Results of a Randomized, Open-Label, Phase IIIb Study of 2 Schedules of Decitabine in Higher-Risk Myelodysplastic Syndrome Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3846-3846
Author(s):  
Depei Wu ◽  
Xin Du ◽  
Jie Jin ◽  
Zhijian Xiao ◽  
Zhixiang Shen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Treatment Group ◽  
Complete Remission ◽  
Myelodysplastic Syndrome ◽  
De Novo ◽  
Day Treatment ◽  
Treatment Schedule ◽  
Open Label ◽  
Treatment Groups ◽  
The Mean

Abstract Abstract 3846 Aim: To evaluate the efficacy and safety of 3-day and 5-day treatment schedules of decitabine (nucleoside analogue) in Chinese patients with Myelodysplastic Syndrome (MDS). Methods: In this open-label, multi-center, phase 3b study, consenting men and women (n=132) above 18 years of age with de novo or secondary MDS fitting any of the recognized French-American-British classifications, with score on International Prognostic Scoring System (IPSS) ≥ 0.5 within 30 days before randomization, and having Eastern Cooperative Oncology Group performance (ECOG) status of 0–2, were enrolled. Patients were randomized (1:1) to either 3-day treatment schedule (15 mg/m2/day decitabine administered by continuous intravenous infusion within a 3-hour period, repeated every 8 hours for 3 consecutive days/cycle; cycles repeated every 6 weeks) or to 5-day treatment schedule (20 mg/m2 decitabine administered by a 1-hour infusion once-daily, on days 1 through 5/cycle; cycles repeated every 4 weeks), until minimum of 30 patients were included in the 3-day treatment group. All remaining patients were enrolled for the 5-day treatment. Patients were treated for ≥4 treatment cycles and for a maximum of 2 years, as long as the patient continued to benefit (absence of overt progression of disease or unacceptable toxicity). The primary efficacy endpoint was overall response rate (ORR) that included complete remission, bone marrow complete remission and partial remission, according to the International Working Group (IWG) 2006 response criteria. The secondary endpoints included hematological improvement, time to acute myeloid leukemia (AML) progression or death, and overall survival (OS). Safety and pharmacokinetics of decitabine were evaluated. Assuming a 10% dropout rate, with 132 enrolled patients, the study had 90% power at a 5% significance level to detect a >10% ORR. Results: Thirty-four patients were included in the 3-day treatment group and 98 patients were included in the 5-day treatment group. Overall, 78 (59.5%) patients prematurely discontinued the study (16 [12.2%] patients discontinued due to disease progression). The demographic and baseline characteristics were comparable between the 2 treatment groups. In the overall population, the median age was 53.9 years (range: 18.5 – 84.0), 59% were men, all had de novo MDS, the mean (SD) time since diagnosis of MDS was 4.2 (9.38) months, 41.4% patients were IPSS Intermediate-1 (0.5–1.0), 43% were IPSS Intermediate −2 (1.5–2.0) and 15.6% were IPSS high risk (≥2.5) and the majority (68.9% of patients) had ECOG score of 1. Median number of treatment cycles was 3 for each of the treatment groups. Based on the single sample proportion comparison with given value (10%), the significant ORR was achieved in the overall population (22.9%; 95% CI: 16.0, 31.1; p<0.001) as well as in the 3-day treatment group (26.5%; 95% CI: 12.9, 44.4) and 5-day treatment group (21.6%; 95% CI: 13.9, 31.2). The hematological improvement (CR+PR+HI) rate (% [95% CI]) for overall population, 3-day treatment group and 5-day treatment group was 39.7 (31.3, 48.6), 44.1 (27.2, 62.1) and 38.1 (28.5, 48.6) respectively. AML transformations or deaths occurred in 21 (16.0%) patients overall, and in 5 (14.7%) and 16 (16.5%) patients in the 3-day and 5-day treatment group respectively. For the overall population, the maximum estimated time to AML transformations or death was 27.8 months (3-day treatment: 17.9 months, 5-day treatment: 27.8 months). For the overall population, the 12-month OS was 80.6 % and 24-month OS was 60.7%. At steady state, the mean (SD) maximum plasma concentration and mean (SD) area under plasma concentration-time curve (AUC0-∞) was 54.44 (20.07) ng/mL and 118.93 (50.55) ng.hr/mL, respectively for the 3-day treatment group (n=7) and 222.35 (53.74) ng/mL and 180.43 (43.78) ng.hr/mL, respectively for the 5-day treatment group (n=17). Overall, at least one treatment-emergent adverse event (TEAE) occurred in 97 (74%) patients (32 [94.1%] patients in the 3-day treatment group and in 65 [67%] patients in the 5-day treatment group); TEAEs were related to study drug in 31 (91.2%) patients in the 3-day treatment group and 60 (61.9%) patients in the 5-day treatment group. Conclusion: Decitabine was found to be efficacious and safe for treatment of MDS. Results of this study were consistent with similar decitabine studies conducted previously. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

2003 ◽  
Vol 47 (3) ◽  
pp. 1072-1080 ◽  
Author(s):  
Spotswood L. Spruance ◽  
Terry M. Jones ◽  
Mark M. Blatter ◽  
Mauricio Vargas-Cortes ◽  
Judy Barber ◽  
...  
Keyword(s):  
Day Treatment ◽  
High Dose ◽  
Herpes Labialis ◽  
Lesion Development ◽  
Multicenter Studies ◽  
Double Blind ◽  
Cold Sore ◽  
Treatment Groups ◽  
The Mean ◽  
Cold Sores

ABSTRACT Oral valacyclovir is better absorbed than oral acyclovir, increasing acyclovir bioavailability three- to fivefold. This provides the opportunity to explore whether high systemic acyclovir concentrations are effective in the treatment of cold sores (herpes labialis). Two randomized, double-blind, placebo-controlled studies were conducted. Subjects were provided with 2 g of valacyclovir twice daily for 1 day (1-day treatment), 2 g of valacyclovir twice daily for 1 day and then 1 g of valacyclovir twice daily for 1 day (2-day treatment), or a matching placebo and instructed to initiate treatment upon the first symptoms of a cold sore. In study 1, the median duration of the episode (primary endpoint) was reduced by 1.0 day (P = 0.001) with 1-day treatment and 0.5 days (P = 0.009) with 2-day treatment compared to placebo. Similarly, the mean duration of the episode was statistically significantly reduced by 1.1 days with 1-day treatment and 0.7 days with 2-day treatment compared to placebo. The proportion of subjects in whom cold sore lesion development was prevented and/or blocked was increased by 6.4% (P = 0.096) with 1-day treatment and 8.5% (P = 0.061) with 2-day treatment compared to placebo. The time to lesion healing and time to cessation of pain and/or discomfort were statistically significantly reduced with valacyclovir compared to placebo. In study 2, results similar to those in study 1 were obtained. AEs were similar across treatment groups. These studies provide evidence supporting a simple, 1-day valacyclovir treatment regimen for cold sores that is safe and effective. The 1-day valacyclovir regimen offers patients a unique and convenient dosing alternative compared to available topical therapies.

scholarly journals Effects of imidacloprid and thiamethoxam on the development and reproduction of the soybean aphid Aphis glycines

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0250311
Author(s):  
Aonan Zhang ◽  
Lin Zhu ◽  
Zhenghao Shi ◽  
Tianying Liu ◽  
Lanlan Han ◽  
...  
Keyword(s):  
Treatment Group ◽  
Reproductive Rate ◽  
Soybean Aphid ◽  
Aphis Glycines ◽  
Intrinsic Rate Of Increase ◽  
Control Group ◽  
Net Reproductive Rate ◽  
Treatment Groups ◽  
Rate Of Increase ◽  
The Mean

The soybean aphid Aphis glycines Matsumura (Hemiptera: Aphididae) is a primary pest of soybeans and poses a serious threat to soybean production. Our studies were conducted to understand the effects of different concentrations of insecticides (imidacloprid and thiamethoxam) on A. glycines and provided critical information for its effective management. Here, we found that the mean generation time and adult and total pre-nymphiposition periods of the LC50 imidacloprid- and thiamethoxam-treatment groups were significantly longer than those of the control group, although the adult pre-nymphiposition period in LC30 imidacloprid and thiamethoxam treatment groups was significantly shorter than that of the control group. Additionally, the mean fecundity per female adult, net reproductive rate, intrinsic rate of increase, and finite rate of increase of the LC30 imidacloprid-treatment group were significantly lower than those of the control group and higher than those of the LC50 imidacloprid-treatment group (P < 0.05). Moreover, both insecticides exerted stress effects on A. glycines, and specimens treated with the two insecticides at the LC50 showed a significant decrease in their growth rates relative to those treated with the insecticides at LC30. These results provide a reference for exploring the effects of imidacloprid and thiamethoxam on A. glycines population dynamics in the field and offer insight to agricultural producers on the potential of low-lethal concentrations of insecticides to stimulate insect reproduction during insecticide application.

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1202-1210 ◽  
Author(s):  
Eric Solary ◽  
Bernard Drenou ◽  
Lydia Campos ◽  
Patricia de Crémoux ◽  
Francine Mugneret ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Complete Remission ◽  
Significant Influence ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
P Glycoprotein ◽  
Acute Myelogenous ◽  
The Mean

Abstract Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein–mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ± 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P = .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

scholarly journals 1159. Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Pediatric Participants With Confirmed or Suspected Gram-negative Bacterial Infections: A Phase 1b, Open-label, Single-Dose Clinical Trial

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S671-S671
Author(s):  
John S Bradley ◽  
Nataliia Makieieva ◽  
Camilla Tøndel ◽  
Emmanuel Roilides ◽  
Matthew S Kelly ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Bacterial Infections ◽  
Geometric Mean ◽  
Complicated Urinary Tract Infection ◽  
Research Support ◽  
Open Label ◽  
Gram Negative ◽  
Age Cohorts ◽  
The Mean

Abstract Background Imipenem/cilastatin/relebactam (IMI/REL) is approved for treating hospital-acquired/ventilator-associated bacterial pneumonia, complicated urinary tract infection, and complicated intra-abdominal infection in adults. This study assessed single-dose pharmacokinetics (PK), safety, and tolerability of IMI/REL in neonatal and pediatric participants with confirmed or suspected gram-negative bacterial infections. Methods This was a phase 1, open-label, non-comparative study (NCT03230916). Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to characterize the PK profiles for imipenem and relebactam after a single intravenous dose of IMI/REL. PK parameters were analyzed using population modeling. The PK target for imipenem was the percent time of the dosing interval that the unbound plasma concentration exceeded the minimum inhibitory concentration (%fT &gt;MIC) of ≥30% (MIC used, 2 µg/mL). The PK target for relebactam was an area under the curve (AUC)/MIC ratio &gt;8 (MIC used, 2 µg/mL), corresponding to AUC0-24h &gt;58.88 μM∙h. Safety and tolerability were assessed for up to 14 days after drug infusion. Results Of the 46 participants who received IMI/REL, 42 were included in the PK analysis. The mean plasma concentration-time profiles for imipenem and relebactam were generally comparable across age cohorts (Figure). For imipenem, the geometric mean %ƒT &gt;MIC ranged from 50% to 94% and the mean maximum concentration (Cmax) ranged from 65 μM to 126 μM (Table 2). For relebactam, the geometric Cmax ranged from 33 μM to 87 μM and mean AUC0-6h ranged from 51 μM·h to 159 μM·h across the age cohorts (Table 2). IMI/REL was well tolerated with 8 (17.4%) participants experiencing ≥1 adverse events (AE) and 2 (4.3%) participants experiencing AE that were deemed drug related by the investigator. Drug-related AE were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, and diarrhea, which were non-serious, mild in severity, and resolved within the follow-up period of 14 days. Figure 1 Conclusion Imipenem and relebactam exceeded the pediatric plasma PK targets across pediatric age cohorts in the study; the single doses of IMI/REL were well tolerated. These results will inform IMI/REL dose selection for further pediatric clinical evaluation. Disclosures Camilla Tøndel, MD, PhD, Merck & Co., Inc., (Grant/Research Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, FECMM, FISAC, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew S. Kelly, MD, MPH, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Munjal Patel, PhD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Pavan Vaddady, PhD, Merck Sharp & Dohme Corp. (Employee) Alok Maniar, MD, MPH, Merck Sharp & Dohme Corp. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck Sharp & Dohme Corp. (Employee, Shareholder) Joan R. Butterton, MD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee)

scholarly journals A Phase III, Randomized, Multi-Center, Open-Label, Fixed Dose, Neulasta Active-Controlled Clinical Trial of F-627, a Novel G-CSF, in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4290-4290
Author(s):  
John Glaspy ◽  
William Daley ◽  
Igor Bondarenko ◽  
Dean Rutty ◽  
Jianmin Chen
Keyword(s):  
Breast Cancer ◽  
Study Drug ◽  
Phase Iii ◽  
Chemotherapy Cycle ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Controlled Study ◽  
Open Label ◽  
Treatment Groups ◽  
The Mean

Abstract Background - Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients receiving myelotoxic chemotherapy which is associated with increased morbidity and early mortality. Ryzneuta TM (F-627), a recombinant fusion protein containing human granulocyte-colony stimulating factor (G-CSF) and IgG2-Fc fragment, is intended to reduce CIN by utilizing the neutrophilic proliferating and activating properties of G-CSF. F-627 was designed as a novel, non-pegylated molecule with dimeric G-CSF, which may possess stronger G-CSF receptor activating properties and improved efficacy compared to filgrastim and pegfilgrastim. The primary objective of this study was to evaluate the safety and efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe (PFS) as compared to Neulasta® (6 mg) in the first chemotherapy cycle. Methods - This was a phase III, multi-center, randomized, open-label, two-arm, active-controlled study that randomized female patients with Stage I to III invasive breast cancer who received 4 cycles of myelotoxic taxane + cyclophosphamide chemotherapy treatment. Forty-one (41) sites across 5 countries participated in the trial, including Bulgaria, Hungary, Russia, Ukraine, and US. Patients were randomized to F-627 or Neulasta® in a 1:1 ratio on the day of chemotherapy and administered study drug 24 hours after chemotherapy administration in each cycle. A total of 393 patients were randomized and analyzed for efficacy and safety. Clinical assessments were cycle-specific and included physical examination, serum samples for immunogenicity before each chemotherapy cycle, laboratory assessments, hematology and CBC with differentials, urinalysis, body weight, vital signs, adverse event (AE) collection, and concomitant medications. The pharmacokinetics (PK) and the pharmacodynamics (PD) of F-627 were also assessed. The primary efficacy endpoint was the duration in days of Grade 4 (severe) neutropenia (ANC &lt;0.5 × 10 9/L) during cycle 1 of chemotherapy. Results - The mean duration of Grade 4 neutropenia in chemotherapy cycle 1 was 0.2 days for both F-627 and Neulasta®. F-627 was non-inferior compared to Neulasta® for the duration of Grade 4 neutropenia in chemotherapy cycle 1 with a mean difference of 0.0 days (95% CI: -0.1, 0.1), utilizing a non-inferiority margin of 0.6 days. The incidence of Grade 4 neutropenia in chemotherapy cycle 1 was comparable between F-627 and Neulasta®, 11.7% for both treatment groups. For chemotherapy cycles 2, 3, and 4, the incidence and duration of Grade 4 neutropenia was generally lower than in chemotherapy cycle 1. The mean durations of Grade 4 neutropenia were 0.1, 0.0, and 0.0 days for F-627 and 0.1, 0.1, and 0.1 days for Neulasta® in chemotherapy cycles 2,3,4, respectively. The incidence of Grade 4 neutropenia was 4.6%, 2.6%, and 1.6% for F-627 and 5.1%, 6.3%, and 5.3% for Neulasta® in chemotherapy cycles 2, 3, and 4, respectively. Across all chemotherapy cycles and for each chemotherapy cycle, the mean duration and the incidence of IV antibiotic use and hospitalization due to febrile neutropenia or any infection were low and comparable between F-627 and Neulasta®. The depth of ANC nadir was comparable in each chemotherapy cycle between F-627 and Neulasta®. For each chemotherapy cycle, time to ANC nadir was slightly longer for patients treated with F-627 than those with Neulasta®; the mean time to ANC nadir was 6.4, 6.1, 6.2, and 6.2 days for F-627, compared to 6.1,5.3, 5.7, and 5.5 days for Neulasta® in cycles 1, 2, 3, and 4, respectively. F-627 was well tolerated, with a low incidence of serious AEs and AEs leading to discontinuation, comparable to the profile for Neulasta®. There were 3 deaths during the study (1 for F-627 and 2 for Neulasta®). None of the deaths were related to study drug treatment. Clinical laboratory abnormalities were observed to be similar between the two treatment groups. Conclusion - Once-per-cycle F-627, given as a fixed 20 mg dose, was non-inferior to Neulasta® in reducing the duration of severe neutropenia following TC chemotherapy. F-627 was well tolerated during the study with an overall safety profile comparable to that for Neulasta®. F-627 is a safe, effective, and easy to use alternative to current CIN therapy. Disclosures Daley: Evive: Current Employment, Current holder of stock options in a privately-held company. Chen: Evive: Current Employment.

46 Effect of Bioxcell® and Triladyl® Extenders on Washed Semen of South African Indigenous Bucks

2018 ◽  
Vol 30 (1) ◽  
pp. 162
Author(s):  
L. P. Nethenzheni ◽  
M. L. Mphaphathi ◽  
N. C. Negota ◽  
T. L. Nedambale
Keyword(s):  
Treatment Group ◽  
South African ◽  
Liquid Nitrogen ◽  
Seminal Plasma ◽  
Semen Parameters ◽  
Mean Values ◽  
Treatment Groups ◽  
Frozen Semen ◽  
The Mean

Semen extenders and seminal plasma are vital for cryopreservation of buck semen. The objectives of the study were to evaluate the effect of 2 extenders: Triladyl® (Minitube, Tiefenbach, Bavaria) and Bioxcell® (IMV, L’Aigle, France) and the removal of seminal plasma on buck semen. Six indigenous bucks were used in this study and 6 ejaculates were collected from individual bucks. The semen was pooled and then randomly allocated into 6 groups: (1) raw-washed, (2) raw-non-washed, (3) Triladyl®-washed, 4) Triladyl®-non-washed, (5) Bioxcell®-washed, and (6) Bioxcell®-non-washed. Spermatozoa viability was assessed using Eosin-Nigrosin and morphology using Spermac® (Vitrolife, Göteborg, Sweden) stains. The washed semen samples were all diluted into (1:4 v/v) with PBS and centrifuged at 1500 × g for 10 min. Semen samples were then extended with Triladyl® or Bioxcell® per treatment groups and equilibrated for 2 h at 5°C. The semen samples were loaded into straws per treatment groups and placed 5 cm above a liquid nitrogen vapour for 10 min and then stored at –196°C until use. After 1 month of storage, frozen semen straws per treatment group were thawed at 37°C for 30 s, and spermatozoa parameters were analysed post-thaw. Significant differences among the mean values of semen parameters were determined by Tukey’s test using ANOVA, GLM procedure of SAS version 12.1 of 2010 (SAS Institute Inc., Cary, NC, USA). There was a higher (P < 0.05) live and normal spermatozoa percentage in non-washed semen extended with Bioxcell® (45.7 ± 21.2) than the semen extended with Triladyl® (24.5 ± 22.2%). Live and normal spermatozoa percentages were drastically reduced in the Bioxcell® (5.2 ± 4.9) and Triladyl® (6.9 ± 8.6%) washed semen groups. There was a higher (P < 0.05) percentage of spermatozoa with head abnormalities in non-washed semen extended with Triladyl® (20.4 ± 10.2), compared with the semen extended with Bioxcell® (18.3 ± 12.4%) following freeze-thawing. There was a higher (P < 0.05) percentage of spermatozoa with head abnormalities in washed semen samples extended with Triladyl® (34.0 ± 16.0) compared with the semen extended with Bioxcell® (10.1 ± 7.0%). There were higher (P < 0.05) percentages of spermatozoa with coiled tail abnormalities in washed semen extended with Bioxcell® (65.4 ± 25.0) compared with Triladyl® (35.9 ± 21.6%). In conclusion, the liveability of spermatozoa was negatively affected by washing of semen extended with Bioxcell® and Triladyl® extender. Bioxcell® significantly increased tail abnormalities and Triladyl® gave less protection against head abnormalities following cryopreservation of South African unimproved indigenous bucks’ semen.

A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1570-1570 ◽  
Author(s):  
Steven M. Horwitz ◽  
Julie M. Vose ◽  
Ranjana Advani ◽  
Kamalesh Sankhala ◽  
Swaminathan Padmanabhan ◽  
...  
Keyword(s):  
Treatment Group ◽  
B Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Hodgkin's Lymphoma ◽  
Open Label ◽  
Dosing Schedule ◽  
Treatment Groups ◽  
Heavily Pretreated ◽  
Group A

Abstract Background: Pralatrexate (PDX) is a novel targeted antifolate that is designed to accumulate preferentially in cancer cells. Pralatrexate has demonstrated activity in the treatment of non-Hodgkin’s lymphoma (NHL). Single-agent gemcitabine (Gem) has demonstrated promising activity in relapsed Hodgkin’s lymphoma, T-cell lymphoma, and select sub-types of B-cell NHL. Based on pre-clinical data demonstrating a schedule dependent synergy for this combination (pralatrexate + Gem) (Clin Cancer Res2006; 12(3):924–932), a Phase 1/2a, non-randomized, open-label, multi-center trial was designed to assess the potential co-administration of these 2 agents. The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose when pralatrexate and Gem are administered with vitamin B12 and folic acid supplementation to patients (pts) with relapsed/refractory lymphoma. Methods: Initially, pts were assigned to a schedule of pralatrexate, followed the next day by Gem, once weekly for 3 of 4 weeks (Treatment group A). When this schedule was poorly tolerated, new cohorts were enrolled in a dose escalating fashion: Treatment group B – pralatrexate (10 mg/m2) followed the next day by Gem (300–400 mg/m2) once every 2 weeks (q 2 weeks); and Treatment group C – pralatrexate (10 mg/m2) followed 1 hour later by Gem (300–400 mg/m2) q 2 weeks. Eligibility criteria include histologically confirmed lymphoma, documented disease progression (PD) after 3 1 prior treatment, and ECOG PS £ 2. Results: As of August 2008, 20 pts have been treated on this study, including 11 males (55%) and 9 females (45%). Pt histology is as follows: 8 pts [40%] diffuse large B-cell lymphoma [DLBCL]; 1 pt [5%] follicular lymphoma, Hodgkin lymphoma (HL) (5 pts [26%]), T/NK-cell (5 pts [26%]), and composite DLBCL and PTCL (1 pt [5%]). Pts were heavily pre-treated having received a median of 4 prior regimens (range 3–12) with a median of 3 prior systemic regimens (range 2–10). Treatment group A was not well tolerated as evidenced by the incidence of Grade (Gr) 3–4 hematological toxicities. In comparison pts in treatment groups B and C had far fewer adverse events (AEs) with lower severity toxicities. Across all dose cohorts and treatment groups, the most frequently reported Gr 3–4 AEs considered to be treatment related have been neutropenia (9 pts [45%]) thrombocytopenia (9 pts [45%]), and anemia (8 pts [40%]). Preliminary efficacy data show 6 pts (30%) with partial response (PR): 4 with HL, 1 with DLBCL, and 1 with composite DLBCL and PTCL. PRs occurred on both the sequential dosing schedule (5 pts) and the same-day dosing schedule (1 pt). The HL pts with a PR were heavily pretreated (7, 8, 11, and 12 prior therapies) and all had received previous Gem, 3 of the 4 without response. Conclusion: The combination of pralatrexate and Gem can be safely administered on a q 2 week schedule. The MTD was established for the sequential day schedule as pralatrexate 10/Gem 300 (mg/m2). Dose escalation continues on the same day schedule. Pralatrexate and Gem administration at a frequency of 3/4 weeks is not feasible in heavily pretreated pts due to hematologic toxicity; however, when administered on a 2 q week schedule, the combination has shown a favorable safety profile. The combination of pralatrexate and Gem has shown encouraging activity in pts with heavily pre-treated, refractory lymphomas and enrollment in the study is ongoing to define the MTD on a same day schedule. Cohort Number of Pts Dose Pralatrexate/Gem (mg/m2) Schedule #DLTs DLT (Grade) A1 2 15/400 Sequential days, 3/4 weeks 2 Thrombocytopenia (Gr 4); Neutropenia (Gr 3) & Thrombocytopenia (Gr 3) A-1 2 10/400 Sequential days, 3/4 weeks 2 Neutropenia (Gr 3) Thrombocytopenia Gr 3) A-2 3 10/300 Sequential days, 3/4 weeks 2 Thrombocytopenia (Gr 3) Neutropenia (Gr 3) B1 3 10/300 Sequential days, q 2 weeks 0 B2 3 10/400 Sequential days, q 2 weeks 0 B3 2 15/400 Sequential days, q 2 weeks 2 Cellulitis (Gr 3) Pulmonary embolus (Gr 3) C1 3 10/300 Same day, q 2 weeks 0 C2 2 10/400 Same day, q 2 weeks 1 Hypoxia (Gr 3) &

scholarly journals Mycobacterium tuberculosis Proteome Response to Antituberculosis Compounds Reveals Metabolic “Escape” Pathways That Prolong Bacterial Survival

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Lia Danelishvili ◽  
Natalia Shulzhenko ◽  
Jessica J. J. Chinison ◽  
Lmar Babrak ◽  
Jialu Hu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
De Novo ◽  
Day Treatment ◽  
Bacterial Survival ◽  
Content Type ◽  
Treatment Groups ◽  
Metabolic Remodeling ◽  
Tuberculosis Therapy

ABSTRACTTuberculosis (TB) continues to be one of the most common bacterial infectious diseases and is the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of the infecting organism, increasing the risk for the development of a tolerance phenotype and drug resistance. Studies indicate thatMycobacterium tuberculosistakes several days to be killed upon treatment with lethal concentrations of antibiotics bothin vitroandin vivo. To investigate how metabolic remodeling can enable transient bacterial survival during exposure to bactericidal concentrations of compounds,M. tuberculosisstrain H37Rv was exposed to twice the MIC of isoniazid, rifampin, moxifloxacin, mefloquine, or bedaquiline for 24 h, 48 h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using quantitative shotgun mass spectrometry. Numerous sets ofde novobacterial proteins were identified over the 6-day treatment. Network analysis and comparisons between the drug treatment groups revealed several shared sets of predominant proteins and enzymes simultaneously belonging to a number of diverse pathways. Overexpression of some of these proteins in the nonpathogenicMycobacterium smegmatisextended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins inM. tuberculosisprevented the pathogen from escaping the fast killingin vitroand in macrophages, as well. Our biology-driven approach identified promising bacterial metabolic pathways and enzymes that might be targeted by novel drugs to reduce the length of tuberculosis therapy.

scholarly journals Topical estrogen, testosterone, and vaginal dilator in the prevention of vaginal stenosis after radiotherapy in women with cervical cancer: a randomized clinical trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jumara Martins ◽  
Ana Francisca Vaz ◽  
Regina Celia Grion ◽  
Lúcia Costa-Paiva ◽  
Luiz Francisco Baccaro
Keyword(s):  
Clinical Trial ◽  
Cervical Cancer ◽  
Randomized Clinical Trial ◽  
Open Label ◽  
Treatment Groups ◽  
Vaginal Stenosis ◽  
Significant Difference ◽  
Vaginal Dilators ◽  
The Mean ◽  
Topical Estrogen

Abstract Background We aimed to evaluate the effects of different therapeutic options to prevent the evolution of vaginal stenosis after pelvic radiotherapy in women with cervical cancer. Methods open-label randomized clinical trial of 195 women, stage I-IIIB, aged 18–75 years, using topical estrogen (66), topical testosterone (34), water-based intimate lubricant gel (66), and vaginal dilators (29) to assess the incidence and severity of vaginal stenosis after radiotherapy at UNICAMP-Brazil, from January/2013 to May/2018. The main outcome measure was vaginal stenosis assessed using the Common Terminology Criteria for Adverse Events (CTCAE) scale and percental changes in vaginal volume. The women were evaluated at four different times: shortly after the end of radiotherapy, and four, eight, and 12 months after the beginning of the intervention. Statistical analysis was carried out using Symmetry test, Kruskal-Wallis test and multiple regression. Results the mean age of women was 46.78 (±13.01) years, 61,03% were premenopausal and 73,84% had stage IIB-IIIB tumors. The mean reduction in vaginal volume in the total group was 25.47%, with similar worsening in the four treatment groups with no statistical difference throughout the intervention period. There was worsening of vaginal stenosis evaluated by CTCAE scale after 1 year in all groups (p < 0.01), except for the users of vaginal dilator (p = 0.37). Conclusions there was a reduction in vaginal volume in all treatment groups analyzed, with no significant difference between them. However, women who used vaginal dilators had a lower frequency and severity of vaginal stenosis assessed by the CTCAE scale after one year of treatment. Trial registration Brazilian Registry of Clinical Trials, RBR-23w5fv. Registered 10 January 2017 - Retrospectively registered.

scholarly journals Efficacy and Safety of Inhaled Ciclesonide in Treating Patients With Asymptomatic or Mild COVID-19 in the RACCO Trial: Protocol for a Multicenter, Open-label, Randomized Controlled Trial (Preprint)

2020 ◽  
Author(s):  
Junko Terada-Hirashima ◽  
Manabu Suzuki ◽  
Yukari Uemura ◽  
Masayuki Hojo ◽  
Ayako Mikami ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Treatment Group ◽  
Controlled Trial ◽  
Symptomatic Treatment ◽  
Open Label ◽  
Exacerbation Rate ◽  
Treatment Groups ◽  
Randomized Controlled ◽  
Computed Tomography Images ◽  
Study Results

BACKGROUND Currently, there are no specific effective treatments for SARS-CoV-2 infection; however, various COVID-19 treatment options are under investigation. It is vital to continue investigating the landscape of SARS-CoV-2–induced pneumonia and therapeutic interventions. OBJECTIVE This paper presents the protocol for a randomized controlled trial that aims to compare the pneumonia exacerbation rate between ciclesonide (ALVESCO; Teijin Pharma Limited) administration and symptomatic treatment in patients with COVID-19 and to determine the efficacy of ciclesonide. The secondary objectives are to investigate the safety of ciclesonide administration, changes in clinical and laboratory findings, and the number of viral genome copies of SARS-CoV-2 over time between the 2 groups. METHODS In this investigator-initiated, exploratory, prospective, multicenter, parallel-group, open-label, randomized controlled trial, a total of 90 patients diagnosed with COVID-19 will be recruited from 21 hospitals in Japan based on specific inclusion and exclusion criteria. Participants will be randomized either to the ciclesonide group, which will receive a 400-µg dose of ciclesonide 3 times per day over a 7-day period, or to the symptomatic treatment group. Both groups will receive antitussives and antipyretics as required. Data collection for various parameters will be conducted on days 1, 2, 4, 8, 22, and 29 to record baseline assessments and the findings over an extended period. Computed tomography images taken prior to drug administration and 1 week following treatment will be compared, and efficacy will be confirmed by checking for pneumonia exacerbation. Primary endpoint analysis will be performed using the Fisher exact test to determine statistically significant differences in the pneumonia exacerbation rate between the ciclesonide and symptomatic treatment groups. RESULTS The first trial participant was enrolled on April 3, 2020. Recruitment is expected to be completed on September 30, 2020, while follow-up assessments of all participants are expected to be completed by October 31, 2020. The study results will be published in a peer-reviewed scientific journal. CONCLUSIONS The RACCO (Randomized Ciclesonid COVID-19) study will provide definitive comparative effectiveness data and important clinical outcomes data between the ciclesonide and symptomatic treatment groups. If the hypotheses that pneumonia exacerbation rate reduction is more significant in the ciclesonide treatment group than in the symptomatic treatment group and that ciclesonide is safe for use are valid, ciclesonide will serve as an important therapeutic option for patients with COVID-19. CLINICALTRIAL Japan Registry of Clinical Trials jRCTs031190269; https://jrct.niph.go.jp/en-latest-detail/jRCTs031190269 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/23830

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