Phase 1 Clinical Trial of a Conditionally Replication-Defective Human Cytomegalovirus (CMV) Vaccine in CMV-Seronegative Subjects

2019 ◽  
Vol 220 (3) ◽  
pp. 411-419 ◽  
Author(s):  
Stuart P Adler ◽  
Nicole Lewis ◽  
Anthony Conlon ◽  
Mark P Christiansen ◽  
Mohamed Al-Ibrahim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Injection Site ◽  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Phase 1 ◽  
Vaccine Dose ◽  
Genetically Engineered ◽  
Clinical Trial Registration ◽  
Viral Shedding

Abstract Background A conditionally replication-defective human cytomegalovirus (CMV) vaccine (V160) derived from AD169 and genetically engineered to express CMV pentameric complex (gH/gL/pUL128/pUL130/pUL131) was developed and evaluated for phase 1 vaccine safety and immunogenicity in CMV-seronegative and CMV-seropositive adults. Methods Subjects received 3 doses of V160 or placebo on day 1, month 1, and month 6. Four vaccine dose levels, formulated with or without aluminum phosphate adjuvant, were evaluated. Injection-site and systemic adverse events (AEs) and vaccine viral shedding were monitored. CMV-specific cellular and humoral responses were measured by interferon-gamma ELISPOT and virus neutralization assay up to 12 months after last dose. Results V160 was generally well-tolerated, with no serious AEs observed. Transient, mild-to-moderate injection-site and systemic AEs were reported more frequently in vaccinated subjects than placebo. Vaccine viral shedding was not detected in any subject, confirming the nonreplicating feature of V160. Robust neutralizing antibody titers were elicited and maintained through 12 months postvaccination. Cellular responses to structural and nonstructural viral proteins were observed, indicating de novo expression of viral genes postvaccination. Conclusions V160 displayed an acceptable safety profile. Levels of neutralizing antibodies and T-cell responses in CMV-seronegative subjects were within ranges observed following natural CMV infection. Clinical Trial Registration . NCT01986010.

scholarly journals Phase 1 Clinical Trial of a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S308-S309 ◽  
Author(s):  
Stuart Adler ◽  
Nicole Lewis ◽  
Anthony Conlon ◽  
Mark Christiansen ◽  
Mohamed S Al-Ibrahim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Injection Site ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Aluminum Phosphate ◽  
Post Dose ◽  
Viral Shedding ◽  
Vaccine Type ◽  
Dose Levels ◽  
Research Grant

Abstract Background Congenital CMV remains an unmet medical need worldwide. Naturally acquired CMV immunity in women prior to pregnancy has been shown effective in reducing maternal-fetal transmission. V160 is engineered as a replication-defective CMV, and its replication in culture is controlled by a synthetic chemical. V160 can’t replicate in humans but it maintains all virological properties for presentation of viral antigens, including gH/gL/pUL128-131 pentameric complex, important for potent neutralizing antibodies (NABs). Methods Approximately 190 CMV seronegative and seropositive adults at study entry received 3 doses of V160 or placebo administered via intramuscular (IM) or intradermal (ID) route on Day 1, Month 1, and Month 6. Four antigen levels (10, 30, 100, and 250 units per dose) formulated with or without aluminum phosphate adjuvant were evaluated. In each vaccination group, approximately 10 and 4 subjects received study vaccine and placebo, respectively. Injection site and systemic adverse events (AEs) were collected for 14 days after each vaccination. Serious AEs (SAEs) were assessed up to Month 18. Viral shedding (urine and saliva) were monitored up to Month 12. CMV-specific NABs and cell-mediated immune responses (CMI) were measured prior and 1 month after each vaccination, and at Months 12 and 18. Results During the study, no serious AEs were reported and only one CMV seropositive subject had non-vaccine type viral shedding. In both seronegative and seropositive cohorts, proportion of subjects who reported injection site AEs was higher in V160 recipients than placebo controls. Proportion of subjects who reported systemic AEs was comparable across V160 doses/formulations and placebo. In the CMV seronegative cohort, immune responses increased with incremental dosing. More importantly, recipients of V160 from several dose levels mounted NAB and CMI responses at 1 month post dose 3 (PD3) that were comparable to baseline levels measured in seropositive subjects. Conclusion V160 had acceptable safety profile across all dose levels and formulations studied; Vaccine was immunogenic and elicited NAB and CMI responses at 1 month PD3 that were comparable to natural CMV infection. Disclosures S. Adler, Merck: Investigator, Research grant. N. Lewis, Merck: Employee, Salary. A. Conlon, Merck: Employee, Salary. M. Christiansen, Merck: Investigator, Research grant. M. S. Al-Ibrahim, Merck: Investigator, Research grant R. Rupp, Merck: Investigator, Research grant. T. M. Fu, Merck: Employee, Salary. O. Bautista, Merck: Employee, Salary. H. Tang, Merck: Employee, Salary.T. Culp, Merck: Employee, Salary. R. Das, Merck: Employee, Salary. K. Beck, Merck: Employee, Salary. G. Tamms, Merck: Employee, Salary. L. Musey, Meck: Employee, Salary.

Phase II efficacy results using an oncolytic herpes simplex virus (NV1020) in patients with colorectal cancer metastatic to liver (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4089-4089
Author(s):  
S. K. Geevarghese ◽  
A. Chen ◽  
D. A. Geller ◽  
H. A. de Haan ◽  
A. Iagaru ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Salvage Chemotherapy ◽  
Primary Resection ◽  
Genetically Engineered ◽  
Hepatic Artery Infusion ◽  
Phase 2 ◽  
Best Response ◽  
Heavily Pretreated ◽  
Simplex Virus

4089 Background: NV1020 is a genetically engineered oncolytic Herpes virus. Published Phase 1 dose-ranging results reported no significant related toxicity except for a mild (<24 hr) viral syndrome. Initial Phase 2 tumor response data using the optimal biological dose (OBD) are now presented. Methods: Patients with heavily pretreated, progressing liver mCRC received 4 doses of NV1020 (1 X108 pfu) by weekly hepatic artery infusion followed by two cycles of conventional chemotherapy. Follow-up (≥1 year) evaluation included 4 X 3-monthly scans, then telephone contact to determine survival. Blinded, independent radiologists interpreted CT (modified RECIST) and FDG PET (EORTC) scans. Results: All 22 patients had prior 5FU-based treatment: 77% and 58% also had oxaliplatin or irinotecan, respectively (50% both agents); 86% had one targeted therapy (24% ≥2 such agents); 29% had radiofrequency ablation. Mean time from primary resection was 95 weeks, mean CEA was 182 ng/mL, and 55% had pulmonary lesions. Two patients received only 2 NV1020 infusions due to rapidly progressing disease. Virus tolerability was unchanged from Phase 1 and no related, serious or Grade 4 toxicity was found. NV1020 neutralizing antibodies rose in all patients but no NV1020 was shed (saliva, skin). After NV1020 alone, 10/22 (45%) and 8/20 (40%) on CT and PET, respectively, showed stable disease. 21 patients subsequently received chemotherapy, 45% with drugs to which they were previously refractory and 36% with only one new drug. 14% refused both planned cycles. Best response observed with CT was 55% (1 CR, 1 PR, 10 SD) and 59% (5 PR, 8 SD) with PET. Despite intrahepatic delivery, some remote responses were observed. Response did not correlate with initial tumor size, SUV, or CEA, with time since primary resection, pre- or post NV1020 chemotherapy type. Nine (41%) remain alive > 1 year. Kaplan-Meier median time to progression is 28 weeks (95% CI [9–37]); median survival probability is 52 weeks (95% CI [36–90]). Conclusions: NV1020 stabilizes liver metastases in highly advanced mCRC and may sensitize tumors to salvage chemotherapy resulting in extended overall survival. A controlled Phase 2/3 trial is justified. [Table: see text]

scholarly journals Ciclesonide Inhaler Treatment for Mild-to-Moderate COVID-19: A Randomized, Open-Label, Phase 2 Trial

2021 ◽  
Vol 10 (16) ◽  
pp. 3545
Author(s):  
Joon-Young Song ◽  
Jin-Gu Yoon ◽  
Yu-Bin Seo ◽  
Jacob Lee ◽  
Joong-Sik Eom ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Care ◽  
Eradication Rate ◽  
Clinical Status ◽  
Antiviral Agents ◽  
Outpatient Setting ◽  
Open Label ◽  
Clinical Trial Registration ◽  
Viral Shedding ◽  
Phase 2 Trial

Although some intravenous drugs have been used to treat coronavirus disease 2019 (COVID-19), no effective antiviral agents are currently available in the outpatient setting. We aimed to evaluate the efficacy and adverse events of 14-day ciclesonide treatment vs. standard care for patients with mild-to-moderate COVID-19. A randomized, open-label, multicenter clinical trial of ciclesonide inhalers was conducted in patients with mild-to-moderate COVID-19. Patients were enrolled within 3 days of diagnosis or within 7 days from symptom onset and randomly assigned to receive either ciclesonide (320 µg inhalation twice per day for 14 days) or standard care. The primary endpoint was the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) eradication rate on day 14 from study enrollment. Clinical status was assessed once daily, and serial nasopharyngeal viral load was evaluated by quantitative reverse transcription polymerase chain reaction. There were 35 and 26 patients in the ciclesonide and standard care groups, respectively. The SARS-CoV-2 eradication rate at day 14 was significantly higher in the ciclesonide group (p = 0.021). In multivariate analysis, SARS-CoV-2 negative conversion within 14 days was 12 times more likely in the ciclesonide group (95% confidence interval, 1.187–125.240). Additionally, the clinical failure rate (high-flow nasal oxygen therapy or mechanical ventilation) was significantly lower in the ciclesonide group (p = 0.034). In conclusion, ciclesonide inhalation shortened SARS-CoV-2 viral shedding duration, and it may inhibit the progression to acute respiratory failure in patients with mild-to-moderate COVID-19. Clinical Trial Registration NCT04330586.

scholarly journals First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours

2020 ◽  
Vol 123 (12) ◽  
pp. 1730-1736 ◽  
Author(s):  
Malaka Ameratunga ◽  
Irene Braña ◽  
Petri Bono ◽  
Sophie Postel-Vinay ◽  
Ruth Plummer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Solid Tumours ◽  
Trial Registration ◽  
Therapeutic Window ◽  
Open Label ◽  
Clinical Trial Registration ◽  
Bet Inhibitor ◽  
Dose Limiting Toxicity

Abstract Background Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours. Methods This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed. Conclusions ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window. Clinical trial registration The clinical trial registration number is NCT03035591.

scholarly journals 12. Randomized Studies of Two Clostridioides (Clostridium) difficile Vaccine Formulations

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S29-S29
Author(s):  
Jody Lawrence ◽  
Nicholas Kitchin ◽  
Annaliesa S Anderson ◽  
Michael W Pride ◽  
Kathrin U Jansen ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Injection Site ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Age Groups ◽  
Stopping Rules ◽  
Vaccine Formulation ◽  
Randomized Studies ◽  
Grade 3 ◽  
To Receive

Abstract Background Two formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) were assessed for safety and immunogenicity in randomized studies in healthy adults 50–85 years of age. Methods The Phase 1 study of QS-21 adjuvanted toxoid vaccine randomized subjects 3:1 to 100 μg QS-21-containing C difficile vaccine or placebo; 3 doses were given according to 2 different schedules: a shortened month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The Phase 2 toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3. Three doses were given on a day (Days 1, 8, 30) regimen. Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A– and B–specific neutralizing antibodies. Results In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%–75.0% and 16.7%–50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen), and remained above baseline throughout follow-up. Conclusion Both formulations demonstrated robust immunogenicity. However, both studies stopped early due to grade 3 injection site redness postdose 2 of the day (Days 1, 8, 30) regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies. Disclosures Jody Lawrence, MD, Pfizer, Inc (Employee) Nicholas Kitchin, MD, Pfizer, Inc (Employee) Annaliesa S. Anderson, PhD, Pfizer (Employee, Shareholder) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Charles Knirsch, MD, Pfizer (Employee) Chris Webber, MD, Pfizer Inc (Employee, Shareholder)

Remissions after Third Induction Chemotherapy for Primary Non-Responders with Acute Myeloid Leukemia (AML) Are Uncommon and Short-Lived

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2800-2800
Author(s):  
Sara Farshchi Zarabi ◽  
Steven M. Chan ◽  
Vikas Gupta ◽  
Dina Khalaf ◽  
Andrzej Lutynski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Palliative Care ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Cell Transplant ◽  
Advisory Committees ◽  
De Novo Aml

Abstract The outcome of adult patients with AML who are primary non-responders to two courses of induction chemotherapy is poor. However, the utility of a 3rd induction for a select subgroup of these patients is uncertain. Here, we evaluated the rates of response and survival after a 3rd course of induction chemotherapy for primary non-responders with AML. We identified 98 patients from the Princess Margaret Cancer Centre between May 1999 and March 2015 who were non-responders to induction and reinduction chemotherapy. No-response to re-induction chemotherapy was defined according to the Revised Recommendations of the International Working Group for AML (JCO, 2003) as patients who survived > 7 days post re-induction and had persistent AML in blood or bone marrow (>5%). Median age was 58.3 years [range: 20-76.6]. 50 (51%) were male. 2% had favorable, 18% normal, 18% intermediate, and 48% adverse cytogenetics. 50% had de novo AML, 23% had AML secondary to MDS or MPN, and 17% had therapy-related AML. Induction chemotherapy consisted of "7+3" (n =88), Nove-HiDAC (n=1), Flag-Ida (n= 2), or similar variants (n=7). Reinduction chemotherapy consisted of Nove-HiDAC (n=70), Flag-Ida (n=7), "7+3" (n=1) or other similar variants (n =20). No patients received the same regimen for both induction and reinduction. Of the 98 primary non-responders, 15 received a 3rd induction regimen, while the others received supportive/palliative care ± low-dose chemotherapy (57 pts), or a non-induction clinical trial (26 pts). Average age was 56.4 (sd: 12.9) for patients who received supportive/palliative care and 47.0 (sd: 17.5) for patients who received a 3rd induction (p=0.008). Other baseline characteristics including gender, cytogenetic risk, marrow blast count post 2nd induction, and time between 1st and 2nd induction, did not differ between patients who did and did not receive a 3rd induction. Time to 3rd induction was a median of 54 days [range:36-126] from the start of the 2nd induction. Of the 15 third inductions, 7 were clinical trials evaluating novel agents in combination with induction chemotherapy, while the other 8 were combinations of standard chemotherapeutics (Flag-Ida n=1), AMSA+HiDAC (n=2), Daunorubicin+ HiDAC (n=1), Nove-HiDAC (n=4). Of the 15 patients who received a 3rd induction, 3 (20%) achieved a CR following Nove-HiDAC and Flag-Ida or AMSA+HiDAC chemotherapy, where the Ara-C was given as continuous infusion. 1 patient underwent allogeneic stem cell transplant (SCT) approximately 3.7 months after 3rd induction and remains alive 4.6 years post CR. 2 patients relapsed 2.3 and 4.7 months post CR without having received alloSCT. None of the 12 other patients responded to the 3rd induction and none had prolonged aplasia. 2 of 15 (13%) died during 3rd induction. Among the 83 patients who did not receive a 3rdinduction, 1 achieved a CR after a phase 1 clinical trial (MDM2 inhibitor) and remains in CR 3.6 years following an alloSCT. For patients who survived the immediate post induction period and were discharged from hospital median overall survival from the start of the 2nd induction did not differ between patients who did and did not receive a 3rd induction (276 days [range: 78-1304] vs 181.5 days [range: 47-1855] respectively p= 0.14). Median duration of hospital stay (including subsequent admissions) was longer for patients receiving a 3rd induction compared to those who did not (94 days following start of the 2nd induction [range: 47-169] vs 57 days [range: 51-181], respectively;(p= 0.003)). In summary, remissions after 3rd inductions for primary non-responders are uncommon, and short-lived, suggesting that 3rd inductions should be considered with caution and only when an SCT strategy is in place. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schimmer:Novartis: Honoraria.

Phase I/II clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 in patients with unresactable, chemotherapy-resistant peritoneal carcinomatosis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3098-3098 ◽  
Author(s):  
Ulrich Lauer ◽  
Martina Zimmermann ◽  
Julia Sturm ◽  
Ursula Koppenhoefer ◽  
Michael Bitzer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Vaccinia Virus ◽  
Peritoneal Carcinomatosis ◽  
Cancer Cells ◽  
Recombinant Vaccinia Virus ◽  
Genetically Engineered ◽  
Viral Shedding ◽  
Dramatic Decline ◽  
Anti Tumor Activity

3098 Background: For therapy-resistant peritoneal carcinomatosis (PC) viruses exhibiting oncolytic properties open up new perspectives. Our phase I/II study in patients with refractory PC (NCT01443260) is designed to assess the safety, MTD, and anti-tumor activity of GL-ONC1, a recombinant vaccinia virus (VACV) genetically engineered to selectively replicate in and destroy cancer cells. Methods: GL-ONC1 was administered intraperitoneally up to 4 times every 28 days under a standard 3+3 dose escalation design. Safety was assessed using CTCAEv4.0. Anti-tumor activity was determined by “fluid biopsies” obtained via repetitive paracenteses and by serial PET-CT scans. Patient samples were collected for pharmacokinetics, pharmacodynamics and viral shedding analysis. Results: Up to now, 4 patients have received 10 doses of GL-ONC1 ranging from 107 to 108 infectious viral particles per application.Adverse events have generally been limited to grade 1/2, being mostly transient flu-like symptoms as well as increased abdominal pain resulting from treatment-induced peritonitis. No DLT was reported. No viral shedding was observed. In one gastric cancer patient, effective intraperitoneal replication of GL-ONC1 was demonstrated for more than 3 weeks. Using either anti-EpCAM or anti-VACV specific antibodies, around 5% of all ascitic cells were found to be EpCAM-positive 3 days after treatment in this patient, and only around 5-10% of these cancer cells were VACV positive at the same time point. In contrast, 4 days later (i.e. 7 days after virotherapeutic treatment), less than 2% of all ascitic cells were still EpCAM-positive, and more than 90% of these cancer cells were VACV positive. Of note, VACV-positive cancer cells morphologically showed significant degenerative changes. Conclusions: Preliminary data demonstrate that GL-ONC1 is well tolerated when infused intraperitoneally. Importantly, a single intraperitoneal delivery of GL-ONC1 was found to be sufficient to cause a dramatic decline in the number of malignant cells in the ascitic fluid, suggesting that GL-ONC1 effectively removes tumor cells in the ascites of patients with PC. Clinical trial information: NCT01443260.

scholarly journals 2754. Phase 1 Trial of an mRNA-Based Combination Vaccine Against hMPV and PIV3

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S970-S970 ◽  
Author(s):  
Christine Shaw ◽  
Heather Lee ◽  
Conor Knightly ◽  
Shiva Kalidindi ◽  
Tal Zaks ◽  
...  
Keyword(s):  
Single Dose ◽  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Geometric Mean ◽  
Vaccine Dose ◽  
Neutralizing Antibody ◽  
Combination Vaccine ◽  
Tract Infections ◽  
Dose Levels

Abstract Background Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) are important causes of upper and lower respiratory tract infections, particularly in young children. Despite their public health impact, no effective therapeutic or preventive options are available. mRNA-1653 is a mRNA-based investigational combination vaccine against hMPV and PIV3, and consists of two distinct mRNA sequences encoding the fusion proteins of hMPV and PIV3, co-formulated in lipid nanoparticles. Methods This phase 1, first-in-human, randomized, placebo-controlled, dose-ranging study assesses the safety and immunogenicity of mRNA-1653 in healthy adults aged 18–49. The 124-subject study evaluates four vaccine dose levels (25, 75, 150, and 300 µg) administered intramuscularly in either single-dose or two-dose (Day 1, Month 1) vaccination schedules, with follow-up through 1 year after the last vaccination. Objectives include safety and immunogenicity measured by hMPV- and PIV3-specific neutralizing antibody titers. Results An interim analysis demonstrated that the mRNA-1653 vaccine was generally well-tolerated at all dose levels. Neutralizing antibodies against hMPV and PIV3 were present at baseline in all subjects, consistent with prior exposure to both viruses. A single dose of mRNA-1653 boosted serum neutralization titers against both hMPV and PIV3, and the magnitude of boosting was similar at all dose levels. The geometric mean ratio of Month 1 to baseline titers was approximately 6 for hMPV and 3 for PIV3. A second dose of mRNA-1653 at Month 1 was not associated with further increase of hMPV or PIV3 neutralization titers. Conclusion mRNA-1653 is well-tolerated and induces a functional immune response, and is therefore a promising vaccine candidate for the prevention of pediatric respiratory tract diseases caused by hMPV and PIV3. Disclosures All authors: No reported disclosures.

scholarly journals A First in Human Trial Implanting Microalgae Shows Safety of Photosynthetic Therapy for the Effective Treatment of Full Thickness Skin Wounds

2021 ◽  
Vol 8 ◽  
Author(s):  
Miguel Luis Obaíd ◽  
Juan Pablo Camacho ◽  
Marianne Brenet ◽  
Rocío Corrales-Orovio ◽  
Felipe Carvajal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase 1 ◽  
Skin Wounds ◽  
Full Thickness ◽  
Clinical Trial Registration ◽  
Full Thickness Skin ◽  
Thickness Skin ◽  
Photosynthetic Cells

Insufficient oxygen supply represents a relevant issue in several fields of human physiology and medicine. It has been suggested that the implantation of photosynthetic cells can provide oxygen to tissues in the absence of a vascular supply. This approach has been demonstrated to be successful in several in vitro and in vivo models; however, no data is available about their safety in human patients. Here, an early phase-1 clinical trial (ClinicalTrials.gov identifier: NCT03960164, https://clinicaltrials.gov/ct2/show/NCT03960164) is presented to evaluate the safety and feasibility of implanting photosynthetic scaffolds for dermal regeneration in eight patients with full-thickness skin wounds. Overall, this trial shows that the presence of the photosynthetic microalgae Chlamydomonas reinhardtii in the implanted scaffolds did not trigger any deleterious local or systemic immune responses in a 90 days follow-up, allowing full tissue regeneration in humans. The results presented here represent the first attempt to treat patients with photosynthetic cells, supporting the translation of photosynthetic therapies into clinics.Clinical Trial Registration:www.clinicaltrials.gov/ct2/show/NCT03960164, identifier: NCT03960164.

scholarly journals A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

2020 ◽  
Vol 123 (10) ◽  
pp. 1481-1489
Author(s):  
Christophe Le Tourneau ◽  
Jean-Pierre Delord ◽  
Nuria Kotecki ◽  
Edith Borcoman ◽  
Carlos Gomez-Roca ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Solid Tumours ◽  
Trial Registration ◽  
Hepatic Enzymes ◽  
Dna Breaks ◽  
Dose Escalation Study ◽  
Clinical Trial Registration ◽  
Grade 3

Abstract Background AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation. Methods The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design. Results The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies. Conclusion The dose of 600 mg was identified as the optimal dose for further clinical development. Clinical trial registration Clinical trial registration (NCT number): NCT03579628.

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