scholarly journals Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD

2019 ◽  
Vol 3 (14) ◽  
pp. 2218-2229 ◽  
Author(s):  
Madan Jagasia ◽  
Christof Scheid ◽  
Gérard Socié ◽  
Francis Ayuketang Ayuk ◽  
Johanna Tischer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Standard Of Care ◽  
Response Assessment ◽  
Controlled Study ◽  
First Line ◽  
Serious Adverse Events ◽  
Hematopoietic Stem ◽  
Intention To Treat ◽  
First Line Therapy

Abstract The investigation of extracorporeal photopheresis (ECP) plus standard of care (SoC) (SoC+ECP) in chronic graft-versus-host disease (cGVHD) within prospective, randomized clinical studies is limited, despite its frequent clinical use. This phase 1/pilot study was the first randomized, prospective study to investigate ECP use as first-line therapy in cGVHD, based on the 2015 National Institutes of Health (NIH) consensus criteria for diagnosis and response assessment. Adult patients with new-onset (≤3 years of hematopoietic stem cell transplantation) moderate or severe cGVHD were randomized 1:1 to 26 weeks of SoC+ECP vs SoC (corticosteroids and cyclosporine A/tacrolimus) between 2011 and 2015. The primary endpoint was overall response rate (ORR), defined as complete or partial response, at week 28 in the intention-to-treat population (ITT). Other outcomes included quality of life (QoL) measures and safety. Sixty patients were randomized; ITT included 53 patients (SoC+ECP: 29; SoC: 24). Week 28 ORR was 74.1% (SoC+ECP) and 60.9% (SoC). Investigator-assessed ORR was 56.0% (SoC+ECP) and 66.7% (SoC). Patients treated with SoC experienced a decline in QoL over the 28-week study period; QoL remained unchanged in SoC+ECP patients. Most frequent treatment-emergent adverse events (TEAEs) in SoC+ECP patients were hypertension (31.0%), cough (20.7%), dyspnea (17.2%), and fatigue (17.2%). Seventeen patients (SoC+ECP: 8; SoC: 9) experienced 35 serious adverse events (SAEs). No TEAEs or SAEs were considered related to the ECP instrument or methoxsalen. The encouraging short-term results of this study could inform the design of subsequent studies. This trial was registered at www.clinicaltrials.gov as #NCT01380535.

scholarly journals A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 296
Author(s):  
Irina Kiseleva ◽  
Irina Isakova-Sivak ◽  
Marina Stukova ◽  
Marianna Erofeeva ◽  
Svetlana Donina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Influenza Vaccine ◽  
Phase 1 ◽  
Healthy Adults ◽  
Controlled Study ◽  
Temperature Sensitive ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Human Influenza Virus ◽  
Live Attenuated Influenza Vaccine

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

SAINT: Results of a phase 1/2 study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11016-11016 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Seiya Liu ◽  
Nicole Angel ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Safety Analysis ◽  
Phase 2 ◽  
First Line ◽  
Efficacy Analysis ◽  
First Line Therapy ◽  
Pre Treatment ◽  
Grade 3

11016 Background: Sarcoma cells are most immunogenic earlier in the disease course and prior to treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Methods: This is an IRB-approved dose-seeking Phase 1/2 protocol using defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks) and escalating doses of T (1.0, 1.2, 1.5 mg/m2 i.v. q 3 weeks), employing the “Cohort of Three” design, followed by a Phase 2 using the MTD of trabectedin. Results: Nine subjects were treated in Phase 1 of the study, and 31 subjects in Phase 2. Safety analysis: at Dose 1: Grade 3 treatment-related adverse events (TRAEs) included fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs included thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs included anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). Efficacy analysis (evaluable patients): At Dose 1: Disease Control Rate (DCR = CR, PR, SD) was 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1), DCR 60%, median PFS, 24 weeks; median OS, > 46 weeks. At Phase 2, MTD Dose 2 (PUPs): Safety analysis (n = 31): Grade 3 TRAEs included fatigue (n = 2), increased ALT (n = 6), increased AST (n = 4), hypernatremia (n = 1), hyponatremia (n = 1), dehydration (n = 1), rash (n = 1), port cellulitis (n = 1), psoriasis exacerbation (n = 1), increased TSH (n = 1), decreased hemoglobin (n = 2), neutropenia (n = 1). Efficacy analysis (N = 23 evaluable): PR (n-5; 2 UPS, 1 synovial sarcoma, 1 liposarcoma, 1 leiomyosarcoma,), BORR 22%, DCR 96%. Median PFS and OS not yet reached. After 4 treatment cycles, one resected tumor showed 80% necrosis and a greater number (30%) of CD8+ killer T cells, in the TME compared to archived pre-treatment tumor. Conclusions: These data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. Phase 2 of the study is on-going. Clinical trial information: NCT03138161.

scholarly journals Proposal for a new therapeutic high dosage of Pidotimod in children with Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled 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 ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Group A ◽  
Pfapa Syndrome ◽  
Decision Group ◽  
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 400mg daily) in combination with betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group A) or betamethasone 0.5-1mg on need, based on parents/caregivers' decision (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, pharyngitis, or 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 use betametasone showed a significant decrease in frequency of fevers (p=0.002); number of episodes of pharyngitis (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 could be an effective and safe to reduce the PFAPA attacks in children.

CTIM-08. SAFETY, EFFICACY, AND SURVIVAL RESULTS FROM A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWED BY STANDARD OF CARE RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi50-vi51
Author(s):  
Jaime Gállego Pérez-Larraya ◽  
Marc Garcia-Moure ◽  
Ana Patiño-García ◽  
Marisol González-Huarriz ◽  
Jasper Van der Lugt ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Oncolytic Adenovirus ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Serious Adverse Events ◽  
Tumor Biopsy ◽  
Grade 3

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is the most lethal pediatric brain tumor. Median overall survival (OS) with standard of care radiation therapy (RT) is approximately 8-10 months and 2-year survival is < 10%. A Phase 1 single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT for DIPG. METHODS Newly-diagnosed DIPG patients 1-18 years old received a tumor biopsy through the cerebellar peduncle followed by intratumoral injection of 1e10 – 5e10 vp DNX-2401 and conventional RT 1-3 weeks later. RESULTS Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 years (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone 3 K27M mutations were identified in 10 subjects, including H3F3A (n=8), HIST2H3C (n=1), and HIST1H3B (n=1); 1 subject was H3 wildtype (n=1). TP53 mutations were identified in 5 subjects (42%). DNX-2401 was administered followed by RT (n=11; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported adverse events (≥ 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three serious adverse events were reported including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) responses per RAPNO criteria. As of the data cutoff, median OS is 19.7 months and OS-24 is 32% with follow-up ongoing for 3 subjects (26.9, 25.6, 13.7 months). CONCLUSIONS DNX-2401 followed by RT can be safely administered to DIPG. Survival outcomes are encouraging, thus warranting further evaluation in a Phase 2 study.

scholarly journals Human Safety, Tolerability, and Pharmacokinetics of a Novel Broad-Spectrum Oral Antiviral Compound, Molnupiravir, with Activity Against SARS-CoV-2

2020 ◽  
Author(s):  
Wendy P. Painter ◽  
Wayne Holman ◽  
Jim A. Bush ◽  
Firas Almazedi ◽  
Hamzah Malik ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Influenza Viruses ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Antiviral Compound ◽  
Multiple Doses

AbstractMolnupiravir, EIDD-2801/MK-4482, the prodrug of the ribonucleoside analog ß-d-N4-hydroxycytidine (NHC), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, seasonal and pandemic influenza viruses, and respiratory syncytial virus.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.Clinical trial identifierThis study was registered at ClinicalTrials.gov with the identifier NCT04392219.

Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for advanced esophageal squamous cell carcinoma (ESCC): A multicenter, single-arm, open-label phase Ⅱ clinical trial.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 181-181
Author(s):  
Junsheng Wang ◽  
Suxia Luo ◽  
Ning Li ◽  
Tao Wu ◽  
Yonggui Hong ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Response Assessment ◽  
First Line ◽  
Open Label ◽  
First Line Therapy ◽  
Line Therapy

181 Background: The prognosis of pts with advanced ESCC remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. As a novel multitarget tyrosine kinase inhibitor mainly targeting antiangiogenic single pathway, anlotinib was demonstrated to be an effective second-line monotherapy for pts with advanced or recurrent ESCC in China. Consequently, the aim of this study was to investigate the efficacy and toxicity of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible subjects were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with anlotinib monotherapy (10mg, po, d1~14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans every two cycles. And the calculated sample size of this study was 47. The primary endpoint was PFS, secondary endpoints were safety, objective response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: From Oct 2019 to Aug 2020, 27 pts were available for efficacy and safety evaluation. In best overall response assessment, there were 7.4% CR (2/27), 66.7% PR (18/27) and 25.9% SD (7/27). ORR was 74.1% (95%CI: 53.7. ~ 88.9), and DCR was 100.0% (95%CI: 87.2~100.0). The median PFS of the 27 pts was not yet available. The safety profile indicated that the most common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia and hepatotoxicity. The common grade 3-4 treatment-related adverse events were myelosuppression (18.5%), hypertension (7.4%). Conclusions: The current results indicated that paclitaxel and cisplatin combined with anlotinib as first line therapy for advanced ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04063683. [Table: see text]

scholarly journals Catheter ablation versus antiarrhythmic drugs as first-line therapy for symptomatic atrial fibrillation: a systematic review and meta-analysis

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
M Casula ◽  
L Pignalosa ◽  
F Fortuni ◽  
E Baldi ◽  
A Sanzo ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Catheter Ablation ◽  
Adverse Events ◽  
Antiarrhythmic Drugs ◽  
Therapeutic Regimen ◽  
First Line ◽  
Serious Adverse Events ◽  
Atrial Tachyarrhythmias ◽  
First Line Therapy ◽  
Line Therapy

Abstract Funding Acknowledgements Type of funding sources: None. Background In patients with symptomatic atrial fibrillation (AF), current international guidelines favor the use of antiarrhythmic drugs (AAD) as initial therapy for the maintenance of sinus rhythm. Previous studies have compared catheter ablation for pulmonary vein isolation versus AAD in this clinical scenario but the best first-line therapeutic option in patients with symptomatic AF candidates for rhythm control strategy remains an open issue. Aim To compare efficacy and safety of catheter ablation versus AAD as first-line therapy in patients with symptomatic AF. Methods We searched electronic databases for randomized controlled trials (RCTs) comparing catheter ablation versus AAD as first-line therapy for symptomatic AF. The primary efficacy outcome was any recurrence of atrial tachyarrhythmias. The secondary efficacy outcomes were symptomatic arrhythmic recurrences. The safety outcomes were serious adverse events related to the therapeutic regimen. Outcome events were defined according to the definition used in each original study. The effect size was estimated using a random-effect model as risk ratio (RR) and relative 95% confidence interval (CI) with the statistical software Review Manager 5.3. Results Five RCTs counting 997 patients (503 treated with catheter ablation and 494 with AAD) were included in the analysis. Mean age was 57 ± 3 years, 30% were female. Mean left ventricle ejection fraction was 60%±4% and mean left atrial diameter was 40 mm ± 1 mm. At baseline 52% of patients were treated with a beta-blocker and 11% with a calcium channel blocker. In the catheter ablation group 258 patients (51%) underwent cryoablation and 245 (49%) radiofrequency ablation. Median follow-up was 12 months (IQR 12-24 months). Patients treated with catheter ablation had statistically significant lower risk of atrial tachyarrhythmias recurrences (RR 0.59; 95%CI 0.45-0.76; p < 0.0001 – Figure A) and of symptomatic arrhythmia recurrences (RR 0.45; 95%CI 0.25-0.80; p = 0.007 – Figure B) compared with those treated with AAD. The risk of serious adverse events related to the therapeutic regimen did not differ significantly between patients undergoing catheter ablations and those treated with AAD (RR 0.85; 95%CI 0.45-1.59 – Figure C). Conclusions In patients with symptomatic AF, catheter ablation as first-line therapy is associated with a reduced risk of atrial tachyarrhythmias recurrences compared with AAD, without statistically significant differences in the risk of serious adverse events related to the treatment. Abstract Figure.

scholarly journals Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2

2021 ◽  
Author(s):  
Wendy P. Painter ◽  
Wayne Holman ◽  
Jim A. Bush ◽  
Firas Almazedi ◽  
Hamzah Malik ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Influenza Viruses ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve ◽  
Multiple Doses

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics. EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.

CHOP-R (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, Rituximab) Compared to CPOP-R (Cyclophosphamide, Pixantrone, Vincristine, Prednisone, Rituxamib) in First-Line Therapy of Diffuse Large B Cell Lymphoma (DLBCL): An Interim Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3445-3445 ◽  
Author(s):  
Raoul Herbrecht ◽  
Stephen Couban ◽  
Florian Weissinger ◽  
Igor Gorbatchevsky ◽  
Richard H. van der Jagt
Keyword(s):  
Heart Failure ◽  
Adverse Events ◽  
Interim Analysis ◽  
Phase 1 ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

Abstract The CHOP-R regimen is the standard regimen for first-line therapy of patients with DLBCL. Pixantrone (BBR 2778) is a novel aza-anthracenedione with structural similarities to mitoxantrone. In a phase 1/2 study of CPOP in 65 patients with relapsed NHL who had received a first-line anthracycline-containing regimen, patients received pixantrone at 80–180 mg/m2. This study indicated substantial activity with an overall response rate of 77% and complete response (CR) rate of 54% with acceptable toxicity. Studies in indolent NHL demonstrated that the combination of pixantrone with rituximab is well tolerated and more active than rituximab alone (JCO, 24(18S), 2006:7578). To evaluate the safety and activity of CPOP-R with special regard to cardiac safety in the first-line setting, a randomized phase 2 study in untreated patients with DLBCL comparing CPOP-R to CHOP-R is being conducted. Patients with untreated, histologically confirmed CD20-positive DLBCL receive CHOP-R or CPOP-R every 21 days for 6–8 cycles. An interim analysis for efficacy was prospectively planned to be performed when 40 patients had completed 4 cycles of therapy to test whether the CR rate of CPOP-R (pixantrone dose of 150 mg/m2) is, with 95% confidence, not more than 15% less than the CR rate of CHOP-R. We report the results of this analysis, which included 40 patients (21 CPOP-R and 19 CHOP-R) who had completed 4 cycles or had prematurely withdrawn from the study. Preliminary safety data (CPOP-R=27 patients, CHOP-R=30 patients) were also evaluated. CR rates after 4 cycles based on investigators’assessment were similar between arms (CPOP-R=33%, CHOP-R=37%). In general, adverse events were equal between arms. There were no more grade 3–4 adverse events (41% CPOP-R vs 50% CHOP-R) and no more grade 3–4 treatment-related adverse events (33% in CPOP-R vs 40% in CHOP-R) in the CPOP-R arm compared to the CHOP-R arm. 8 patients in each arm had asymptomatic absolute LVEF declines of ≥10%. 3 patients in the CPOP-R arm had a LVEF decline of >15% and ≤20% compared to 5 patients in the CHOP-R arm. No patients in the CPOP-R arm had a >20% LVEF decline compared to 2 patients in the CHOP-R arm. No heart failure or deaths resulting from heart failure have been reported. Infections reported as serious adverse events occurred in 1 patient (4%) in the CPOP-R arm and 3 patients (10%) in the CHOP-R arm. Grade 3–4 neutropenia was similar (CPOP-R = 34%, CHOP-R = 30%). Febrile neutropenia was less frequent in the CPOP-R arm (4% vs 23%). There were 2 deaths within 30 days of the last dose of study drug on CPOP-R arm. Both patients were > 80 years; 1 of the events was attributed to study treatment secondary to neutropenic infection. No deaths were reported in the CHOP-R arm. Based on this preliminary analysis, we conclude that for 1st-line therapy of patients with DLBCL, CPOP-R has similar activity to CHOP-R with no more toxicity. Further follow-up is required.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

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