interventional Phase (Part 3) during which patients will receive preparative lymphodepleting chemotherapy followed by infusion of GSK3377794. The first patient was screened on December 31, 2018. ClinicalTrials.gov identifier: NCT03709706 Study is funded by GlaxoSmithKline and is in collaboration with Merck &amp; Co., Inc. Citation Format: Karen L. Reckamp, Wallace Akerley, Martin J. Edelman, Balazs Halmos, Kai He, Melissa Johnson, Raja Mudad, Joel W. Neal, Taofeek K. Owonikoko, Jyoti D. Patel, Sandip P. Patel, Jonathan W. Riess, Adrian G. Sacher, Simon Turcotte, Liza C. Villaruz, Marjorie G. Zauderer, Benedetto Farsaci, Aisha Hasan, Roma Patel, Yuehui Wu, Michael Chisamore, Vincent Lam. A Phase Ib/IIa randomized pilot study to investigate the safety and tolerability of autologous T-cells with enhanced T-cell receptors specific to NY-ESO-1/LAGE-1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT225.

Onasemnogene Abeparvovec: First Global Approval.

Onasemnogene abeparvovec (onasemnogene abeparvovec-xioi; formerly AVXS-101; ZOLGENSMA®) is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the human survival motor neuron (SMN) gene to the motor neuron cells of patients with spinal muscular atrophy (SMA). It has been developed by AveXis, a Novartis company, and was approved in May 2019 in the USA for the treatment of paediatric patients aged <2years with SMA and bi-allelic mutations in the SMN1 gene (the primary gene encoding survival motor neuron protein). Onasemnogene abeparvovec is the first gene therapy to be approved for SMA in the USA. The recommended dose is 1.1 × 1014 vector genomes per kg of bodyweight, administered as a single intravenous infusion over 60min. Regulatory assessments for this formulation of onasemnogene abeparvovec are underway in the EU and Japan; an intrathecal formulation is currently undergoing clinical development in the USA. This article summarizes the milestones in the development of onasemnogene abeparvovec leading to this first approval for the treatment of paediatric patients aged <2years with SMA and bi-allelic mutations in SMN1.

Abstract CT118: CARPETS: A Phase I study of the safety and immune effects of an escalating dose of autologous GD2 chimeric antigen receptor-expressing peripheral blood T cells in patients with GD2-positive metastatic melanoma and refractory solid tumors

Abstract Background: Chimeric antigen receptor (CAR) T cells are genetically engineered to recognize tumor-associated antigens and have potent cytolytic activity against tumors. Adoptive therapy with CAR-T cells has been highly successful in B-cell malignancies but is yet to demonstrate significant clinical benefit in patients with solid tumors. Currently, we are conducting the CARPETS study (ACTRN12613000198729 at www.anzctr.org.au), which is a phase I clinical trial of third-generation GD2-specific CAR-T cells in metastatic melanoma patients at the Royal Adelaide Hospital. This is a world-first trial using CAR T-cell therapy for melanoma and combines a single intravenous infusion of CAR-T cells with standard kinase inhibitor therapy. In vitro correlative studies support cytolytic targeting of melanoma cells by the GD2-CAR-T cells but the ex vivo analyses of study patients’ post-infusion peripheral blood samples indicate poor CAR-T cell expansion and persistence with evidence of an exhausted T-cell phenotype. Further in vitro developmental work has resulted in optimized CAR-T cell manufacturing conditions that now favour generation of GD2-CAR-T cells with a dominant memory phenotype, which may have greater potential for long-term persistence in vivo. Methods:This trial is open but not recruiting while we await Human Research Ethics Committee approval of a clinical protocol amendment, which is expected by March 2019. Currently, six patients have been recruited of a planned enrolment of 12 patients. Dose escalation has proceeded through three dose levels using a Bayesian continual reassessment method. No dose limiting toxicities were observed in the previously enrolled cohorts. Under the proposed protocol amendment, the remaining six patients will be recruited with eligibility broadened to include other adult GD2-positive malignancies such as bony and soft tissue sarcomas, small cell lung cancer, and triple negative breast cancer. In future correlative studies, the purpose of the additional patient recruitment will be to compare the in vivo expansion and persistence of GD2-CAR-T cells, which will now be manufactured to carry the favorable memory phenotype, with previously transferred GD2-CAR-T cells, the manufacture of which was associated with the unfavorable exhausted phenotype. Because of the potential risk of additional toxicity conferred by the altered ex vivo CAR-T cell manufacturing conditions, dose escalation will proceed from dose level 2 and lympho-depleting chemotherapy will not be given. The next data analysis will be related to completed dose escalation using CAR-T cell products manufactured according to the new conditions. Citation Format: Michael Brown, Tessa Gargett. CARPETS: A Phase I study of the safety and immune effects of an escalating dose of autologous GD2 chimeric antigen receptor-expressing peripheral blood T cells in patients with GD2-positive metastatic melanoma and refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT118.

Bone Marrow-Derived Stem Cells as a Cytotherapy for Sirolimus-Induced Periodontal Ligament and Alveolar Bone Injury in a Rat Model

Background: Sirolimus is known to be the most common immunosuppressive and anti-cancer drug regardless to its adverse side effects. Bone marrow derived -mesenchymal cells represent a great interest, particularly in the areas of regenerative medicine. Aim of the study: The current research aimed to examine the efficacy of stem cell transplantation for treating the periodontal ligament and alveolar bone affection that caused by Sirolimus.Materials and methods: Fifty male albino rats with average body weight 200-250 gram were used in this investigation. The animals were divided into the following groups: Group I: 20 rats served as controls and subdivided into 2 subgroups 10 animals each: Group I.1: Using a curved metallic oral gavage, ethanol and saline were given in a daily oral dose of 10 mg/kg body weight to Group I.1 for 3 months. Group I.2: treated with the same way as group I.1 then left untreated for 2 weeks Group II: 20 animals subdivided into 2 subgroups, 10 animals each: Group II.1 (Sirolimus group) treated with immunosuppressive drug (Rapamycin) dissolved in ethanol and saline in a daily oral dose of 10 mg/kg body weight using a curved metallic oral gavage for 3 months. Group II.2: (Recovery group) treated with the same dose and route of administration of group II.1 for 3 months then left untreated for 2 weeks as a recovery period. Group III: 10 rats treated with the same dose of Rapamycin in group II then injected by a single intravenous infusion of mesenchymal bone marrow stem cells. For bone marrow- mesenchymal cells isolation and culture, ten adult male albino rats were used as a source of bone marrow. At the end of experiment, the rats were sacrificed, the jaws of rats were dissected out and processed to be stained with: Hematoxylin and eosin staining for histological examination. Streptavidin-biotin immunohistochemical method for Vimentin and CD44 localization for stem cells characterization and homing detection respectively and streptavidin-biotin immunohistochemical method of Bcl2 for anti-apoptotic expression detection. Results: Sirolimus showed dramatic degenerative changes on the periodontal ligaments and alveolar bone, however the transplanted stem cell helped tissues to partially retain their texture and accelerate their healing. Conclusion Sirolimus caused severe adverse effects on the periodontal ligaments and alveolar bone which did not resolved after recovery period of 2 weeks, however, the degeneration was more dramatic. Interestingly, bone marrow- derived stem cells transplantation represented a promising attempt to overcome the Sirolimus drawbacks.

Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE)

ABSTRACT Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78–1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555

Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

IntroductionTo investigate the absolute bioavailability of esaxerenone and the effects of food on its pharmacokinetics (PK) after a single oral dose in healthy Japanese subjects.MethodsTwenty-four Japanese males aged 20–45 years were randomised to six groups (each n = 4) in this single-centre, open-label, three-way, three-period crossover study. Esaxerenone (5 mg) was administered in the fasting state as a single oral dose, single intravenous infusion over 1 h, or in the postprandial state as a single oral dose. Plasma samples were taken before and during the 96 h after drug administration. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry. PK parameters were calculated using noncompartmental analysis, and safety was assessed.ResultsAfter fasting intravenous administration, total body clearance was 3.69 L h−1 and volume of distribution was 92.7 L. The plasma concentration–time profile of esaxerenone was similar after fasting and postprandial administration. Absolute bioavailability of a single oral 5-mg dose of esaxerenone was 89.0% in the fasting state and 90.8% postprandially. Point estimates (1.010 and 1.019, respectively) and 90% confidence intervals for geometric least squares mean peak plasma concentrations and area under the plasma concentration–time curve ratios after postprandial versus fasting oral esaxerenone were within the prespecified range (0.80, 1.25). No severe adverse events occurred throughout the study.ConclusionsEsaxerenone has a high absolute bioavailability of approximately 90% and food has no effect on esaxerenone PK after a single oral dose of 5 mg in healthy Japanese subjects. Additionally, no safety concerns were identified.Clinical Trial RegistrationJapicCTI No. 163452.FundingDaiichi Sankyo Co., Ltd.

HD204: Analytical biocomparability and clinical trial I progression of bevacizumab.

e15014 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar of the EU-approved and US-licensed Bevacizumab (Avastin) that is approved treatment for a variety of tumour types. Bevacizumab is a recombinant humanized monoclonal antibody (IgG1) that binds to soluble vascular endothelial growth factor (VEGF), thus prevent interaction with VEGF receptors. Due to heterogeneity nature of antibody drug, extensive characterization of antibody from physicochemical and biological properties using multiple bioanalytical assays is required. The development of HD204 from analytical biocomparability to clinical trial I are demonstrated. Methods: Analytical biocomparability in physiocochemical and biological properties of HD204 was compared to Avastin sourced from EU and US using multiple bioanalytical assays as below. Clinical phase I (SAMSON), a randomized, double-blind, single dose and 3-way parallel group was initiated recently to compare pharmacokinetic and to evaluate the safety, tolerability and immunogenicity of HD204, EU-Avastin and US-Avastin. Approximately 120 healthy human subjects (assigned to 3 treatment group) was administered with a single intravenous infusion of 1 mg/kg of either HD204, EU- and US-Avastin. Results: HD204 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. For phase I study, patient recruitment was completed with treatment for come patients initiated but still ongoing. Conclusions: HD204 was shown to be equivalent in all parameters in the analytical biocomparability testing. Clinical Phase 1 trial (SAMSON) is ongoing on and key data from SAMSON trial will be reported in ASCO meeting. [Table: see text]

Staccato pulse interleukin-2 (IL-2) in metastatic melanoma (MM) previously treated with checkpoint inhibitors (CPI).

e21022 Background: The CPI ipilimumab, nivolumab, and pembrolizumab have been adopted into common use for patients (pts) with MM. While their clinical activity is undeniable, a substantial fraction of pts treated with these agents experience disease progression. Additional approaches are therefore needed. Intravenous IL-2 given via daily single intravenous infusions (pulses) has been developed to mitigate toxicity while maintaining anticancer activity against MM. Staccato pulse IL-2 is based on three prior observations. Daily IL-2 schedules have previously been demonstrated to induce Lymphokine Activated Killer cell (LAK) activity [Mitchell, 1989]. LAK generated by IL-2 then subsequently exposed to more IL-2 display enhanced cytotoxicity in vitro [Hank, 1990]. Increased numbers of LAK are seen in pts with melanoma treated with daily IL-2 [Quan, 2011]. Methods: In this retrospective study, ten pts with MM were treated with IL-2 18 Million IU/M2 intravenously over 15-30 minutes on days 1-3 and 21.6 Million IU/M2 intravenously over 15-30 minutes on day 5 on an outpatient basis. Cycles were repeated every 3 weeks. Results: Characteristics: 8 females/ 2 males, median age-56 (range: 21-74), median ECOG-1 (0-1); common disease sites: lymph nodes (12), subcutaneous (6), lungs (5), soft tissue (4). Prior CPI: Ipilimumab (8); Pembrolizumab (5); Nivolumab (2). Common toxicities: nausea/emesis (8), myalgia/arthralgia (5), sinus/catarrhal symptoms (5), fatigue (5), and hypotension requiring intravenous fluids (5). No pts required hospitalization for toxicity related to therapy. Median number of cycles: 3 (2-8). Four pts have had partial responses (total response rate = 40%; 95% CI: 10-70%). The median duration of response exceeds 7.4+ months. One pt having had resolution of prior lung, lymph node, and peritoneal metastases (partial response of 24.5+ months) underwent surgical resection of the residual intraabdominal disease focus and is free of disease at 36.5+ months. Overall, responses have occurred in lung, lymph nodes, subcutaneous, bones, peritoneum, small bowel, and soft tissue sites. Conclusions: Staccato pulse intravenous IL-2 has activity in melanoma pts previously treated with CPI.

Usefulness of an Initial Single Intravenous Immunoglobulin Infusion with Delayed Use of Aspirin against Kawasaki Disease Relapse: A Single-Center Retrospective Study

Background: Kawasaki Disease (KD) relapse is a risk factor for Coronary Artery Lesion (CAL) development. However, the frequency and outcomes of patients with relapse remain unclear. Objective: To determine the frequency and outcomes of patients with KD relapse and to ascertain the usefulness of treatment with initial single intravenous immunoglobulin (IVIG) therapy (2g/kg) with delayed use of aspirin (DUA). Materials and Methods: The outcomes of 207 patients who underwent initial single IVIG therapy at 2 g/ kg/ dose with DUA for KD were analyzed retrospectively. The patient data were divided according to whether the patients had relapses (relapse group, n=5) or not (non-relapse group, n=202). KD presentations were considered as relapses when a second episode appeared within 2 months of the first one. Stat Flex version 6 for Windows was used for all statistical analyses. Chi-square, Fisher’s exact, and Mann-Whitney U tests were used as appropriate, with sample size considerations. Results: The frequency of patients with disease relapse was 2.4%. The five patients who experienced relapses (two boys and three girls; median age, 10 months; range, 3 months to 3 years 11 months) received initial IVIG therapy at 5 days of illness. The median day of illness for the relapse was 16 (range, 12-29). No patients with disease relapse developed CAL. The rate of incomplete type, IVIG resistance and CAL, and timing of initial IVIG therapy with regard to the days of illness were similar between the relapse group and the non-relapse group. Three parameters, including serum C-reactive protein, albumin values, and Neutrophil-to-Lymphocyte ratio (NLR) before and after initial IVIG, were similar between the two groups. Although not statistically significant (P=0.055), the median NLR after initial IVIG therapy of the relapse group was higher than that of the non-relapse group (2.48 vs. 0.84). Conclusion: An initial single IVIG therapy (2g/ kg/ dose) with DUA for KD may lead to a low KD relapse frequency and to favorable patient outcomes.

Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

Modulation of Renal Parenchyma in Response to Allogeneic Adipose-Derived Mesenchymal Stem Cells Transplantation in Acute Kidney Injury.

Background and ObjectivesIn regenerative medicine, mesenchymal stem cells derived from adipose tissues (Ad-MSCs) are a very attractive target to treat many diseases. In relation to nephrology, the aim of the current study is to investigate the effects of Ad-MSCs for the amelioration of acute kidney injury and to explore the mechanism of renal parenchymal changes in response to allogeneic transplantation of Ad-MSCs.Methods and ResultsThe nephrotoxicity was induced by cisplatin (CP) in balb/c mice according to RIFLE Class and AKIN Stage 3. PCR, qRT-PCR and fluorescent labeled cells infusion, histopathology, immunohistochemistry, functional analyses were used for genes and proteins expressions data acquisition respectively. We demonstrated that single intravenous infusion of 2.5×107/kg mAd-MSCs in mice pre-injected with CP recruited to the kidney, restored the renal structure, and function, which resulted in progressive survival of mice. The renal tissue morphology was recovered in terms of diminished necrosis or epithelial cells damage, protein casts formation, infiltration of inflammatory cells, tubular dilatation, and restoration of brush border protein; Megalin and decreased Kim-1 expressions in mAd-MSCs transplanted mice. Significant reduction in serum creatinine with slashed urea and urinary protein levels were observed. Anti-BrdU staining displayed enhanced tubular cells proliferation. Predominantly, downgrade expressions of TNF-α and TGF-β1 were observed post seven days in mAd-MSCs transplanted mice.ConclusionsAd-MSCs exerts pro-proliferative, anti-inflammatory, and anti-fibrotic effects. Ad-MSCs transplantation without any chemical or genetic manipulation can provide the evidence of therapeutic strategy for the origin of regeneration and overall an improved survival of the system in functionally deprived failed kidneys.