scholarly journals Safety and Immunogenicity of Nanocovax, a SARS-CoV-2 Recombinant Spike Protein Vaccine

2021 ◽  
Author(s):  
Thuy P Nguyen ◽  
Quyet Do ◽  
Lan T Lan ◽  
Duc V Dinh ◽  
Hiep Khong ◽  
...  
Keyword(s):  
Adverse Events ◽  
Aluminum Hydroxide ◽  
Dose Escalation ◽  
Phase 1 ◽  
Vaccine Safety ◽  
Antibody Responses ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
To Receive ◽  
Trial Phase

Background Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. Methods We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 microgram (mcg), 50 mcg, and 75 mcg doses, aluminum hydroxide adjuvanted). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2 which involved in 560 healthy adults, the primary outcomes are vaccine safety; and anti-S IgG antibody response. Secondary outcomes were surrogate virus neutralization, wild-type SARS-CoV-2 neutralization, and T-cell responses by intracellular staining (ICS) for interferon gamma (IFNg). We performed primary analyses at day 35 and day 42. Results For phase 1 study, no serious adverse events (SAE) were observed for all 60 participants. Most adverse events (AE) were grade 1 and disappeared shortly after injection. For phase 2 study, after randomization, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive placebo. Reactogenicity was absent or mild in the majority of participants and of short duration (mean, ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. There was no statistical difference in antibody responses among dose strengths on Day 42, in terms of anti S-IgG level and neutralizing antibody titer. Conclusions Up to 42 days, Nanocovax vaccine was safe, well tolerated and induced robust immune responses. We propose using Nanocovax 25 mcg for Phase 3 to evaluate the vaccine efficacy. (Research funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04683484.)

scholarly journals Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD protein vaccine against COVID-19 in adults: pooled analysis of two randomized, double-blind, placebo-controlled, phase 1 and 2 trials

2020 ◽  
Author(s):  
Shilong Yang ◽  
Yan Li ◽  
Lianpan Dai ◽  
Jianfeng Wang ◽  
Peng He ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Phase 1 ◽  
Phase 2 ◽  
Protein Subunit ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Phase 2 Study ◽  
To Receive

SummaryBackgroundA safe and effective coronavirus disease 2019 (COVID-19) vaccine is urgently needed to control the ongoing pandemic. Although progress has been made recently with several candidates reporting positive efficacy results, COVID-19 vaccines developed so far cannot meet the global vaccine demand. We developed a protein subunit vaccine against COVID-19, using dimeric form of receptor-binding domain (RBD) as the antigen. We aimed to assess the safety and immunogenicity of this vaccine in humans and determine the appropriate dose and schedule for an efficacy study.MethodsWe did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults aged 18-59 years were enrolled and randomly allocated to three groups to receive three doses of vaccine (25 μg or 50 μg RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 years were enrolled and randomly allocated to six groups to receive vaccine (25 μg or 50 μg RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the former 3 groups given two doses and the latter 3 groups given three doses, 30 days apart. For phase 1 trial, the primary outcome was safety, as measured by the occurrence of adverse events and serious adverse events. The secondary outcome was immunogenicity as measured by the seroconversion rate and magnitude of antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For phase 2 trial, the primary outcome included both safety and immunogenicity. These trials are registered with ClinicaTrials.gov, NCT04445194 and NCT04466085.FindingsBetween June 22 and September 15, 2020, 50 participants were enrolled to the phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-dose schedule. For both trials, local and systemic adverse reactions were absent or mild in most participants. There were no serious adverse events related to vaccine in either trial. After three doses, neutralizing antibodies were detected in all participants receiving either 25 μg or 50 μg dose of vaccine in phase 1 study, and in 97% (the 25 μg group) and 93% (the 50 μg group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 μg group and 117.8 for the 50 μg group in phase 1, and 102.5 for the 25 μg group and 69.1 for the 50 μg group in phase 2, exceeding the level of a panel of COVID-19 convalescent samples (GMT, 51). Vaccine induced balanced TH1 and TH2 responses. The 50 μg group did not show enhanced immunogenicity compared with the 25 μg group.InterpretationThe protein subunit vaccine ZF2001 is well-tolerated and immunogenic. The safety and immunogenicity data from phase 1 and 2 trials for ZF2001 support the use of 25 μg vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy.FundingNational Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical.

scholarly journals Proposal for a new therapeutic high dosage of Pidotimod in children with Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: an observational study.

2020 ◽  
Author(s):  
Sara Manti ◽  
Federica Filosco ◽  
Giuseppe Fabio Parisi ◽  
Giuseppe Germano Finocchiaro ◽  
Maria Papale ◽  
...  
Keyword(s):  
Adverse Events ◽  
Periodic Fever ◽  
Phase 1 ◽  
Aphthous Stomatitis ◽  
Potential Treatment ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Group A ◽  
Pfapa Syndrome ◽  
Group B

Abstract Background. Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome.Methods. 22 children with PFAPA syndrome were randomly allocated to treatment with Pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5-1 mg on need (group A) or betamethasone 0.5-1 mg on need (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, tonsillitis, and aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment.Results. Patients receiving Pidotimod and betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of tonsillitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups.Conclusions. We firstly showed that high dosage of Pidotimod is an effective and safe to reduce the PFAPA attacks in children.

Phase 2 study of zanubrutinib (BGB-3111) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7568-TPS7568
Author(s):  
Stephen Opat ◽  
Robert Marcus ◽  
Craig Anthony Portell ◽  
William Reed ◽  
Melannie Co ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase 1 ◽  
Critical Role ◽  
Safety Data ◽  
Drug Discontinuation ◽  
Phase 2 ◽  
Open Label ◽  
Serious Adverse Events ◽  
Major Hemorrhage

TPS7568 Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, mediating B-cell proliferation, migration, adhesion and survival. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MZL. In preclinical studies, zanubrutinib was shown to be a potent, irreversible, highly specific BTK inhibitor with excellent oral bio-availability and favorable pharmacokinetic/pharmacodynamic properties. Clinical data to date have shown that complete and sustained 24-hour BTK occupancy is associated with durable responses and suggested that zanubrutinib is generally well tolerated with low rates of serious adverse events. Preliminary results from the MZL cohort enrolled in the open-label, multicenter, phase 1 study demonstrated responses in 7 of 9 patients for an overall response rate (ORR) of 78%. Cumulative safety data also showed that zanubrutinib monotherapy was associated with infrequent incidence of atrial fibrillation and major hemorrhage and infrequent drug discontinuation due to treatment-related adverse events. This study is designed to evaluate the safety and efficacy of zanubrutinib in patients with R/R MZL. Methods: This ongoing global phase 2, single-arm, open-label study is examining zanubrutinib monotherapy in patients with R/R MZL who have received one or more prior lines of systemic therapy. Patients are treated with oral zanubrutinib at 160 mg twice-daily until progressive disease, unacceptable toxicity, or withdrawal of consent. Eligible patients must have histologically confirmed MZL, have received prior anti-CD20 antibody therapy, and have measurable disease. Disease response is assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The primary endpoint is ORR determined by independent review committee (IRC). Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), and overall survival and safety. Recruitment is ongoing.

Phase 1 Clinical Trial of a Novel Proteasome Inhibitor (NPI-0052) in Patients with Lymphomas and Solid Tumors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4504-4504
Author(s):  
Razelle Kurzrock ◽  
Paul Hamlin ◽  
Anas Younes ◽  
David Hong ◽  
Michael Gordon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Elimination Half

Abstract NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity in multiple myeloma, lymphoma, leukemia and solid tumor models. Phase 1 dose escalation studies are ongoing in patients with myeloma, lymphomas and solid tumors. Data from the Phase 1 study in patients with lymphomas or solid tumors are presented herein to examine the endpoints of pharmacodynamics (proteasome inhibition), pharmacokinetics and safety at doses below the MTD. Patients in this study were treated with NPI-0052 administered as a weekly IV bolus, for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. In addition to weekly safety monitoring, proteasome inhibition and pharmacokinetics were assayed after the 1st and 3rd dose and with intrapatient dose escalations. Sixteen patients have been treated at doses ranging from 0.0125 mg/m2 to 0.112 mg/m2 for up to 7 cycles without reaching an MTD. Although, one SAE of MRSA sepsis and renal failure was reported at a dose of 0.1 mg/m2, drug related adverse events have not been reported at 0.112 mg/m2. Proteasome inhibition in whole blood has been assayed from 0.0125 mg/m2 through 0.075 mg/m2, with results ranging from no inhibition to 63% inhibition of CT-L activity and indication of a correlation of inhibition with dose, inclusive of intrapatient dose increases. Preliminary pharmacokinetic data demonstrate a rapid elimination half-life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L. No responses have been confirmed, however, 4 patients have had stable disease for 4 or more months, including patients with hepatocellular carcinoma (6 months), adenoid cystic carcinoma (4 months and 4 months), and cervical carcinoma [7 months with investigator reported complete resolution of target (lymph node) lesion(s) to palpation]. These data suggest that NPI-0052 is affecting parameters relevant to pharmacodynamics, pharmacokinetics and potentially clinical benefit at doses below the MTD. Dose escalation continues to define a recommended phase 2 dose and further investigate the relevance of these outcomes in larger Recommended Phase 2 Dose Cohorts.

scholarly journals A Phase 1 Study of TP-3654, an Orally-Delivered PIM Kinase Inhibitor, in Patients with Intermediate-2 or High-Risk Primary or Secondary Myelofibrosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Claudia Lebedinsky ◽  
Stephen P. Anthony ◽  
Golam Mohi ◽  
Huyuan Yang ◽  
Jian Mei ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Dose Escalation ◽  
Peripheral Blood ◽  
Phase 1 ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Phase 1 Study ◽  
To Receive

Background: Myelofibrosis (MF) is characterized by bone marrow fibrosis (BMF) and ineffective extramedullary hematopoiesis resulting in splenomegaly and debilitating symptoms. An activating Janus kinase 2 (JAK2) mutation (V617F) has been frequently observed in MF. Ruxolitinib (a JAK1/JAK2 inhibitor) reduces splenomegaly and improves constitutional symptoms, but appears to offer a modest reduction of BMF. Patients with MF who are intolerant to JAK inhibitors or their components, or for whom JAK inhibitors have failed, have limited treatment options. The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine kinases are overexpressed in hematological malignancies. Because PIM kinase expression is regulated by JAK2 signaling, PIM kinase inhibition is a potential therapeutic target for JAK2 mutant-driven malignancies, such as MF. TP-3654, an investigational agent, has been shown to reduce proliferation and increase apoptosis in murine and human hematopoietic cells expressing the JAK2V617F mutation. TP-3654 alone reduced leukocytosis and spleen size in an in vivo murine model of JAK2V617F-induced MF, as well as an apparent reduction of BMF. A phase 1 study is being conducted to evaluate TP-3654 monotherapy in patients with MF. Study Design and Methods: This phase 1, multicenter, dose-escalation, open-label study is evaluating TP-3654 monotherapy in patients with MF who previously failed a JAK inhibitor or who are ineligible to receive ruxolitinib or fedratinib (NCT04176198). Primary objectives are to determine the incidence of dose-limiting toxicities (DLT) at escalated doses of TP-3654 and treatment emergent adverse events. Secondary objectives are to determine QT interval changes, establish the pharmacokinetic profile, and assess preliminary disease activity. Exploratory objectives are pharmacodynamic markers in peripheral blood and bone marrow biopsy samples. Eligible patients have a primary or secondary MF (post-polycythemia vera-MF/post-essential thrombocythemia-MF) based on the World Health Organization diagnostic criteria and intermediate-2 or high-risk primary or secondary MF based on the Dynamic International Prognostic Scoring System; previously failed, or are ineligible to receive, treatment with a JAK inhibitor; grade ≥2 MF, as confirmed by BM biopsy ≤12 weeks prior to screening; have a platelet count >50x109/L, absolute neutrophil count ≥1x109/L, hemoglobin level ≥8 g/L, peripheral blood blast counts <10%, Eastern Cooperative Oncology Group performance status ≤2, life expectancy ≥3 months, and adequate renal and hepatic function; have spleen length ≥5 cm by palpation or spleen volume ≥450 cm3 by computerized tomography/magnetic resonance imaging, and show ≥2 measurable symptoms per the MF Symptom Assessment Form, version 4.0. Patients must not have received prior systemic antineoplastic therapy or any experimental therapy within 14 days or 5 half-lives before TP-3654; had major surgery ≤2 weeks before first study dose; have had splenic irradiation ≤6 months prior to screening; have acute myeloid leukemia or myelodysplastic syndrome; or had prior stem cell transplantation (SCT) or be eligible for allogeneic bone marrow or SCT. Enrollment of approximately 50 patients is planned. Patients will receive oral TP-3654. Dose-escalation will be performed using a Bayesian logistic regression model with escalation with overdose control. Adverse events occurring during the first cycle will be considered in the determination of the maximum tolerated dose (MTD). Dose escalation will continue until identification of the MTD or a suitable recommended phase 2 dose. This study is currently recruiting patients. Disclosures Lebedinsky: Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Anthony:Exact Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Mohi:Tolero Pharmaceuticals Inc.: Research Funding. Yang:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Mei:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Braendle:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment.

scholarly journals The Safety of Novel Drugs Targeting Factor XI and XII in Human Clinical Trials:a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4966-4966
Author(s):  
Gillian E Mair ◽  
Sven Reid Olson ◽  
Joseph J Shatzel
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Adverse Events ◽  
Dose Escalation ◽  
Phase 1 ◽  
Postoperative Bleeding ◽  
Phase 2 ◽  
Risk Of Bleeding ◽  
Novel Drugs ◽  
Contact Pathway

Introduction While effective at treating and preventing thrombosis, modern forms of anticoagulation universally increase the risk of hemorrhage. Data suggests that factors FXI and FXII could serve as druggable targets to provide anticoagulation without increasing the risk of bleeding. The purpose of this systematic review is to evaluate the safety of novel drugs targeting FXI and FXII in human clinical trials. Methods We performed a search in Ovid MEDLINE to identify published manuscripts describing administration of contact pathway-inhibiting drugs to humans. All human clinical trials evaluating a drug specific to FXI or FXII were included. Outcomes of interest collected for analysis included primarily bleeding events of any type, total adverse events (AEs)as well as other treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE). Results A total of 338 published articles were identified from the original search. After screening, one phase 2 study of an antisense oligonucleotide (ISIS 416858) and three phase 1 trials of monoclonal antibodies (AB023, BAY1213790, MAA868) were included. A total of 465 patients across these 4 clinical trials were included. No patients experienced spontaneous bleeding. Postoperative bleeding occurred in 3% of patients treated with ISIS 416858 at each dose level and one patient experienced major bleeding. For comparison an 8% postoperative bleeding rate was seen in the arm treated with prophylactic low molecular weight heparin (LMWH). AB023, a monoclonal antibody inhibiting FXIIa-mediated activation of FXI to FXIa, was examined in a phase 1, dose-escalation trial in 21 healthy adults. Overall, there were no severe AEs. Minor AEs occurred in 10 of the 21 patients. 3 patients were deemed to possibly have TRAE. There was no statistical difference in bleeding time compared to placebo. activated thromboplastin time (aPTT) was prolonged for over a month after the highest dose level. BAY1213790 is a monoclonal antibody targeting the enzymatic active site of FXIa, and was studied in a phase 1 dose escalation trial in 83 healthy men. There were no severe AEs. Of the 54 subjects experiencing AEs, 34 were mild and 20 were moderate. TRAE were reported in 6 subjects. One subject had an infusion reaction and another subject requested the infusion be stopped. APTT showed a dose-dependent increase while bleeding times also did not increase compared to placebo. ISIS 416858 is an antisense oligonucleotide targeting FXI mRNA for degradation at its source within the hepatocyte. ISIS416858 was studied in a phase 2, randomized controlled trial in patients undergoing total knee arthroplasty. The safety and efficacy at preventing post-operative venous thromboembolism (VTE) was assessed at 200 mg or 300 mg doses compared to standard-of-care with LMWH. Bleeding occurred in 4 (3%), 2 (3%), and 6 (8%) patients in these three study groups, respectively. This was the only study drug where one patient experienced major bleeding. Mild AEs affected 219 subjects, with severe AEs occurring in 4 patients; only 2 discontinued ISIS416858. Patients in the 300 mg dose cohort of ISIS416858 experienced statistically fewer VTE events compared with LMWH; bleeding rates were numerically low compared to LMWH (3% vs 8%), though statistical significance was not reached. MAA868 is a monoclonal antibody targeting both the zymogen and active forms of FXI at the enzymatic active site, and was studied in a phase 1, dose-escalation clinical trial. MAA868 is unique due to its subcutaneous route of administration. Of the total 61 patient cohort, 34 patients experienced AEs and 9 TRAE. Only 2 severe, unrelated AEs occurred after the trial: one fatal cardiac arrest after elective surgery, and a gunshot wound requiring urgent surgery. MAA868 resulted in prolonged FXI suppression for up to four weeks. Conclusion Contact pathway-inhibiting drugs show promise as novel anticoagulation strategies that could significantly reduce the risk of bleeding seen with traditional anticoagulants. Additional studies are needed to further develop these drugs to test their efficacy at targeting the coagulation pathway in common settings of high risk for VTE, or existing thrombosis. The paradigm that anticoagulants cause bleeding could be broken in the near future based on this promising clinical data on contact pathway inhibition. Table Disclosures Shatzel: Aronora, Inc.: Consultancy.

Results of a Phase 1/2 Study for KW-0761, a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4), In CTCL Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 962-962 ◽  
Author(s):  
Madeleine Duvic ◽  
Lauren Pinter-Brown ◽  
Francine M Foss ◽  
Lubomir Sokol ◽  
Jeffrey Jorgensen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Chemokine Receptor ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Open Label ◽  
Serious Adverse Events ◽  
Cc Chemokine ◽  
Overall Response

Abstract Abstract 962 Introduction: KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is over expressed in PTCL and CTCL, and is a potential target for anti-neoplastic therapy in these disorders. Study Design: This multicenter, open-label, dose escalation phase 1/2 study is in patients with previously treated PTCL and CTCL (including MF and SS). The study is composed of a dose escalation phase (Phase 1) and preliminary assessment of safety and efficacy (Phase 2). The phase 1 portion is a standard 3+3 design at doses of 0.1, 0.3, and 1 mg/kg. In the first treatment course, KW-0761 is administered i.v. once a week for four weeks, followed by a 2-week observation period. Subjects demonstrating a response or maintaining stable disease may receive additional infusions of KW-0761 every other week until progression or withdrawal from study. For CTCL patients, the overall global response score is a composite of response in all compartments (skin, lymph nodes, viscera). For subjects with Sezary Syndrome (SS), response in blood is also considered for overall response. For PTCL patients, the response is based on criteria defined by the International Working Group (IWG). Results: Forty-two patients who had received at least one prior systemic therapy (median 5; range 1–17) are enrolled. The median age is 67 (range: 35–85) years with more males (57%) than females (43%). A total of 40 patients received at least four doses of KW-0761 at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3) and 1 mg/kg (n=34). There are no dose limiting toxicities (DLT) or drug-related serious adverse events (SAEs) reported in the dose escalation portion of the study. Most observed adverse events (AEs) are mild to moderate in severity. There does not appear to be any dose relationship with the incidence or severity of the AEs. The most frequent AEs are chills, headache, nausea, pyrexia, infusion related reactions and back pain. There does not seem to be an increase in the rate of infections associated with the use of this drug. Six of 42 patients who received at least one dose of KW-0761 developed a new skin eruption not consistent with the patients' underlying disease, including one grade 3 hypersensitivity rash with eosinophils. No significant hematologic AEs have been observed except for lymphopenia which is due to the pharmacologic effect of the drug. A total of 38 patients (23 with MF; 15 with SS) are evaluable for efficacy (only one subject with PTCL was enrolled and is not included in this analysis). A summary of all patients evaluable for efficacy to date is presented in the table belowa: Conclusions: KW-0761 is well tolerated at doses of 0.1–1.0 mg/kg. The MTD has not been reached in this study. The overall response rate is 39% for all patients in the phase 1/2 trial with a higher rate in SS patients (47%) versus MF patients (35%). Additionally, 12 of 15 SS patients had a response in the blood, including 7 CRs. These promising results warrant further clinical studies using KW-0761 in refractory or relapsed CTCL patients. Disclosures: Duvic: Kyowa-kirin-pharma.com: Consultancy, Research Funding. Pinter-Brown:Kyowa-Kirin: Consultancy, Research Funding. Foss:Kyowa-Kirin: Consultancy, Research Funding. Sokol:Kyowa-Kirin: Research Funding. Jorgensen:Kyowa Hakko Kirin Co, Ltd.: Research Funding. Spitalny:Kyowa-Kirin: Employment. Kim:Kyowa-Kirin: Consultancy, Research Funding.

scholarly journals A Randomized Phase 2 Study of VT-1161 for the Treatment of Acute Vulvovaginal Candidiasis

2020 ◽  
Author(s):  
Stephen R Brand ◽  
Jack D Sobel ◽  
Paul Nyirjesy ◽  
Mahmoud A Ghannoum ◽  
Robert J Schotzinger ◽  
...  
Keyword(s):  
Adverse Events ◽  
Vulvovaginal Candidiasis ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Once Daily ◽  
Treatment Groups ◽  
Phase 2 Study ◽  
Dose Levels ◽  
To Receive

Abstract Background Acute vulvovaginal candidiasis (VVC) is common among women, but current azole antifungal treatments are often associated with safety and resistance issues. VT-1161 (oteseconazole) is an oral agent with increased selectivity for fungal CYP51. In this phase 2 clinical study, we evaluated the efficacy and safety of VT-1161 vs fluconazole in participants with moderate to severe acute VVC. Methods Participants presenting with an acute episode of VVC (n = 55) were randomized to receive VT-1161 300 mg once daily (q.d.) for 3 days, 600 mg q.d. for 3 days, or 600 mg twice daily (b.i.d.) for 3 days or to receive a single dose of fluconazole 150 mg (FDA-approved dose to treat acute VVC). Participants were followed for 6 months. The primary outcome was the proportion of participants with therapeutic (clinical and mycological) cure at day 28. Results A larger proportion of participants in the per-protocol population experienced therapeutic cure in the VT-1161 300 mg q.d. (75.0%), VT-1161 600 mg q.d. (85.7%), and VT-1161 600 mg b.i.d. (78.6%) groups vs the fluconazole group (62.5%); differences were not statistically significant. At 3 and 6 months, no participants in the VT-1161 groups vs 28.5% and 46.1% in the fluconazole group, respectively, had evidence of mycological recurrence. No serious adverse events or treatment-emergent adverse events leading to discontinuation were reported. Conclusions The majority of participants across all treatment groups achieved therapeutic cure at day 28. VT-1161 was well tolerated at all dose levels through 6 months of follow-up. Clinical Trials Registration NCT01891331.

scholarly journals Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial

2017 ◽  
Vol 4 (4) ◽  
pp. e367 ◽  
Author(s):  
Christopher LaGanke ◽  
Lawrence Samkoff ◽  
Keith Edwards ◽  
Lily Jung Henson ◽  
Pavle Repovic ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Controlled Study ◽  
Antibody Treatment ◽  
Double Blind ◽  
Semaphorin 4D

Objective:To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS.Methods:Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation.Results:VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment–related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 μg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance.Conclusions:These results support the continued investigation of VX15/2503 in neurodegenerative diseases.ClinicalTrials.gov identifier:NCT01764737.Classification of evidence:This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference −0.7%, 95% CI −28.0% to 32.7%).

A Phase 1 Study of Safety, Tolerability and Pharmacokinetics of Single Ascending Doses of a First in Human Engineered Cationic Peptide, PLG0206, Intravenously Administered in Healthy Subjects

2021 ◽  
Author(s):  
David Huang ◽  
Despina Dobbins ◽  
Parviz Ghahramani ◽  
Ian Friedland ◽  
Jonathan Steckbeck
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Dose Range ◽  
Human Study ◽  
Serious Adverse Events ◽  
Cationic Antimicrobial Peptide ◽  
Post Infusion ◽  
Life Threatening ◽  
To Receive

Background : In this first in human study, PLG0206, a novel engineered cationic antimicrobial peptide was evaluated for safety, tolerability and pharmacokinetics when intravenously administered as a single dose to healthy subjects. Methods : Six cohorts of 8 subjects received escalating single IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1-to-4-hours. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 hours post infusion. Safety and tolerability were assessed throughout the study. Results : The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment emergent adverse events (TEAE) related to PLG0206 was low and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion related reactions, which were mitigated with increasing infusion time and volume. There were no serious adverse events (SAE), life-threatening events, or deaths throughout the study. IV PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t ½ ) ranged from 7.37 to 19.97 hours. Conclusion : Following a single IV infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of IV PLG0206 as an antimicrobial agent.

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