TROPICS 2: A Phase III, Open-Label, Single-Arm Study of Tenecteplase for Restoration of Function in Dysfunctional Central Venous Catheters.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1074-1074
Author(s):  
Cameron Tebbi ◽  
John Costanzi ◽  
Robert J Shulman ◽  
Luke Dreisbach ◽  
Brian R Jacobs ◽  
...  
Keyword(s):  
Intracranial Hemorrhage ◽  
Major Bleeding ◽  
Thrombolytic Agent ◽  
Treatment Success ◽  
Central Venous Catheters ◽  
Phase Iii ◽  
Central Venous ◽  
Open Label ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 1074 Poster Board I-96 Introduction: For many patients, central venous catheters (CVCs) are the only option for vascular access. Thrombotic occlusion is a common complication of CVCs and can prevent delivery of treatment. The objectives of this phase III, open-label, single-arm study were to evaluate the safety and efficacy of the thrombolytic agent tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, in restoring function to occluded CVCs. Methods: Pediatric and adult subjects with dysfunctional non-hemodialysis CVCs, defined by the inability to withdraw 3 mL of blood (1 mL of blood for subjects weighing <10 kg) were eligible. Subjects received intraluminal tenecteplase at a dose of up to 2 mL (2 mg); subjects weighing <30 kg received instillations of tenecteplase equal to 110% of the internal lumen volume (maximum volume, 2 mL). Tenecteplase was allowed to dwell in the lumen for up to 120 minutes. CVC function, defined as the ability to both withdraw 3 mL of blood or fluid and infuse 5 mL of normal saline (1 mL and 3 mL, respectively, for subjects <10 kg), was assessed at 15, 30, and 120 minutes after drug instillation. If function was not restored at 120 minutes, the initial dose was withdrawn, and a second dose was instilled for up to 120 minutes. CVC assessments were repeated as for the first dose. The primary efficacy endpoint was restoration of CVC function within 120 minutes after a single administration of tenecteplase. All adverse events (AEs) were documented from instillation of the first tenecteplase dose through 48-96 hours after treatment. Targeted AEs (intracranial hemorrhage, major bleeding, embolic events, thrombosis, catheter-related bloodstream infection [CRBSI], and catheter-related complications) and study-drug–related serious AEs were recorded through 7 days after treatment. Results: Tenecteplase was administered to 246 subjects (mean age 43.6 years; range, 0-92 years), 72 (29.2%) of whom were under 17 years of age. Most subjects had a port catheter (69.5%), and the most frequent indication for catheter insertion was chemotherapy (78.0%). Most subjects (186; 75.6%) received only a single dose of tenecteplase, and 60 (24.3%) subjects required a second dose of tenecteplase. Restoration of CVC function was achieved in 177 (72.0%) subjects within 120 minutes after the first dose of tenecteplase. Following instillation of up to 2 doses of tenecteplase, CVC function was restored in 200 (81.3%) subjects, with similar restoration rates observed in pediatric (83.3%) and adult (80.5%) subjects. Among those who had treatment success and underwent catheter assessment within 7 days of treatment, 111 (81.0%) subjects maintained catheter patency. Thirty-one (12.6%) subjects experienced a treatment-emergent AE; the most common events were pyrexia (6 subjects), neutropenia (3 subjects), and nausea (2 subjects).Two targeted AEs were reported, both CRBSIs, but neither event was judged by the investigator to be related to tenecteplase; and in both cases, blood cultures were subsequently reported negative. No cases of intracranial hemorrhage, major bleeding, thrombosis, embolism, or catheter-related complications were reported. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase; however, this subject was concurrently receiving a chemotherapeutic agent, which the investigator also considered to be related to the AE. Conclusions: Serial administration of up to 2 doses of tenecteplase into CVCs is safe and effective for restoration of catheter function in pediatric and adult subjects with dysfunctional CVCs. Disclosures: Off Label Use: Tenecteplase is a thrombolytic agent under study for clearance of dysfunctional central venous catheters. Shulman:Takeda Pharmaceuticals: Research Funding; NPS Pharmaceuticals: Consultancy. Jacobs:Speaking engagements unrelated to commercial activity: Honoraria. Blaney:Genentech: Employment, Equity Ownership. Ashby:Genentech: Employment, Equity Ownership. Gillespie:Quintiles: Employment, Quintiles is a contract research organization contracted by Genentech to execute the TROPICS trials.. Begelman:Genentech: Employment, Equity Ownership.

TROPICS 1: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Tenecteplase for Restoration of Function in Central Venous Catheters.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 173-173
Author(s):  
Nashat Gabrail ◽  
Eric Sandler ◽  
Veena Charu ◽  
Nick Anas ◽  
Eduardo Lim ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Central Venous Catheters ◽  
Controlled Study ◽  
Central Venous ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Catheter Function

Abstract Abstract 173 Introduction: Central venous catheters (CVCs) are vital to the management of many acute and chronic diseases. These catheters facilitate infusion of therapeutic agents and nutritional products, withdrawal of blood and its constituents, and accurate assessment of hemodynamic variables. A common cause of CVC dysfunction is occlusion, most frequently due to thrombosis. In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy and safety of the thrombolytic tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, for restoring function to occluded CVCs. Methods: A dysfunctional CVC was defined as a catheter from which one could not withdraw 3 mL of blood (1 mL of blood for subjects weighing <10 kg). Eligible adult and pediatric subjects with dysfunctional non-hemodialysis CVCs were stratified by body weight (<30 kg and ≥30 kg) and randomized 1:1 to two treatment arms. In the first arm (TTP), subjects received an initial dose of intraluminal tenecteplase (T) and, if indicated, a second dose of tenecteplase and a third dose, consisting of placebo (P). In the PTT arm, placebo was instilled first followed by up to 2 doses of tenecteplase, if needed for restoration of catheter function. The dose of study drug was 2 mL (2 mg tenecteplase) in subjects weighing ≥30 kg. Subjects weighing <30 kg received a dose equal to 110% of the internal lumen volume of the CVC. Following the administration of each dose, CVC function was assessed at 15, 30, and 120 minutes. Restoration of catheter function was defined as the ability to withdraw at least 3 mL blood or fluid and infuse 5 mL normal saline (1 mL and 3 mL, respectively, for subjects <10 kg). Once catheter function was restored, or at 120 minutes after catheter assessment following the third dose, subjects exited the treatment algorithm. The primary efficacy endpoint was the percentage of subjects with restoration of catheter function within 120 minutes after a single administration of study drug. Secondary endpoints included cumulative rates of restoration of catheter function after up to 2 doses of tenecteplase and the percentage of subjects who maintained catheter patency up to 7 days after drug instillation. Adverse events (AEs) were monitored through 48–96 hours after treatment. Serious AEs judged related to the study drug and targeted AEs (intracranial hemorrhage [ICH], major bleeding, embolic events, thrombosis, catheter-related bloodstream infection [CRBSI], and catheter-related complications) were recorded through 7 days after treatment. Results: A total of 97 subjects received TTP (n = 50) or PTT (n = 47). The mean age was 39.6 years (range, 1–87 years); 34 subjects (35.1%) were <17 years old. The most common indication for catheter insertion was chemotherapy (n = 81; 83.5%). The majority of subjects had port catheters (n = 62; 63.9%), and 25 subjects (25.8%) had double-lumen catheters. Within 120 minutes of initial study drug instillation, catheter function was restored to 30 subjects (60.0%) in the TTP arm and 11 subjects (23.4%) in the PTT arm, for a treatment difference of 36.6 percentage points (95% CI, 18.4–54.8; P = .0002). Cumulative restoration rates for CVC function increased to 88.0% after a second dose of tenecteplase in the TTP arm, and the overall cumulative restoration rate was 86.6% after the second dose of tenecteplase in both arms combined. Catheter patency was 80.4% among subjects who had treatment success and whose catheters were accessed within 7 days posttreatment. Twenty subjects (20.6%) reported a treatment-emergent AE, with a similar incidence between treatment arms. Two targeted AEs, both deep vein thromboses, were reported, one of which was felt to be study drug related by the investigator. No cases of ICH, major bleeding, embolic events, CRBSIs, or catheter-related complications were reported. Conclusions: Tenecteplase is safe and effective for restoration of catheter function in pediatric and adult subjects with dysfunctional CVCs. Disclosures: Off Label Use: Tenecteplase is a thrombolytic agent under study for clearance of dysfunctional central venous catheters . Sandler:Governors Cancer Control and Reserach Advisory Board: Chair; Children's Oncology Group: Voting body steering committee; Wolfson Children's Hospital: Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Membership on an entity's Board of Directors or advisory committees. Charu:Glaxo-Smith-Kline: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anas:Genentech: Honoraria. Blaney:Genentech: Employment, Equity Ownership. Ashby:Genentech: Employment, Equity Ownership. Gillespie:Quintiles: Employment, Quintiles is a contract research organization contracted by Genentech to execute the TROPICS trials. Begelman:Genentech: Employment, Equity Ownership.

A Phase III, Open-Label, Single-Arm Study of Tenecteplase for Restoration of Function in Dysfunctional Central Venous Catheters

2011 ◽  
Vol 22 (8) ◽  
pp. 1117-1123 ◽  
Author(s):  
Cameron Tebbi ◽  
John Costanzi ◽  
Robert Shulman ◽  
Luke Dreisbach ◽  
Brian R. Jacobs ◽  
...  
Keyword(s):  
Central Venous Catheters ◽  
Phase Iii ◽  
Central Venous ◽  
Open Label

Safety and Efficacy of Alteplase for Restoring Function in Occluded Central Venous Catheters: Results of the Cardiovascular Thrombolytic to Open Occluded Lines Trial

2002 ◽  
Vol 20 (1) ◽  
pp. 317-324 ◽  
Author(s):  
Steven R. Deitcher ◽  
Mark R. Fesen ◽  
Paul M. Kiproff ◽  
Patricia A. Hill ◽  
Xin Li ◽  
...  
Keyword(s):  
Adverse Events ◽  
Multicenter Trial ◽  
Central Venous Catheters ◽  
Phase Iii ◽  
Central Venous ◽  
Open Label ◽  
Serious Adverse Events ◽  
Safety And Efficacy ◽  
End Point ◽  
Bleeding Episodes

PURPOSE: To evaluate the safety and efficacy of alteplase (TPA) for restoring function to occluded central venous catheters (CVCs). PATIENTS AND METHODS: The study design was a phase III, open-label, single-arm multicenter trial. Subjects with occluded, nondialysis CVCs were enrolled. All subjects received a 2-mg dose of TPA within the dysfunctional catheter lumen that was allowed to dwell for 30 to 120 minutes. Functionality was tested at 30 and 120 minutes. If the CVC remained obstructed at 120 minutes, a second 2-mg TPA dose was allowed to dwell for 30 to 120 minutes. The primary safety end point was the rate of intracranial hemorrhage (ICH) within 5 days of treatment, and serious adverse events were recorded up to 30 days. RESULTS: Nine hundred ninety-five patients received treatment (female, 562; male, 433; mean age, 50.7 years; range, 2 to 91 years). CVCs treated were as follows: single (26%), double (39%), or triple (6%) lumen catheters or ports (29%). The primary end point was 0% ICH within 5 days. There were no cases of death, major bleeding episodes, or embolic events attributable to treatment. Flow was successfully restored in 52% and 78% of CVCs at 30 and 120 minutes after one dose, and 84% and 87% at 30 and 120 minutes after a second dose, respectively. Restoration of flow was 86%, 93%, 90%, and 79%, for single, double, and triple lumen catheters and ports, respectively. Estimated 30-day catheter patency was 74%. CONCLUSION: A regimen of up to two 2-mg doses of TPA is safe and effective for the restoration of flow to occluded central venous catheters.

Antimicrobial central venous catheters do not reduce infections in pre-term babies

BMJ ◽  
2019 ◽  
pp. l4993
Author(s):  
Rob Cook ◽  
Duncan Fortescue-Webb ◽  
Rosie Martin
Keyword(s):  
Randomised Controlled Trial ◽  
Controlled Trial ◽  
Health Technology ◽  
Central Venous Catheters ◽  
Central Venous ◽  
Open Label ◽  
Health Technology Assessment Programme ◽  
Parallel Group ◽  
Randomised Controlled ◽  
Pragmatic Randomised Controlled Trial

The studyGilbert R, Brown M, Rainford N et al. Antimicrobial-impregnated central venous catheters for prevention of neonatal bloodstream infection (PREVAIL): an open-label, parallel-group, pragmatic, randomised controlled trial. Lancet Child Adolesc Health 2019;3:381-90.The study was funded by the NIHR Health Technology Assessment programme (project number 12/167/02).To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000782/antimicrobial-central-venous-catheters-for-pre-term-babies-do-not-reduce-infections

Final Results of Open-Label Treatment with Eltrombopag During ENABLE 1: A Study of Eltrombopag As An Adjunct for Antiviral Treatment of Hepatitis C Virus Associated with Thrombocytopenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2232-2232 ◽  
Author(s):  
Geoffrey Dusheiko ◽  
Nezam H Afdhal ◽  
Edoardo Giannini ◽  
Pei-Jer Chen ◽  
Kwang-Hyub Han ◽  
...  
Keyword(s):  
Platelet Count ◽  
Hepatitis C ◽  
Research Funding ◽  
Antiviral Treatment ◽  
Treatment Phase ◽  
Open Label ◽  
Employment Equity ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 2232 Introduction: Thrombocytopenia (TCP) is a common complication of cirrhosis in patients with hepatitis C virus (HCV) infections (Louie et al 2011); the presence of TCP impairs the ability to initiate peginterferon alpha (PEG) therapy and necessitates PEG dose reduction or discontinuation, thus reducing the potential for sustained virologic response (SVR). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic immune thrombocytopenia, increases platelet counts in patients with TCP due to HCV-related cirrhosis (McHutchison et al 2007). ENABLE 1 was a phase 3, multicenter, two-part study of eltrombopag for the treatment of HCV-associated TCP. Part 1 involved open-label, pre-antiviral treatment with eltrombopag. Patients achieving platelet counts ≥90,000/μL were randomized in Part 2 to receive eltrombopag or placebo in combination with antiviral therapy (PEG-2a plus ribavirin). Aim: To assess the safety and efficacy of eltrombopag during the open-label, pre-antiviral treatment phase (Part 1) of ENABLE 1 in patients with cirrhosis. Methods: Patients with chronic HCV and a baseline platelet count <75,000/μL were enrolled. In Part 1, all patients received open-label oral eltrombopag (25 mg daily with dose escalations every 2 weeks to a maximum dose of 100 mg) for up to 9 weeks or until platelet counts reached ≥90,000/μL. Patients who failed to achieve platelet counts ≥90,000/μL following 3 weeks of eltrombopag 100 mg daily did not enter Part 2 and attended scheduled follow-up visits. Patients achieving these counts were randomized 2:1 to eltrombopag or placebo (Part 2) at the final dose received in Part 1, in combination with antiviral therapy for up to 48 weeks. Results: A total of 716 patients were enrolled; 1 patient withdrew due to a protocol deviation, and 715 entered the open-label pre-antiviral phase. At study entry, most patients were male (62%) and Caucasian (72%); 17% were of Japanese/East Asian heritage. The median age was 52 years (range, 19–76). 488 patients (68%) had cirrhosis (FibroSURE™ score equivalent to METAVIR F4). The median duration of treatment during Part 1 was 20 days and the median of the mean daily dose was 25 mg (range, 0.8–75 mg). Median baseline platelets were 59,000/μL; these increased to 89,000/μL by week 2 and remained consistently elevated throughout open-label treatment (Figure). Following a median of 2 weeks of treatment (range, 0.1–9.6 weeks), 691 patients (97%) achieved platelet counts ≥90,000/μL. Treatment was discontinued during Part 1 for 33 patients (5%): platelets <90,000/μL (11); adverse events (AEs, 9); investigator discretion (7); patient decision (3); loss of follow-up (2); or a protocol deviation (1). During Part 2, 682 patients (95%) were randomized, 2 patients withdrew consent following randomization, and 680 patients (95%) initiated antiviral treatment. Of the patients who initiated treatment, 451 (66%) did so within 2 weeks and 627 (92%) did so within 4 weeks. The most common AEs observed during the open-label treatment phase were headache (7%), fatigue (4%), nausea (3%), and diarrhea (3%). Ninety-five patients (13%) experienced platelet counts >200,000/μL. No thromboembolic events were observed during open-label treatment. Conclusions: Eltrombopag was generally well-tolerated and resulted in sustained increase in platelet counts during the open-label, pre-antiviral treatment phase. Platelet count increases were seen as early as 2 weeks following initiation of treatment. The vast majority of patients (97%) achieved platelet count increases to ≥90,000/μL, the threshold for initiating PEG-2a plus ribavirin therapy, and most did so within 4 weeks of initiating eltrombopag treatment. Disclosures: Dusheiko: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Off Label Use: Eltrombopag, inteferon and Ribavirin; eltrombopag is a thrombopoetin receptor agonist. Its efficacy and safety in raising platelet counts in hepatitis C positive patients (most with cirrhosis) and thrombocyotopaenia was studied in this protocol. Afdhal:Merck: Consultancy, Honoraria, Research Funding; Vertex: Consultancy, Honoraria, Research Funding; Idenix: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Springbank: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmasett: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding. Giannini:GlaxoSmithKline: Consultancy, Speakers Bureau; Hoffman-LaRoche: Consultancy, Speakers Bureau. Chen:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Geib:GlaxoSmithKline: Employment. Vasey:GlaxoSmithKline: Employment. Patwardhan:GlaxoSmithKline: Employment, company shares. Campbell:GlaxoSmithKline: Employment, Equity Ownership. Theodore:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

Results of the OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects with Treatment Refractory or Relapsed Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 767-767
Author(s):  
Jorge E. Cortes ◽  
Eric J Feldman ◽  
Karen Yee ◽  
David A. Rizzieri ◽  
Anjali S. Advani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Iii ◽  
Elderly Subjects ◽  
Primary Therapy ◽  
Primary Analysis ◽  
Employment Equity ◽  
Once Daily ◽  
Equity Ownership

Abstract Abstract 767 Background: Tosedostat is a novel oral inhibitor of the M1/17 family of aminopeptidases which induces an amino acid deprivation response that is selectively toxic for myeloid blasts (Leuk Res. 2011: 5:677-81) and has shown promising activity in elderly relapsed/refractory AML patients (J Clin Oncol 2010:28:4333-8). Aims: The OPAL study was undertaken to compare the activity of tosedostat at a once-daily dose of 120 mg for 24 weeks compared to 240 mg once daily for 8 weeks followed by 120 mg once daily for a further 16 weeks., as measured by bone marrow and hematology responses at 24 weeks. Methods: This was a phase II randomized (1:1) multi-center study. Patients were eligible if aged 60 years or older with previous CR lasting <12 months, or no CR after primary therapy, had a peripheral blast count <30,000/μl, PS<2 and adequate renal, hepatic and cardiac function. The primary analysis was performed at 24 weeks using IWG 2003 criteria. Results: Seventy-three patients were randomized and received tosedostat, 38 at 120 mg and 35 at 240 mg. Median age was 72 (range, 64 to 86), and 59% were male. Twenty-six patients (36%) had secondary or therapy-related AML, of which 19 (26%) had prior MDS. Median time since AML diagnosis was 211 days and 38% had received primary therapy with cytarabine/anthracyclines; 36% with a hypomethylating agent (HMA) and 23% with other cytarabine regimes. Fifty-two percent had been refractory to primary therapy, 19% had previously had a remission of up to 6 months and 29% a 6–12 month remission (mean 97 days including refractory). Twenty-three patients (32%) had no post-treatment bone marrow sample taken, predominantly due to early progression: 34% completed 12 weeks on study and 14% completed 24 weeks and were eligible to enter an extension study which is ongoing. The overall response rate was 22%; (CR/CRp/MLFS 12%; PR 10%) and an additional 29% had a best response of stable disease. The most common adverse events which occurred (total; grade 3 or worse) were diarrhea (58%; 4.1%), peripheral edema (55%; 0%), fatigue (49%; 21%), dyspnea (41%; 16%), nausea (38%; 0%), decreased appetite (37%; 3%), febrile neutropenia (36%; 29%) and hypotension (36%, 10%). Median overall survival (OS) (at 15 July 2011) was 126 days. Median OS in patients with CR/CRp/MLFS, PR and SD were 280, 195 and 162 days respectively, and 261.5 days for patients with a response of PR or better. Median OS for patients with progression of disease or who were unevaluable was 61 days. Similar responses were seen in the two dose groups. Additional non protocol-specified analyses showed that the following types of patient appeared to respond well: AML NOC vs other AML types 16% vs 29% response, median OS 75 vs 168 days; patients with poor risk cytogenetics compared to intermediate/better, median OS 159 vs 107 days; those who received prior HMA compared to others, 38% vs 13% response, median OS 171 vs 104 days; and absence of prior CR 29% vs 14% response and median OS 169 vs 103 days. Conclusions: These results provide further encouraging evidence of efficacy and a favorable toxicity profile in a difficult to treat patient population. A phase III program of pivotal studies with tosedostat in AML and MDS will start in the near future. Disclosures: Cortes: Chroma Therapeutics Ltd.: Consultancy, Research Funding. Feldman:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Yee:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Rizzieri:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Advani:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Charman:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Toal:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Kantarjian:Chroma Therapeutics Ltd.: Consultancy, Research Funding.

A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3448-3448 ◽  
Author(s):  
Maria-Domenica Cappellini ◽  
John Porter ◽  
Raffaella Origa ◽  
Gian Luca Forni ◽  
Adberrahmane Laadem ◽  
...  
Keyword(s):  
Dose Level ◽  
Research Funding ◽  
Total Bilirubin Level ◽  
Thalassemia Major ◽  
Hemoglobin Level ◽  
Thalassemia Intermedia ◽  
Open Label ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background Beta (β)-thalassemia is characterized by ineffective erythropoiesis leading to anemia, bone marrow erythroid hyperplasia, iron overload, and organ failure. Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor (ActRIIA) fusion protein that increases the release of mature erythrocytes into circulation by acting mainly on late-stage erythropoiesis (Carrancio S, et al. Blood. 2012;120:abstract 372). Clinical data in healthy volunteers have shown that treatment with sotatercept results in increased red blood cell (RBC) parameters, including hemoglobin level (Ruckle J, et al. J Bone Miner Res. 2009;24:744-52). RAP-011, a murine ortholog of sotatercept, was efficacious in a mouse model of β-thalassemia intermedia, reducing ineffective erythropoiesis as well as significantly improving anemia and decreasing bilirubin levels, supporting the clinical development of sotatercept (Dussiot M et al. Blood 2012;120:abstract 247). Methods This is an ongoing phase 2a, multicenter, open-label, dose-finding study to determine a safe and active dose level of sotatercept in adult patients with RBC-transfusion dependent (TD) β-thalassemia major or patients with β-thalassemia intermedia who are either TD or non-transfusion dependent (NTD). The dose levels of sotatercept studied to date are 0.1, 0.3, and 0.5 mg/kg, given subcutaneously once every 3 weeks. Safety is assessed according to NCI-CTC grading. Efficacy is assessed by hemoglobin increase from baseline and/or reduction in transfusion burden. Secondary endpoints include assessment of biomarkers for erythropoiesis, hemolysis, iron metabolism, and bone metabolism, as well as in vitro dyserythropoiesis. Dose escalation to higher dose levels is planned contingent on data review and favorable safety profile as determined by the Steering Committee. Results Patient demographics. A total of 25 patients have been enrolled as of July 26, 2013; 8 in the 0.1 mg/kg cohort, 9 in the 0.3 mg/kg cohort, and 8 in the 0.5 mg/kg cohort. Treatment and analysis for the 0.5 mg/kg cohort is underway and will be updated and presented. In the 0.1 and 0.3 mg/kg cohorts, 3 (18%) patients had β-thalassemia major and 14 (82%) had β-thalassemia intermedia (12 of whom were NTD and 2 of whom were TD). Of the 12 NTD β-thalassemia intermedia patients, 6 were treated at the 0.1 mg/kg dose level and 6 at the 0.3 mg/kg dose level. Median baseline hemoglobin for these NTD patients was 8.6 g/dL (range 5.8 to 10.7 g/dL). Median number of sotatercept doses administered was 4 (range 2 to 7) in the 0.1 mg/kg cohort and 8 (range 3 to 9) in the 0.3 mg/kg cohort; 13/17 (76%) patients remained on treatment. Safety.Sotatercept was generally well tolerated. There were no dose-limiting toxicities reported. Two serious adverse events were reported in the 0.1 mg/kg cohort: a grade 2 phlebitis in an NTD patient with a history of high D-dimer at baseline, and a worsening grade 3 bone pain in a TD β-thalassemia major patient with a history of osteoporosis; both were considered possibly study drug-related. Hemoglobin levels/transfusion requirements. Among NTD patients, preliminary data showed that 1 (17%) patient in the 0.1 mg/kg cohort and all 6 (100%) patients in the 0.3 mg/kg cohort had at least a 1 g/dL increase in hemoglobin level from baseline; among these, 1 patient treated with sotatercept 0.3 mg/kg showed a 2 g/dL hemoglobin level increase from baseline as well as a decrease in total bilirubin level from 2.7 × upper limit of normal (ULN) at baseline to 1.8 × ULN. No other relevant decrease in total bilirubin level was reported at the lower dose levels (0.1 mg/kg or 0.3 mg/kg). Three TD patients were still receiving treatment (2 β-thalassemia intermedia and 1 β-thalassemia major). There had been no appreciable reduction in transfusion burden in the 0.1 and 0.3 mg/kg cohorts to date; however further follow up is warranted and an update will be presented. Conclusion Based on these preliminary data, sotatercept administered subcutaneously every 3 weeks may improve anemia via a novel mechanism of action with a favorable safety profile, thereby addressing a significant unmet medical need for patients with NTD β-thalassemia intermedia. The current data suggest a dose-dependent response that supports further evaluation of the exposure–effect relationship of sotatercept in patients with NTD β-thalassemia intermedia. The first, second, and last authors contributed equally to this abstract. Disclosures: Cappellini: Genzyme: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Off Label Use: Sotatercept is an investigational agent that is being assessed for efficacy and safety in beta-thalassemia. Porter:Novartis: Consultancy, Research Funding; Shire: Consultancy; Celgene: Honoraria. Forni:Celgene: Research Funding; Shire: Research Funding; Novartis Pharma: Research Funding. Laadem:Celgene Corp.: Employment, Equity Ownership. Galacteros:Celgene: Consultancy. Miteva:Celgene Corp.: Employment. Sung:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Klesczewski:Celgene Corp.: Employment. Attie:Acceleron Pharma: Employment. Hermine:Celgene Corporation: Consultancy, Research Funding.

Progression By Lymphocytosis Correlates with Favourable Long-Term Clinical Outcomes in Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4352-4352
Author(s):  
Alexandra Bazeos ◽  
Craig Gower ◽  
Francine Swann ◽  
Peter C Trask ◽  
Mark Dixon ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Physical Symptoms ◽  
Response To Therapy ◽  
Phase Iii ◽  
Rank Test ◽  
Outcome Analysis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Histological Transformation ◽  
Equity Ownership

Abstract BACKGROUND The evaluation of response to therapy in CLL is widely assessed according to the iwCLL guidelines which define progressive disease (PD) as advancing lymphocytosis, lymphadenopathy, organomegaly, cytopenias or histological transformation (Hallek, Blood, 2008). At the time of PD, considerable heterogeneity exists; patients (pts) with asymptomatic lymphocytosis seem to have a more indolent clinical course than those who progress by other means. On this basis, we hypothesized that the type of PD might impact on subsequent post-progression pt outcomes including the time to next treatment (TTNT) and overall survival (OS). METHODS All analyses were performed on data collected from pts enrolled in the CLL11 trial (NCT01010061), an open-label, randomized, pivotal phase III study comparing the efficacy and safety of obinutuzumab (GA101; GAZYVA) plus chlorambucil (Clb) with rituximab and Clb or Clb alone in treatment-naïve pts with CLL and pre-existing comorbidities (Goede, NEJM, 2014). Pts with defined PD, excluding death, were identified and assigned to 1 of 2 groups according to whether PD was by absolute lymphocyte count (ALC), or other, (non-ALC) causes, as per iwCLL criteria. Individuals could be allocated to only 1 group. To test whether subgroups were balanced at baseline (BL), characteristics between groups were compared for proportional differences using a Pearson chi-square test. Post-progression Kaplan-Meier survival curves for TTNT and OS were plotted by PD type. The log-rank test was used to detect significant differences in the treatment timings and survival distributions between groups, respectively. Group differences in the proportion of pts with cytopenia due to bone marrow (BM) infiltration (excluding autoimmune causes) were tested at BL and the time of PD. Similarly, B symptoms were calculated as the proportion of pts reporting disease-attributable fevers, night sweats or weight loss. Health-related quality of life (HRQoL) data were extracted from the EORTC QLQ-C30 and -CLL16 questionnaires. The mean and mean change scores by progression type were derived from BL and PD assessments. RESULTSOf the 781 pts enrolled in CLL11, progression data were available for 507 (64.9%) subjects. Of these, a total of 329 (64.9%) pts progressed by ALC, while the remaining 178 (35.1%) had PD from an alternative, non-ALC cause. At study BL, there were no differences in the demographics or disease characteristics between groups. The median post-progression TTNT for the ALC group was 373 days (95% CI [320, 449]) versus 120 days (95% CI [101, 209]) for the non-ALC group, (p < 0.0001) (Fig 1). Type of PD was also associated with a better OS in the ALC group (p = 0.0014) but the median time could not be accurately estimated due to insufficient events (Fig 2). A higher proportion of non-ALC pts demonstrated evidence of disease-related BM infiltration at PD (0.38 vs 0.24, p = 0.0013) with anemia (0.24 vs 0.10, p < 0.001) and neutropenia (0.16 vs 0.06, p < 0.001) representing the greatest differences between groups (Fig 3). Despite a trend towards a higher proportion of B symptoms in the non-ALC group at PD, significance was not achieved (p = 0.0624). Mean absolute HRQoL scores at BL, highlighted trends towards a higher level of functioning (higher scores) and milder physical symptoms (lower scores) in the ALC group. At the time of PD, those progressing by ALC reported clinically meaningful (6 point) higher role and physical functioning and measurably less fatigue, insomnia, dyspnea and pain. Within-group, mean score changes between BL and PD highlighted an overall trend towards improved functioning (QLQ-C30) over the course of treatment in the ALC group and a decline in function in the non-ALC group although differences were small. In general, both groups reported milder disease-related symptoms (QLQ-C30 and -CLL16) at PD with pts in the ALC group showing clinically meaningful improvements in fatigue and appetite. CONCLUSION These data provide the first comprehensive outcome analysis in CLL based on the mode of first progression for pts receiving upfront chemoimmunotherapy. We have shown that progression by ALC is consistently associated with a favourable clinical profile but whether our findings apply to pts in the relapsed setting or to those receiving other novel therapies is yet to be determined. An accurate estimate of survival by PD type might guide physician choice/timing of next treatments. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Bazeos: Roche: Employment. Gower:Roche Products Ltd: Employment. Swann:Roche: Employment. Trask:Genentech, Inc.: Employment, Equity Ownership. Dixon:Roche Products Limited: Employment, Equity Ownership. Crompton:Roche: Employment. Kinnersley:Roche-Genentech: Employment, Equity Ownership. Al-Sawaf:Gilead: Other: Travel grants. Goede:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Roche: Consultancy, Honoraria, Other: Travel grant, Research Funding. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:Genentech, Inc.: Employment.

scholarly journals Fostamatinib, a Spleen Tyrosine Kinase Inhibitor, for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia: Initial Results of the Multicenter, Open-Label Extension Period of the Soar Phase 2 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3612-3612 ◽  
Author(s):  
David J. Kuter ◽  
Richy Agajanian ◽  
Donald M. Arnold ◽  
Michael Boxer ◽  
Catherine Broome ◽  
...  
Keyword(s):  
Treatment Period ◽  
Research Funding ◽  
Rescue Therapy ◽  
Primary Efficacy ◽  
Phase 2 ◽  
Open Label ◽  
Employment Equity ◽  
Antiglobulin Test ◽  
Equity Ownership ◽  
Extension Period

Abstract Background: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and often serious disease characterized by antibody-mediated destruction of red blood cells (RBCs). Activation of Fc receptors on macrophages in turn activates spleen tyrosine kinase (SYK), which triggers a signaling cascade leading to phagocytosis of the antibody-bearing cells. Fostamatinib, a SYK inhibitor, markedly improved Hgb levels in 9 of 17 (53%) patients with wAIHA during a phase 2, open-label, multicenter study. This abstract reports the results of ongoing fostamatinib treatment as of 2 July 2018 in patients who completed the 24-week treatment period and rolled over into the extension period of the study. Methods: Eligible adult patients had primary or secondary wAIHA and had failed more than one prior treatment for wAIHA. Patients had to have hemoglobin (Hgb) <10 g/dL, an IgG-positive direct antiglobulin test, haptoglobin <10 mg/dL, and lactate dehydrogenase (LDH) >ULN. In order to enter the extension period of the study, patients had to have [1] met the primary efficacy endpoint (Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion) OR have shown a beneficial trend during the 24-week treatment period and [2] tolerated study drug. Fostamatinib 150mg BID (or the dose taken at the end of the 24-week treatment period, if a dose reduction had occurred) was taken orally with no food restriction, and patients were seen every 6 weeks during the extension period. Results: Six patients have entered the extension period including 5 who had met the primary efficacy endpoint and 1 who showed a beneficial trend at Week 24 (and had a response at Week 30). One patient had lymphoproliferative disease. Prior AIHA treatment included splenectomy (1), steroids (6), and rituximab (2). The median duration of disease was 1.9 years (range 0.4-15.7). The mean age was 58.7 years (range 30-86), 5 were female, all were white, and 4 were Hispanic or Latino. At baseline the median Hgb was 9.1 g/dL (range: 8.6-9.5); the median lactate dehydrogenase was 273 U/L (range 233-781); the median reticulocyte count was 252.2 x109/L (range 7.8-350.0); and the median haptoglobin was 7.0 mg/dL (range 7.0-9.0). The direct antiglobulin test was positive for IgG in 5 patients at screening. Median Hgb levels increased over the course of the study. See figure. Four of 6 patients had an ongoing response as of the data cutoff date, and none has had rescue therapy or an RBC transfusion. All 6 patients had ≥1 adverse event (AE) during the study, including noninfectious diarrhea in 1 (treatment-related), hepatic disorders in 3 (treatment-related in 2; treatment interrupted in 1), and hypertension in 1 (not related). One patient had a serious AE (inappropriate antidiuretic hormone secretion), which was not related to fostamatinib. To date, no new safety signals have been detected. Summary/Conclusion: Patients with wAIHA continued to display markedly improved Hgb levels during the extension period of the study. Side effects were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure. Figure. Disclosures Kuter: ONO: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen Inc.: Consultancy; Principia: Research Funding; Bioverativ: Consultancy, Research Funding; Argenx: Consultancy; Syntimmune: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arnold:Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Boxer:Incyte: Speakers Bureau; Rigel: Speakers Bureau; AbbVie: Speakers Bureau. Broome:Bioverativ: Honoraria; Alexion: Honoraria. Field:Prolong: Research Funding; Ironwood: Consultancy, Research Funding; Incyte: Research Funding. Lowe:Rigel: Consultancy. Tong:Rigel: Employment, Equity Ownership. Zayed:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership.

scholarly journals Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 690-690 ◽  
Author(s):  
Srdan Verstovsek ◽  
Alessandro M. Vannucchi ◽  
Alessandro Rambaldi ◽  
Jason R. Gotlib ◽  
Adam J. Mead ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Phosphate Binders ◽  
Phase 2 ◽  
Open Label ◽  
Employment Equity ◽  
Advisory Committees ◽  
Lymphoid Neoplasms ◽  
Equity Ownership

Abstract Introduction: Myeloid/lymphoid neoplasms (MLNs) with rearrangement of FGFR1 on chromosome band 8p11 are rare but aggressive neoplasms characterized by heterogeneous presentation with myeloid and/or lymphoid proliferation, extramedullary involvement, and rapid progression to blast phase (Strati P, et al., Leuk Lymphoma. 2018;59:1672-1676). FGFR1 gets constitutively activated through fusion genes involving various partner genes, most frequently ZMYM2-FGFR1 or BCR-FGFR1 as consequence of a t(8;13)(p11;q12) or a t(8;22)(p11;q11), respectively. Chemotherapy is usually ineffective, effective targeted treatment has not been described, and allogeneic hematopoietic stem cell transplant (alloHSCT) is the only potentially curative option. Pemigatinib, a selective, potent, oral inhibitor of FGFR1, 2, and 3, has shown efficacy in patients with FGF/FGFR-activated tumors, including cholangiocarcinoma and urothelial carcinoma. We report interim results from the ongoing fight-203 study (NCT03011372) of pemigatinib in patients with FGFR1-rearranged MLNs. Methods: Fight-203 is a phase 2, open-label study enrolling patients ≥ 18 years of age with FGFR1-rearranged MLN. Patients enrolled in the study must have progressed on ≥ 1 prior treatment and be ineligible for alloHSCT. Patients receive a daily oral dose of pemigatinib 13.5 mg on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint is overall clinical benefit rate, which includes complete clinical (CR) or partial clinical response (PR), and either complete or partial cytogenetic response (CCyR, PCyR). Secondary endpoints include duration of response/benefit, progression-free survival, overall survival, and safety/tolerability. Efficacy is assessed by evaluation of bone marrow histomorphology changes, standard cytogenetic and FISH evaluation of the FGFR1 rearrangement, and PET/CT scan. Results: At data cutoff (July 23, 2018), 14 patients were enrolled. Ten patients who had ≥ 1 response assessment were included in the analysis (Table). Patients received an average of 6.9 cycles of pemigatinib (range, 2-12 cycles). Median number of prior lines of therapy was 3 (range, 0-5), including 2 patients who received alloHSCT. Eight patients (80%) had a major CyR, including 6 patients with CCyR and 2 with PCyR. Eight patients (80%) had a CR or PR in bone marrow, peripheral blood, and extramedullary disease. One patient died of progression to myeloid blast crisis, 2 patients were bridged to alloHSCT, and 7 patients are ongoing. The most common treatment-emergent adverse events (AEs) were hyperphosphatemia (n=7 [70%]), diarrhea (n=5 [50%]) and anemia (n=5 [50%]); hyperphosphatemia was managed with diet and phosphate binders. Nine events in 4 patients (40%) were grade 3/4; 2 of these events (diarrhea and leukopenia) in 2 patients were related to pemigatinib. There were no drug-related AEs leading to dose interruption, dose reduction, or discontinuation. Conclusions: Pemigatinib showed promising efficacy, with an 80% major CyR rate accompanied by complete or partial remission, and was generally well tolerated by patients with FGFR1-rearranged MLN. The protocol was amended to allow continuous dosing, and the study is currently enrolling. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gotlib:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Promedior: Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mead:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy; Evotek: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elstar: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. Asatiani:Incyte: Employment, Equity Ownership. Lihou:Incyte: Employment, Equity Ownership. Zhen:Incyte: Employment, Equity Ownership. Reiter:Incyte: Consultancy, Honoraria.

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