scholarly journals Pacifica: A Randomized, Controlled Phase 3 Study of Pacritinib Vs. Physician's Choice in Patients with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocytopenia Myelofibrosis with Severe Thrombocytopenia (Platelet Count <50,000/mL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4175-4175 ◽  
Author(s):  
Claire N Harrison ◽  
Aaron T. Gerds ◽  
Jean-Jacques Kiladjian ◽  
Konstanze Döhner ◽  
Sarah A Buckley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Severe Thrombocytopenia ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Jak2 Inhibitor ◽  
Oncology Research ◽  
Equity Ownership

Background: Myelofibrosis (MF) is a life-limiting condition with severe morbidity in advanced stages. Patients with MF and severe thrombocytopenia (platelet counts <50,000/mL) have a particularly poor prognosis, with more frequent anemia and leukopenia, higher rates of hemorrhagic and thrombotic complications, and worse overall survival (~15 months) compared to the overall MF population (Scotch AH, et al, Leuk Res. 2017; Masarova L, et al, Eur J Haematol. 2018). Moreover, effective treatment options are limited in this high-risk population as the currently approved JAK inhibitor, ruxolitinib (RUX), is associated with treatment-related thrombocytopenia and often requires dose reductions for patients with platelet counts <100,000/mL, with reduced efficacy compared to patients able to tolerate higher doses. Further, there is no approved dose of RUX for patients with platelet counts <50,000/mL, and NCCN guidelines encourage physicians to consider clinical trials for such patients given the lack of approved therapies. Pacritinib (PAC) is an oral JAK2/IRAK1 inhibitor that has demonstrated clinical activity in MF patients in two prior Phase 3 studies (PERSIST-1, PERSIST-2) as well as a Phase 2 dose-finding study (PAC203), including patients with severe thrombocytopenia. The PACIFICA trial has been designed to evaluate the efficacy and safety of PAC 200 mg BID vs. physician's choice (P/C) therapy in patients with MF and severe thrombocytopenia. Study Design and Methods: PACIFICA is a randomized, controlled Phase 3 trial of PAC vs. P/C in adult patients with primary or secondary MF who are not candidates for stem cell transplant, with DIPSS intermediate- or high-risk disease, ECOG PS ≤2, and platelet counts <50,000/mL, who have had up to 90 days of prior treatment with a JAK2 inhibitor or are JAK2 inhibitor-naïve. Additional exclusion criteria exist for patients with recent cardiac or hemorrhagic events, ejection fraction <50%, QTc >450 msec, or use of medications that increase the risk of hemorrhage or QT prolongation. On the PAC arm, patients receive continuous PAC 200mg BID. On the P/C arm, one of the following agents is selected prior to randomization: low-dose ruxolitinib (no more than 5 mg BID while platelet counts remain <50,000/mL), thalidomide, lenalidomide, corticosteroids, or hydroxyurea. The primary objective is to compare the efficacy of PAC vs. P/C based on the proportion of patients achieving a ≥35% spleen volume response (SVR) at Week 24. Secondary objectives include comparisons of the proportion of patients achieving a ≥50% reduction in total symptom score (TSS) at Week 24, overall survival, and proportion of patients who self-assess as "very much improved" or "much improved" as measured by the patient global impression of change (PGIC). Tertiary endpoints include alternative methods of evaluating SVR improvement, hematologic improvement (transfusion independence and improvement in anemia and thrombocytopenia), improvement in fatigue as measured by the PROMIS - Fatigue - Short form 7a, and changes in mutated allelic burden and gene expression (including correlation with response data). The study will enroll ~180 patients in a 2:1 ratio (PAC to P/C), which will have >80% power to achieve the primary endpoint. Enrollment is anticipated to begin in Q3 2019, as PACIFICA is expected to open as an amendment to the Phase 2 PAC203 study (NCT03165734) in select sites. Disclosures Harrison: Janssen: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; AOP: Honoraria; Promedior: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria. Gerds:Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Incyte: Consultancy, Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Buckley:CTI BioPharma: Employment, Equity Ownership. Smith:CTI BioPharma: Employment, Equity Ownership. Craig:CTI BioPharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; NS Pharma: Research Funding; Roche: Research Funding.

Cumulative Response to Eltrombopag and Impact of the Number of Prior ITP Therapies: Interim Results of a Long-Term Extension Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3297-3297
Author(s):  
James B Bussel ◽  
Christine K Bailey ◽  
Andres Brainsky
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 3297 Background: Patients with chronic immune thrombocytopenia (ITP) have an increased risk of bleeding, ranging from minor to life-threatening. The goal of treatment is to increase and maintain platelets in a safe range to prevent bleeding. Guidelines state that achieving platelet counts of 30,000/μL to 50,000/μL in patients without other risk factors avoids the most serious complications of ITP, namely intra-cerebral or gastrointestinal hemorrhage (George 1996; Provan 2010). Many patients are refractory or relapse after multiple treatments. Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic ITP. In 6-week, and 6-month, placebo-controlled trials in patients with heavily pre-treated chronic ITP, eltrombopag increased platelets and reduced bleeding and the need for concomitant ITP therapy (Bussel 2007; Bussel 2009; Cheng 2011). Long-term treatment with eltrombopag is being evaluated in EXTEND, an extension study in chronic ITP patients who completed a previous eltrombopag study (Saleh 2010). Aims: To analyze in EXTEND the ability of eltrombopag to increase platelet counts to ≥50,000/μL in >50% and >75% of assessments and to determine whether the number of prior ITP therapies influences this ability. Methods: Patients in EXTEND received eltrombopag or placebo in 1 of the following prior studies of eltrombopag in chronic ITP: a 6-week phase 2 (TRA100773A; Bussel 2007) or phase 3 (TRA100773B; Bussel 2009) study, a 6-month phase 3 study (RAISE; Cheng 2011), or a phase 3 study of intermittent treatment (REPEAT; Psaila 2008). Dosing in EXTEND is individualized in order to maintain platelet counts ≥50,000/μL and <200,000/μL while minimizing the use of concomitant ITP medications. For the purpose of this analysis, response is defined as a platelet count ≥50,000/μL. Results: Among the 299 patients enrolled in EXTEND between June 2006 and February 2010, 67 (22%), 73 (24%), 47 (16%), and 112 (37%) patients had received 1, 2, 3, and ≥4 prior therapies (excluding eltrombopag). The most commonly used prior therapies were corticosteroids (81%), IVIg (45%), splenectomy (38%), and rituximab (23%). Of the 299 patients enrolled, 70% achieved response in >50% of study assessments and 46% achieved response in >75% of assessments. Among 210 patients treated ≥12 months, 79% achieved response in >50% of assessments and 56% in >75% of assessments. Among 138 patients treated for ≥24 months, 82% achieved response in >50% and 59% in >75% of assessments. Response in >50% and >75% of assessments by the number of prior therapies was similar between the groups (Figure 1). The proportion of patients who achieved a response in >50% of assessments was similar between splenectomized and non-splenectomized patients (65% and 73%, respectively). Conclusion: The majority of patients treated with eltrombopag for ≥12 months achieved a platelet count of ≥50,000/μL in >50% of study assessments. This response was observed even among patients previously treated with 4 or more ITP therapies, suggesting that eltrombopag may be a viable treatment option even for more refractory chronic ITP patients. Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

Case Studies Of Remission In Adults With Immune Thrombocytopenia (ITP) Following Cessation Of Treatment With The TPO Receptor Agonist Romiplostim

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 328-328
Author(s):  
James B. Bussel ◽  
Xuena Wang ◽  
Melissa Eisen
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Regulatory Cell ◽  
Platelet Counts ◽  
Long Term Treatment ◽  
Wide Range ◽  
Equity Ownership

Abstract Background In adults, ITP (characterized by platelet counts <100x109/L) is typically chronic, with remission reported infrequently ≥3 y post-diagnosis (Sailer, Haematol 2006). The TPO-mimetic romiplostim increases platelet counts and reduces use of concomitant ITP medications in chronic ITP. While often perceived as a long-term treatment, dose adjustment rules allow romiplostim to be discontinued when hemostatic platelet counts are reached, as reported in Amgen trials (pivotal trials, 2011 EHA, 2011 ASH) and case reports. Methods Data from 8 romiplostim trials (4 phase 3, 2 single-arm, and 2 extension trials) were examined for cases in which patients receiving romiplostim subsequently had ≥26 consecutive wks of platelet counts ≥50x109/L without romiplostim or any other ITP medications. The number of evaluable patients could not be calculated as many trials had dosing rules that did not allow for the reduction of romiplostim in patients with platelet counts <400x109/L (making remission unlikely), treatment durations varied by study, and follow-up data were not always available. Results Twenty-seven patients had ≥26 wk of platelet counts ≥50x109/L without romiplostim or any other ITP medications (Table; data from 4 of these patients were presented at ASH 2011). These patients had characteristics of median (Q1, Q3) time since ITP diagnosis of 2.1 (0.5, 4.2) y, with 17/27 having ITP >1 y, mean (SD) baseline platelet count of 20.9 (15.41) x109/L, median (Q1, Q3) age of 49.0 (36.0, 67.0) y, and mean (SD) maximum dose prior to remission of 4.6 (3.6) µg/kg. Of the 27 patients, 12 (44%) were splenectomized at baseline and 15 (56%) were male. Patients had from 40 to 276 cumulative wks of romiplostim with doses ranging from 0.1 to 4.3 µg/kg. Prior to romiplostim treatment, minimum platelet counts ranged from 1-37x109/L and individual average platelet counts ranged from 1-152x109/L. On treatment, minimum (1-182x109/L) and average (121-654x109/L) platelet counts ranged widely. The median (Q1, Q3) time to remission was 7.1 (1.9, 12.7) months. Only 3 patients (3, 6, 15) had bleeding of grade 3; the remainder had either bleeding of grade 1 or 2 or none. Conclusions The patient population who entered clinical remission (platelet counts ≥50x109/L for 26 wks) after treatment with romiplostim generally had: ITP of less than 5 y duration, a wide range of ages (23-78 y), about equal proportions of men and women, were as likely to be splenectomized as not, and no significant bleeding. Therefore, it is difficult to predict which patients would have this response. Reporting of these cases was not predefined, so a prospective assessment, such as the phase 2 single-arm study currently underway (NCT01143038), will provide a more comprehensive evaluation of remission with romiplostim. Potential mechanisms for the phenomenon of remission, both in early and late stages of ITP, may involve T-regulatory cell function, increased numbers/activity of natural killer T-cells, or increased B-regulatory cell activity. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; GSK: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Wang:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Baseline Characteristics and Symptom Burden in RESPONSE: A Randomized, Open-Label, Phase 3 Study of Ruxolitinib In Polycythemia Vera Patients Resistant to or Intolerant of Hydroxyurea

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4071-4071 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Jean-Jacques Kiladjian ◽  
Martin Griesshammer ◽  
Tamás Masszi ◽  
Simon Durrant ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Symptom Burden ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Jak2 Inhibitor ◽  
Open Label Phase ◽  
Night Sweats ◽  
Equity Ownership

Abstract Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is characterized by elevated hematocrit requiring phlebotomy, splenomegaly, a variety of symptoms and increased thrombotic risk. Ruxolitinib, a JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses in a phase 2 study of patients (pts) with PV who were resistant to or intolerant of hydroxyurea (HU). Pts experienced phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) counts, platelet (PLT) counts, and disease-related symptoms. Here, we describe the baseline (BL) characteristics and symptom burden of pts in a phase 3 study of ruxolitinib in pts with PV who are resistant to or intolerant of HU. Methods RESPONSE is a randomized (1:1), open-label, phase 3 study (NCT01243944) comparing the efficacy and safety of ruxolitinib with best available therapy (BAT) in pts with PV who are resistant to or intolerant of HU (modified European LeukemiaNet criteria), have splenomegaly, and require phlebotomy for inadequate hematocrit (Hct) control. Fourteen disease-related symptoms were assessed on a scale of 0 (absent) to 10 (worst imaginable) using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Blinded data are presented here. Results BL demographic data are available for the 222 enrolled pts (Table). Apart from HU, other common prior medications for PV included interferons (15%), PLT aggregation inhibitors (10%), alkylating agents (3.6%), alkyl sulfonates (3.2%), pyrimidine analogues (1.8%), and nitrosoureas (1.4%). The majority of pts (54.5%) had 1 phlebotomy within 12 weeks prior to screening; 23.9% had 2 and 17.1% had 3 or more phlebotomies. RESPONSE BL demographics are generally similar in terms of age (60 years vs 57-67); sex (66% male vs 58%-68%); Hct (44% vs 45%-48%); and platelets (419 x 109/L vs 320-429 x 109/L) to other PV studies including trials of givinostat (Finazzi BJH 2013) and AOP2014 (Gisslinger ASH 2012) and the ECLAP-PV (Marchioli JCO 2005) and CYTO-PV studies (Marchioli NEJM 2012). At the time of writing, BL symptom data from the MPN-SAF were available for 164 pts (Table). Pts in this study reported a similar symptom burden as PV pts from a large study of pts with MPNs (Emanuel JCO 2012; N = 1425; PV, n = 538), including similar mean scores for early satiety, abdominal discomfort, concentration problems, night sweats, itching, and tiredness/fatigue. In addition, prior therapy may have adversely affected BL symptom burden, as many of these symptoms (concentration problems, night sweats, fatigue) have been shown to be worsened by the use of conventional therapy to strictly control Hct (< 45%) and cardiovascular risk (Emanuel EHA 2013). BL MPN-SAF symptom data for all 222 pts will be presented. In addition, correlations between BL EORTC QLQ-C30 and MPN-SAF scores will be presented. Summary/Conclusions Demographic and BL symptom data from the RESPONSE study demonstrated that pts with HU refractory or intolerant PV have a significant disease burden that includes a variety of symptoms. These findings are consistent with those of Emanuel (JCO 2012), which showed that pts with PV have a significant symptom burden and a reduced quality of life. Pts with PV in the RESPONSE study are representative of those who have been studied in other clinical trials for the treatment of PV. Disclosures: Vannucchi: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF and by the European Commission and Health Canada for the treatment of disease-related splenomegaly or symptoms in adult patients with MF. Here, we describe the baseline (BL) characteristics and symptom burden of patients in a phase 3 study of ruxolitinib in patients with PV who are resistant to or intolerant of HU. Kiladjian:Novartis: Honoraria; Shire: Honoraria. Durrant:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pane:Novartis: Consultancy, Honoraria; Shire: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; SBio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. He:Incyte: Employment. Leopold:Incyte: Employment, Stock options Other. Li:Novartis: Employment, Equity Ownership. Pirron:Novartis: Employment, Equity Ownership. Lawniczek:Novartis: Employment. Verstovsek:Incyte: Research Funding.

Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3026-3026 ◽  
Author(s):  
Jesús F. San-Miguel ◽  
Vania T.M. Hungria ◽  
Sung-Soo Yoon ◽  
Meral Beksac ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Final Analysis ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Study Therapy

Abstract Introduction: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including epigenetics and protein metabolism. In the phase 3 clinical trial PANORAMA 1, panobinostat in combination with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression-free survival of approximately 4 months compared with that with placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex). Further analyses of patient outcomes by prior treatment demonstrated that the magnitude of PFS benefit was greatest among patients who received at least 2 prior regimens, including bortezomib and an immunomodulatory drug (IMiD; PAN-BTZ-Dex [n = 73]: 12.5 months [95% CI, 7.3-14.0 months]; Pbo-BTZ-Dex [n = 74]: 4.7 months (95% CI, 3.7-6.1 mo; HR 0.47 [95% CI, 0.32-0.72]). These data supported the regulatory approvals of PAN-BTZ-Dex for the treatment of patients with multiple myeloma who received at least 2 prior regimens, including bortezomib and an IMiD. Here we present the final analysis of overall survival (OS) for the entire patient population and among patients who received at least 2 prior regimens, including bortezomib and an IMiD. Methods: The study design for the PANORAMA 1 trial was described previously (San-Miguel. Lancet Oncol. 2014;15:1195-206). The key secondary endpoint was OS. As of June 29, 2015, the 415 events required to conduct the final analysis of OS had been observed. Kaplan-Meier estimation was utilized for OS analyses for the entire population (N = 768), the pre-specified subgroup of patients who received prior bortezomib and IMiD (n = 193), and patients who received at least 2 prior regimens including bortezomib and an IMiD (n = 147). Results: The median OS of patients who received PAN-BTZ-Dex in the overall population was 40.3 months (95% CI, 35.0-44.8 months) vs 35.8 months (95% CI, 29.0-40.6 months) for the Pbo-BTZ-Dex arm with HR 0.94 [95% CI, 0.78-1.14], P = .5435 (Fig 1A). The percentage of patients in each arm who received post-study therapy was 37.7% in the PAN-BTZ-Dex arm and 48.8% in the Pbo-BTZ-Dex arm. The median OS of patients who received at least 2 prior lines, including bortezomib and an IMiD, was 25.5 months (95% CI, 19.6-34.3 months) in the PAN-BTZ-Dex arm vs 19.5 months (95% CI, 14.1-32.5 months) in the Pbo-BTZ-Dex arm (Fig. 1B). The proportion of patients in this subgroup who received post-study therapy was 35.6% in the PAN-BTZ-Dex arm and 66.2% in the Pbo-BTZ-Dex arm. Conclusion: For the overall PANORAMA 1 study population, patients in the PAN-BTZ-Dex arm demonstrated an increase in median OS of 4.5 months vs patients in the Pbo-BTZ-Dex arm, but this result was not statistically significant (P = .5435). Median OS was also slightly longer for the PAN-BTZ-Dex arm among the more heavily pretreated subgroup of patients who received at least 2 prior regimens, including bortezomib and an IMiD. A higher percentage of patients on the Pbo-BTZ-Dex arm received post-study therapy vs the PAN-BTZ-Dex arm, which may have confounded the OS results. In summary, PAN-BTZ-Dex demonstrates statistically significant increases in PFS vs Pbo-BTZ-Dex in patients with relapsed or relapsed and refractory MM; however, this did not translate to a statistically significant increase in OS. Future trials will plan to focus on further optimization of dose and schedule of panobinostat and bortezomib to improve outcome, as well as novel combinations with other agents, including IMiDs and next-generation proteasome inhibitors. Figure 2. Figure 2. Disclosures Beksac: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau. Dimopoulos:Janssen: Honoraria; Janssen-Cilag: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Jedrzejczak:Onconova: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 737-737
Author(s):  
Paul G. Richardson ◽  
Marcie Riches ◽  
Nancy A. Kernan ◽  
Joel A. Brochstein ◽  
Shin Mineishi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Final Analysis ◽  
Occlusive Disease ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), is a rare and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Severe cases, historically defined by multi-organ dysfunction (MOD), may be associated with mortality rates of >80%. There is no FDA-approved treatment for VOD/SOS. Defibrotide (DF) has a proposed mechanism of action that includes stabilization of endothelial cells and restoration of thrombo-fibrinolytic balance. Earlier analyses of a pivotal phase 3 trial of DF in VOD/SOS plus MOD (Richardson et al. Blood. 2009;114:Abstract 654) underpinned approval of DF in the EU to treat severe hepatic VOD/SOS after HSCT. Additional data were obtained at the request of US health authorities. Here we present the final analysis: day +100 survival (primary endpoint) and complete response (CR; secondary). Methods This was a multicenter, open-label, phase 3 historical control (HC) study assessing DF. Eligible patients met Baltimore VOD/SOS criteria (total bilirubin ≥2.0 mg/dL with ≥2 of: hepatomegaly, ascites, or 5% weight gain) by day +21 post-HSCT, plus MOD (renal [trebling of creatinine levels, reduced creatinine clearance, or dialysis] and/or pulmonary [oxygen saturation ≤90%, need for oxygen supplementation/ventilator dependence]) by day +28 post-HSCT. Exclusion criteria included severe graft-versus-host disease (GvHD) of liver or gut, clinically significant bleeding, or need for ≥2 pressors. HC patients were reviewed for inclusion/exclusion criteria in a sequential review of medical charts starting 6 months prior to use of DF at each site; a blinded medical review committee made the final determination of HCs unequivocally meeting criteria for VOD/SOS with MOD. DF dose was 25 mg/kg/d in 4 divided 2-hour IV infusions q6h; recommended treatment duration was ≥21 days. Primary endpoint was day +100 survival. CR by day +100 was a secondary endpoint. Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival (ie, ventilator and/or dialysis dependency at entry, age ≤/>16 years, transplant type, and prior HSCT). Analyses included patients treated with DF and HCs. Results There were 102 patients in the DF group and 32 cases selected as HCs. Baseline characteristics were similar in the DF and HC groups: mean age (26 and 25 years; 43% and 44% ≤16 years), allogeneic graft (88% and 84%), prior HSCT (13% and 9%), ventilator- and/or dialysis-dependent at study entry (33% and 22%), myeloablative conditioning (87% and 94%), and the most common underlying diseases (acute leukemias: 45% and 47%), respectively. In the DF-treated group, common GvHD medications included tacrolimus (49%), methotrexate (41%), and cyclosporine (38%); in the HC group, common medications were cyclosporine (72%) and methotrexate (63%). Survival at day +100 in the DF and HC groups was 38% and 25%, respectively. The propensity-stratified difference in survival was 23.0% (95.1% CI, 5.2-40.8, P = .0109). Respective observed CR rates by day +100 were 25.5% and 12.5%, and the propensity-stratified difference in CR was 19.0% (95.1% CI, 3.5-34.6, P = .0160). Comparing the earlier EU and final analyses, the survival rates at day +100 in each group did not vary; however, the propensity adjusted final analysis provided a different level of statistical significance. Day +100 CR rates in the original analysis were slightly lower in both arms at 24% and 9% due to increased data capture to investigate CR; the P value was essentially unchanged. For the DF group, 45% had an adverse event (AE) at least possibly related to study drug, and 21% had a serious AE at least possibly related to study drug. In this very sick population, percentages of patients with ≥1 AE leading to death were similar between DF and HC patients (64% and 69%), as were hemorrhagic AEs (64%, 75%) and hypotension (39%, 50%). Conclusions Based on observed study data and using a propensity-adjusted rate difference estimator, patients treated with DF had a 23% reduction in risk of death by day +100 and 19% improvement in CR rate. Overall incidence of hemorrhage and fatal AEs were similar between groups with AEs consistent with those expected in this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Marizomib, pmalidomide, and low dose dexamethasone in RR MM. Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. . Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Guinan:Gentium SpA/Jazz Pharmaceuticals: Other: My institution received fees for research.. Martin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Steinbach:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Krishnan:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Jazz: Consultancy; Millenium: Speakers Bureau. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding. Rodriguez:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Doyle:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. D'Agostino:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Massaro:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Iacobelli:Gentium SpA: Employment. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Gentium SpA: Other: Personal fees during conduct of the study.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4248-4248 ◽  
Author(s):  
Uwe Platzbecker ◽  
David P. Steensma ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
The Impact ◽  
Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

Long-Term Safety and Efficacy of Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP): Report of up to 5.5 Years of Treatment in EXTEND.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2198-2198
Author(s):  
Mansoor N Saleh ◽  
Gregory Cheng ◽  
James B Bussel ◽  
Paul Burgess ◽  
Kalpana Bakshi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Drug Induced ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 2198 Background: Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of chronic ITP. Eltrombopag safely increased platelets and reduced bleeding in 6-week and 6-month placebo-controlled trials in patients with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP patients who completed a previous eltrombopag study. Methods: Patients had received eltrombopag or placebo in a prior study. Eltrombopag was started at 50 mg and titrated to between 75 and 25 mg daily or less often, based on platelet counts. Patients were considered to have completed EXTEND if they had received ≥2 years of therapy and transitioned off due to commercial availability of eltrombopag, whether or not they continued with treatment. The study started in June 2006, and an update on long-term safety and efficacy up to February 2012 is presented. Results: Of 302 patients enrolled, 31% (95) completed the study, 48% (146) withdrew, and 20% (61) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), patient decision (14%), and lack of efficacy (11%). Platelet counts at baseline were ≤15,000/μL (43%), >15,000-<30,000/μL (27%), 30,000–50,000/μL (17%), and >50,000/μL (13%); 38% were splenectomized, 33% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. 253 patients were treated for ≥6 months, 217 for ≥1 year, 176 for ≥2 years, and 59 for ≥4 years; 10 patients (3%) were treated for ≥5 years. Median duration of exposure was 121 weeks (range, 0.3–285 weeks), and median average daily dose was 51.4 mg. Overall, 85% (257/302) of patients achieved a platelet count ≥50,000/μL in the absence of rescue therapy, and 62% of patients achieved platelets ≥50,000/μL for ≥50% of on-treatment weeks. The proportion of patients achieving platelets ≥50,000/μL was similar regardless of baseline splenectomy status: splenectomy, 80% vs no splenectomy, 88%. Median platelet counts increased to ≥50,000/μL by Week 2 and remained consistently ≥50,000/μL through Week 241. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 57% at baseline to 16% at Week 52, 19% at Week 104, 12% at Week 156, and 14% at Week 208. Clinically significant bleeding (WHO grades 2–4) decreased from 17% at baseline to 4%, 5%, 0%, and 0% at Weeks 52, 104, 156, and 208, respectively. AEs and serious AEs (SAEs) occurred in 91% (275) and 29% (89) of patients, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (22%). 43 patients (14%) were withdrawn due to AEs, 29 (10%) of which were SAEs. Twenty-five thromboembolic events (TEEs) were reported in 19 patients (6%); the incidence rate is 2.70/100 patient years (95% CI, 1.62–4.21). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 patients experienced the TEE at or shortly after their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (FDA Guidance for Industry Drug-Induced Liver Injury, 2009) were reported in 36 patients (12%). None were associated with signs of liver impairment, and most resolved either while on treatment or after discontinuation. Eight patients were withdrawn as a result of HBLA. An independent central pathology review of bone marrow (BM) biopsies stained for reticulin from 113 patients treated with eltrombopag for up to 4.75 years revealed no clinically relevant increase in reticulin deposition. 2 patients (2%) had maximum reticulin grade of ≥MF-2 after >24 months on treatment; neither experienced any AE or abnormality in hematologic parameters potentially related to impaired BM function. Conclusions: Eltrombopag was effective in increasing and maintaining platelets ≥50,000/μL and reducing bleeding symptoms in patients with chronic ITP. Eltrombopag was well tolerated with exposures up to 5.5 years. Rates of TEE and HBLA have not increased with longer time on treatment, and analyses of BM biopsies revealed no clinically significant increase in reticulin deposition. No new safety signals were observed in this long-term study. Long-term safety and efficacy continue to be assessed. Disclosures: Cheng: GlaxoSmithKline: Honoraria, Speakers Bureau. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties. Bailey:GlaskoSmithKline: Employment, Equity Ownership.

Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3201-3201
Author(s):  
Srdan Verstovsek ◽  
Jean-Jacques Kiladjian ◽  
Ruben Mesa ◽  
Mark M Jones ◽  
Shui He ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Jak2 Inhibitor ◽  
Equity Ownership ◽  
To Receive ◽  
Response Trial

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control. Methods: Phlebotomy-dependent PV pts with splenomegaly, aged ≥18 years, and resistant to or intolerant of HU were enrolled. Pts were required to have HCT between 40%−45% 14 days prior to randomization; those who did not could enter a phlebotomy control period to achieve a HCT in this range within 14 days of randomization. Eligible pts were randomized 1:1 to RUX or BAT. BAT pts could cross over to receive RUX from Wk 32 if they had not met the primary endpoint, or after Wk 32 due to protocol-defined disease progression. The primary composite endpoint comprised HCT control and a ≥35% reduction from baseline in spleen volume (SV) at Wk 32. HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In pts who were HCT control non-responders (HCT-N) as defined by protocol, time to second phlebotomy eligibility was evaluated. For this analysis, pts without phlebotomy eligibility were excluded and phlebotomies in the first 8 wks were not considered. Patient-reported outcomes were evaluated in both HCT control responders (HCT-R) and HCT-N, including the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the Patient Global Impression of Change (PGIC). Results: Of 222 randomized pts (RUX, n=110; BAT, n=112), most were male (RUX, 60%; BAT, 71%) and the median age (range) was similar between treatment arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]). Although pts had a HCT between 40% and 45% within 14 days prior to randomization (with or without phlebotomy), 24% of pts had a HCT >45% on Day 1 (similar between treatment arms) illustrating that many pts have poor HCT control over short intervals of observation. RUX treatment resulted in long-term benefits on HCT levels, even in pts who did not achieve protocol-defined HCT control through Wk 32. Among the RUX HCT-R group, the probability of maintaining HCT response was 97% at 48 wks and 87% at 80 wks. Most BAT pts crossed over to receive RUX immediately after the Wk 32 visit (84% between Wks 32 and 48). In the RUX HCT-N pts, the median time to subsequent phlebotomy eligibility was 52 wks, compared with 21 wks for BAT HCT-N pts (Figure). Compared with the entire BAT group, more RUX-R and RUX-N pts had a ≥50% improvement in the MPN-SAF total symptom score at Wk 32 (RUX-N, 38%; RUX-R, 40%; BAT, 4%). Median changes from baseline at Wk 32 in key symptoms such as tiredness (RUX-N; −50%; RUX-R, −49%; BAT, −4%), itching (RUX-N, −88%; RUX-R, −97%; BAT, −2%), and night sweats (RUX-N, −100%; RUX-R, −97%; BAT, 4%) were also greater among RUX-R and RUX-N pts than BAT pts. RUX-N and RUX-R pts were also more likely to consider their symptoms to be “much improved” or “very much improved” on the PGIC compared with BAT pts (RUX-N, 57%; RUX-R, 74%; BAT, 13%). Conclusion: Among pts receiving RUX who did not achieve protocol-defined HCT control, the median time to subsequent phlebotomy eligibility was 1 year. In contrast, pts on BAT had a median time to subsequent phlebotomy eligibility of 21 wks. Furthermore, pts in the RUX arm achieved meaningful improvements in PV-related symptoms, regardless of meeting the endpoint of HCT control, while pts treated with BAT showed worsening or no improvement. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 409-409 ◽  
Author(s):  
Valeria Santini ◽  
Antonio Almeida ◽  
Aristoteles Giagounidis ◽  
Stephanie Gröpper ◽  
Anna Jonasova ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

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