scholarly journals A multi-centre phase 3 study comparing efficacy and safety of Bemfola® versus Gonal-f® in women undergoing ovarian stimulation for IVF

2021 ◽  
pp. 118-124
Author(s):  
M. Rettenbacher ◽  
A.N. Andersen ◽  
J.A. Garcia-Velasco
Keyword(s):  
Ovarian Stimulation ◽  
Similar Efficacy ◽  
Efficacy And Safety ◽  
Current Standard ◽  
Phase 3 ◽  
Treatment Groups ◽  
Equivalent Number ◽  
To Receive ◽  
Equivalence Margin ◽  
Severe Ovarian Hyperstimulation Syndrome

Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20–38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of ±2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 ± 5.11 versus Gonal-f 10.6 ± 6.06, mean difference: 0.27 oocytes, 95% confidence interval: -1.34–1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols.

scholarly journals EXPRESS: Efficacy and Safety of Tadalafil in a Pediatric Population with Pulmonary Arterial Hypertension: Phase 3 randomized, Double Blind Placebo-Controlled Study

2021 ◽  
pp. 204589402110249
Author(s):  
David D Ivy ◽  
Damien Bonnet ◽  
Rolf MF Berger ◽  
Gisela Meyer ◽  
Simin Baygani ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Statistical Significance ◽  
Significance Testing ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Statistical Significance Testing ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Treatment Groups ◽  
Pulmonary Arterial

Objective: This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH). Methods: This phase-3, international, randomized, multicenter (24 weeks double-blind placebo controlled period; 2-year, open-labelled extension period), add-on (patient’s current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with PAH. Patients received tadalafil 20 mg or 40 mg based on their weight (Heavy-weight: ≥40 kg; Middle-weight: ≥25—<40 kg) or placebo orally QD for 24 weeks. Primary endpoint was change from baseline in 6-minute walk (6MW) distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results: Patient demographics and baseline characteristics (N=35; tadalafil=17; placebo=18) were comparable between treatment groups; median age was 14.2 years (6.2 to 17.9 years) and majority (71.4%, n=25) of patients were in HW cohort. Least square mean (SE) changes from baseline in 6MW distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 [20.41] vs 36.60 [20.78] meters; placebo-adjusted mean difference [SD] 23.88 [29.11]). Safety of tadalafil treatment was as expected without any new safety concerns. During study period 1, two patients (1 in each group) discontinued due to investigator’s reported clinical worsening, and no deaths were reported. Conclusions: The statistical significance testing was not performed between the treatment groups due to low sample size, however, the study results show positive trend in improvement in non invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with PAH. Safety of tadalafil treatment was as expected without any new safety signals.

Efficacy and safety of IBI305 compared with bevacizumab in advanced non-squamous NSCLC patients as first-line treatment in a randomized, double-blind, phase III study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9095-9095
Author(s):  
Li Zhang ◽  
Bin Wu ◽  
Linian Huang ◽  
Meiqi Shi ◽  
Yunpeng Liu ◽  
...  
Keyword(s):  
Comparative Study ◽  
Maintenance Treatment ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
Phase 3 ◽  
Double Blind ◽  
Nsclc Patients ◽  
Equivalence Margin ◽  
First Line Treatment

9095 Background: IBI305 is a recombinant humanized anti-VEGF monoclonal antibody, a biosimilar candidate to bevacizumab in analytical and functional comparisons. Pharmacokinetic similarity has been demonstrated in healthy males. Here we present primary efficacy and safety results from a phase 3 comparative study in non-small cell lung cancer (NSCLC). Methods: In this double-blind, active-controlled study, subjects with advanced non-squamous NSCLC on first-line treatment with carboplatin and paclitaxel were randomized (1:1) to IBI305 or bevacizumab (15 mg/kg IV Q3W). After six cycles, patients were on maintenance treatment with IBI305 or bevacizumab (7.5 mg/kg IV Q3W) till progression. Clinical equivalence of the primary endpoint, confirmed objective response rate (ORR) was evaluated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) between study arms with the prespecified margin (0.75, 1.33). Results: A total of 450 subjects were randomized (IBI305: n = 224; bevacizumab: n = 226). Baseline characteristics were well balanced between treatment arms. ORR evaluated by Independent Radiological Review Committee (IRRC) in full analysis set (FAS) was 44.3% (98/221) for IBI305 and 46.4% (102/220) for bevacizumab; the RR for ORR was 0.95 (90% CI: 0.803, 1.135). Sensitive analysis result on RRs of ORR in Intention to Treat (ITT) population (IBI305: n = 224; bevacizumab: n = 226) and other analysis set were consistent and all within the prespecified equivalence margin. The medium PFS were 8.4 months for IBI305 and 8.3 months for bevacizumab and duration of response (DOR) was also similar in both arms. Treatment-emergent adverse events (TEAEs) were well balanced between treatment arms and consistent with the known adverse event profile of bevacizumab. Patients developing binding antibodies were 0.5% in the IBI305 arm vs 0% in the bevacizumab arm; no subject tested positive for neutralizing antibodies. Conclusions: This is the first released phase 3 clinical study with maintenance treatment for bevacizumab biosimilar in NSCLC patients till now. The comparative study met its predefined primary endpoint that the RR for confirmed ORR was within the prespecified equivalence margin. There was no significant difference between the two arms in safety profile and immunogenicity. Clinical trial information: NCT02954172.

scholarly journals Efficacy and safety of lanreotide autogel compared with lanreotide 40 mg prolonged release in Chinese patients with active acromegaly: Results from a phase 3, prospective, randomized, and open-label study (LANTERN)

2020 ◽  
Author(s):  
Zhenmei An ◽  
Ting Lei ◽  
Lian Duan ◽  
Pei Hu ◽  
Zhongping Gou ◽  
...  
Keyword(s):  
Chinese Patients ◽  
Prolonged Release ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Treatment Groups ◽  
Intention To Treat ◽  
Secondary Endpoints ◽  
Active Acromegaly ◽  
Lanreotide Autogel

Abstract Background: Lanreotide autogel is a somatostatin analog (SSA) approved for the treatment of acromegaly in 73 countries worldwide; however, it is not yet approved in China. The aim of this study was to evaluate the efficacy and safety of lanreotide autogel compared with lanreotide 40 mg prolonged release (PR) in Chinese patients with active acromegaly. Methods: LANTERN was a Phase 3, randomized, open-label, non-inferiority study. Patients with active acromegaly who had undergone surgery ≥3 months prior, or were unlikely or unable to undergo surgery, were treated with lanreotide autogel 60/90/120 mg (monthly deep subcutaneous injection) or lanreotide 40 mg PR (intramuscular injection every 7, 10, or 14 days) for 32 weeks. Primary endpoint was mean change-from-baseline in age-adjusted insulin-like growth factor-1 (IGF-1) standard deviations scores (SDS) at the end-of-study. Secondary endpoints included: growth hormone (GH) levels ≤2.5 µg/L or ≤1.0 µg/L, ≥20% reduction in tumor volume (TV) and safety. Results: In total, 128 patients were randomized and received study treatment. Lanreotide autogel was non-inferior to lanreotide 40 mg PR: treatment difference (95% CI) for IGF-1 SDS between groups was −0.32 (−0.74, 0.11; per protocol population) and −0.27 (−0.63, 0.09; intention-to-treat [ITT] population), respectively. Reductions in IGF-1 (−6.453 vs −7.003) and GH levels (−9.548 µg/L vs −13.182 µg/L), and the proportion of patients with ≥1 acromegaly symptom (−20.3% vs −32.5%) were observed from baseline to end-of-study in lanreotide autogel and lanreotide 40 mg PR groups, respectively. In the lanreotide autogel group, 45.5% (25/55) patients achieved ≥20% reduction in TV compared with 50.9% (25/53) in lanreotide 40 mg PR group (ITT). Safety profiles were similar in both treatment groups. Conclusions: Lanreotide autogel was non-inferior to lanreotide 40 mg PR in Chinese patients with active acromegaly after 32 weeks of treatment.

scholarly journals The Commands Trial: A Phase 3 Study of the Efficacy and Safety of Luspatercept Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low-, Low-, or Intermediate-Risk MDS in Erythropoiesis Stimulating Agent-Naive Patients Who Require RBC Transfusions

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Matteo Della Porta ◽  
Uwe Platzbecker ◽  
Valeria Santini ◽  
Guillermo Garcia-Manero ◽  
Rami S. Komrokji ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Epoetin Alfa ◽  
Phase 3 ◽  
Advisory Committees ◽  
Starting Dose ◽  
To Receive ◽  
Stimulating Factor ◽  
Rbc Transfusion

Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with &lt; 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with &lt; 5% blasts in the bone marrow, have sEPO levels &lt; 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden (&lt; 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but &lt; 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus &gt; 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO &gt; 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

scholarly journals 110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S67-S68
Author(s):  
Yihong Sun ◽  
Jia Fan ◽  
Gang Chen ◽  
Xiaofei Chen ◽  
Xiaoling Du ◽  
...  
Keyword(s):  
Clinical Cure ◽  
Additional Treatment ◽  
Double Blind Study ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Study Drug Administration ◽  
Treatment Groups ◽  
Secondary Endpoints ◽  
Abdominal Infections

Abstract Background In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants. Methods This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%. Results A total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). Conclusion C/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile. Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

scholarly journals Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials

Blood ◽  
2014 ◽  
Vol 124 (12) ◽  
pp. 1968-1975 ◽  
Author(s):  
Nick van Es ◽  
Michiel Coppens ◽  
Sam Schulman ◽  
Saskia Middeldorp ◽  
Harry R. Büller
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Similar Efficacy ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Key Points ◽  
Acute Venous Thromboembolism

Key Points DOACs have similar efficacy as VKAs in the treatment of acute symptomatic VTE, but significantly reduce the risk of major bleeding. The efficacy and safety of DOACs in the treatment of acute VTE are consistent in clinically important subgroups.

scholarly journals Multicenter, Randomized Study of the Efficacy and Safety of Intravenous Iclaprim in Complicated Skin and Skin Structure Infections

2009 ◽  
Vol 53 (7) ◽  
pp. 2834-2840 ◽  
Author(s):  
D. Krievins ◽  
R. Brandt ◽  
S. Hawser ◽  
P. Hadvary ◽  
K. Islam
Keyword(s):  
Randomized Study ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Skin Structure ◽  
Treatment Groups ◽  
Folate Pathway ◽  
Complicated Skin ◽  
Cure Rates ◽  
To Receive ◽  
Vancomycin Treatment

ABSTRACT Iclaprim is a novel antibacterial agent that is currently in development for the treatment of complicated skin and skin structure infections (cSSSI). Iclaprim specifically and selectively inhibits bacterial dihydrofolate reductase, a critical enzyme in the bacterial folate pathway, and exhibits an extended spectrum of activity against various resistant pathogens, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). The objective of this randomized, double-blind phase II study was to compare the efficacy and safety of iclaprim to those of vancomycin in patients with cSSSI. Patients were randomized to receive 0.8 mg iclaprim/kg of body weight, 1.6 mg/kg iclaprim, or 1 g vancomycin twice a day for 10 days. Clinical cure rates for the 0.8- and 1.6-mg/kg-iclaprim treatment groups were comparable to that for the vancomycin treatment group (26/28 patients [92.9%], 28/31 patients [90.3%], and 26/28 patients [92.9%], respectively). Iclaprim also showed high microbiological eradication rates. Iclaprim exhibited an eradication rate of 80% and 72% versus 59% observed with vancomycin for S. aureus, the pathogen most frequently isolated at baseline. Five MRSA cases were observed, four in the 0.8-mg/kg-iclaprim arm and one in the vancomycin arm, and all were both clinically and microbiologically cured. Iclaprim exhibited a safety profile similar to that of vancomycin, an established drug for the treatment of cSSSI. Results from this study indicate that iclaprim is a promising new therapy for the treatment of cSSSI, in particular those caused by S. aureus, including MRSA.

scholarly journals Efficacy and Safety of Azacitidine (AZA) in Combination with the Anti-PD-L1 Durvalumab (durva) for the Front-Line Treatment of Older Patients (pts) with Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy (IC) and Pts with Higher-Risk Myelodysplastic Syndromes (HR-MDS): Results from a Large, International, Randomized Phase 2 Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 829-829 ◽  
Author(s):  
Amer M. Zeidan ◽  
James Cavenagh ◽  
Maria Teresa Voso ◽  
David Taussig ◽  
Mar Tormo ◽  
...  
Keyword(s):  
Research Funding ◽  
Treatment Cycle ◽  
Surface Expression ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Treatment Groups ◽  
End Of Treatment ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
To Receive

Background: Loss of immune surveillance, mediated through immune checkpoint (ICP) interactions, is thought to be a key step in the development of cancers including AML and HR-MDS. AZA is a standard therapy for pts with AML who are unfit for IC and for pts with HR-MDS. AZA can promote immune recognition of tumor cells and potentially increase expression of ICP molecules, which can mediate resistance to AZA. As myeloid cell lines and samples from pts treated with hypomethylating agents demonstrated up-regulation of PD-L1 expression, blockade of the PD-L1 ICP with durva in combination with AZA may enhance antitumor activity and improve clinical outcomes. Here, we report the final results from a large phase 2 study evaluating the efficacy and safety of AZA+durva vs. AZA alone in pts with HR-MDS or AML (NCT02775903). Methods: This randomized, open-label, international, multicenter study enrolled untreated pts in 2 cohorts: 1) MDS (aged ≥18 years; IPSS-R intermediate, high, and very high) and 2) older AML pts (aged ≥65 years) who were ineligible for IC. All pts had ECOG performance status 0-2 and were separately randomized (1:1) to receive SC AZA 75 mg/m2 Days 1-7 and durva 1500 mg IV on Day 1 Q4W (Arm A) or AZA alone (Arm B) and stratified according to cytogenetic risk (MDS, very good/good/intermediate vs. poor/very poor; AML, intermediate vs. poor). Treatment was planned to continue until progression or unacceptable toxicity. Disease status was evaluated every third treatment cycle. Primary MDS endpoints included overall response rate (ORR, defined as complete remission [CR], marrow [m]CR, partial response [PR], or hematologic improvement [HI]) based on IWG 2006 response criteria, while for AML ORR was defined as CR or CR with incomplete blood recovery (CRi) based on modified IWG 2003 response criteria. Secondary endpoints included PFS, OS, and safety. Peripheral blood samples were collected to assess changes in DNA methylation using the EPIC methylation array (Illumina). Bone marrow (BM) aspirates were obtained for quantitation of PD-L1 surface expression by flow cytometry and values are reported as molecules of equivalent soluble fluorochrome. Results: A total of 213 pts, 84 with MDS (each arm, n=42) and 129 with AML (Arm A, n=64; Arm B, n=65) were randomized. As of October 31, 2018, 32 pts (MDS, n=14; AML, n=18) continued to receive trial treatment while 181 (MDS, n=70; AML, n=111) had discontinued. Baseline demographics and disease characteristics were generally balanced across treatment groups in both cohorts. Median number of treatment cycles for AML Arm A vs. B, 6.5 vs. 6.7; for MDS Arm A vs. B, 7.9 vs. 7.0. No statistically significant differences in ORR between treatment arms were observed in either cohort (Tables 1 and 2). In MDS Arm A vs. B, median OS was 11.6 vs. 16.7 months (mo) and PFS was 8.7 vs. 8.6 mo. In the AML cohort, median OS was 13.0 vs. 14.4 mo and PFS was 8.1 vs. 7.2 mo. Caution should be used when interpreting results because &gt;50% of patients were censored. The most frequent TEAEs (≥15%) were hematologic and GI toxicity. In the MDS and AML cohorts, 7 and 17, respectively, immune-mediated AEs were observed; all were treated and resolved. AZA induced similar trends in global hypomethylation, along with focal hypomethylation of PD-L1 and PD-L2 gene loci, at the end of treatment cycle 1 in all treatment groups and cohorts. Mean PD-L1 surface expression in BM immune cells at baseline was highest in monocytes (MDS=1,425; AML=1,536), followed by granulocytes (MDS=550; AML=758) and myeloid blasts (MDS=532; AML=735). Increased surface expression of PD-L1, but not PD-L2, was observed at the end of treatment cycle 3 on BM granulocytes and monocytes from MDS pts and on BM monocytes from AML pts, but no increase was detected on myeloid blasts. Conclusions: To our knowledge, this is the first large randomized trial of AZA with or without ICP blockade in older unfit AML and HR-MDS pts reported to date. No clinically meaningful difference in efficacy was observed between treatments for either cohort. No new safety signals or potential overlapping risks were identified with the combination. While the hypomethylating activity of AZA on PD-L1 gene was confirmed, no treatment-mediated induction of PD-L1 surface expression was observed on myeloid blasts. Disclosures Zeidan: Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria. Voso:Novartis: Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Taussig:Celgene: Research Funding. Boss:Celgene Corporation: Employment, Equity Ownership. Copeland:Celgene Corporation: Employment, Equity Ownership. Gray:Celgene Corporation: Employment, Equity Ownership. Previtali:Celgene Corporation: Employment, Equity Ownership. O'Connor:Celgene Corporation: Employment, Equity Ownership. Rose:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. OffLabel Disclosure: Durvalumab is a PD-L1 blocking antibody indicated for the treatment of patients with 1) locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, or 2) unresectable, stage 3 NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

scholarly journals Rivaroxaban for Treatment of Pediatric Venous Thromboembolism. an Einstein-Jr Phase 3 Dose-Exposure-Response Evaluation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 164-164
Author(s):  
Guy Young ◽  
Anthonie WA. Lensing ◽  
Paul Monagle ◽  
Christoph Male ◽  
Dagmar Kubitza
Keyword(s):  
Venous Thromboembolism ◽  
Similar Efficacy ◽  
Efficacy And Safety ◽  
Response Relationship ◽  
Phase 3 ◽  
Once Daily ◽  
Exposure Response ◽  
Suspension Formulation ◽  
Relationship Of ◽  
Repeat Imaging

Background: Venous thromboembolism (VTE) in children occurs with increasing frequency predominantly as a result of hospital-acquired thrombosis leading to a substantial rise in the use of anticoagulant medications in children. Only one anticoagulant (dalteparin, a subcutaneously administered agent) is licensed for use in children, but the evidence to support the use of anticoagulants in children is lacking. While several direct oral anticoagulants have been licensed and are in widespread use in adults, as of yet, none have been licensed for children and child-appropriate formulations are not commercially available. The EINSTEIN-Jr. program is a comprehensive clinical development program aimed at providing data to support the use (and eventual licensure) of rivaroxaban for children with VTE. The recently completed randomized EINSTEIN-Jr. phase 3 study showed similar efficacy and safety for rivaroxaban compared to standard anticoagulation for treatment of pediatric VTE. This abstract reports the results of the dose-exposure-response relationship of rivaroxaban from this study. The pediatric rivaroxaban dosing regimens were established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling and has been previously reported. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, 12-&lt;30, and &lt;12kg, respectively. In children weighing &lt;12kg, the lower range of the adult exposure range was targeted to avoid excessive concentrations at the end of the dosing interval. Previously, these regimens were confirmed for children weighing ≥20kg but only predicted in those &lt;20kg. Based on sparse blood sampling, the 24-hour area under the plasma concentration-time curve [AUC(0-24)ss] and trough [Ctrough,ss] and maximum [Cmax,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, change in thrombus burden at repeat imaging, and bleeding or adverse events. A taste and texture questionnaire was collected from suspension recipients. Results: Between November, 2014 and September, 2018, a total of 365 children were allocated to receive rivaroxaban in the following age groups: birth-&lt;0.5 years (n=13); 0.5-&lt;2 years (n=21); 2-&lt;6 years (n=44); 6-&lt;12 years (n=65); and 12-&lt;18 years (n=173). Of these, 316 (94.3%) were evaluable for PK analyses. A total of 121 (38.3%) children received the rivaroxaban tablet formulation and 195 (61.7%) the suspension formulation. Symptomatic recurrent VTE occurred in 2 children (0.6%) during rivaroxaban treatment. Repeat imaging outcomes in the asymptomatic children were classified as normalized in 124 (39.2%), improved in 125 (39.6%), no relevant change in 16 (5.1%), and deteriorated in 1 (0.3%). In 48 children (15.2%) the result of repeat imaging was uncertain. No major bleeding events occurred with rivaroxaban treatment, whereas clinically relevant non-major bleeding and trivial bleeding were observed in 10 (3.2%) and 111 (35.1%) children, respectively. With respect to the dose-exposure relationship, the vast majority of the individual values were within the 5th-95th percentile for AUC(0-24)ss, Cmax,ss and Ctrough,ss (see figure below on the left). With respect to exposure-response relationship, no clustering was observed for any of the PK parameters with respect to efficacy, bleeding (shown in the figure below on the right), or adverse event outcomes. The results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Conclusion: Treatment of children with bodyweight-adjusted rivaroxaban regimens resulted in exposures similar to those previously observed in adults receiving 20 mg once daily dosing and the level of exposure was not related to the efficacy, bleeding, or adverse events. Based on this analysis and in conjunction with the previously demonstrated similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that the bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide a new alternative treatment option for VTE in children. Figure Disclosures Young: Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria. Lensing:Bayer: Employment. Male:Bristol Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Bayer: Consultancy. Kubitza:Bayer: Employment. OffLabel Disclosure: Pediatric treatment of VTE for a drug approved only in adults.

Elderly subgroup analysis of a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7665-7665 ◽  
Author(s):  
R. H. Ansari ◽  
R. Gonin ◽  
M. Socinski ◽  
M. Edelman ◽  
R. Catalano ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Similar Efficacy ◽  
Outcome Data ◽  
Stage Iiib ◽  
Advanced Stage ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Platinum Based Chemotherapy ◽  
Specific Subgroup ◽  
Ecog Ps

7665 Background: Efficacy and safety of platinum-based chemotherapy doublets in elderly (ELD) NSCLC pts with good PS have been reported to be similar to those in younger pts (N-ELD). However, little data exists about which of the standard regimens are suitable for the ELD. To compare efficacy and safety of doublet regimens in the ELD, we conducted a retrospective age-specific subgroup analysis of our Phase 3 randomized trial comparing 3 regimens for advanced NSCLC (Treat, et al: Abst#7025, Proc ASCO 2005). Methods: A Phase 3 study in advanced (Stage IIIB/IV) NSCLC chemonaive patients with ECOG PS <2 was designed to compare the efficacy of a G-containing platinum regimen GCb (G 1000 mg/m2 IV D 1, 8 plus Cb AUC 5.5, D 1) to a nonplatinum G doublet GP (G 1000 mg/m2 IV D 1,8 plus P 200 mg/m2, D 1) and a reference regimen of PCb (P 225 mg/m2 plus Cb AUC 6.0, D 1). Outcome data of ELD pts (age =70) vs. N-ELD pts (age <70) were compared. Survival (OS) was the primary endpoint with secondary endpoints being response rate (RR), time to progression (TTP) and toxicity. Data from all 3 arms were pooled for this analysis. Results: A total of 314 ELD and 746 N- ELD pts were analyzed (GCb 111/245, GP 100/251, PCb 103/250). There were no significant differences in the OS or TTP distributions in ELD compared to N-ELD pts ( Table 1 ). In general, the incidence and grade of toxicity in ELD vs. N-ELD were comparable. ELD experienced moderately higher incidences of Grade 3–4 constitutional (12.6% vs. 7.1%), neurologic (16.1% vs. 8.9%), and pulmonary (12.3% vs. 7.9%) toxicities compared with N-ELD pts. Conclusion: Use of G-containing doublets as first-line chemotherapy showed similar efficacy to the standard PCb regimen in ELD and N-ELD patients with advanced/metastatic NSCLC as defined by OS, RR, and TTP. ELD tolerated these regimens well despite experiencing slightly more toxicity than younger patients. No significant financial relationships to disclose. [Table: see text]

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