scholarly journals Rationale and Design of a Phase 3 Study to Evaluate the Efficacy and Safety of ION-682884 in Patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5764-5764 ◽  
Author(s):  
Rodney H Falk ◽  
Morie A Gertz ◽  
Merrill D Benson ◽  
Gustavo Buchele ◽  
Michela Brambatti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Parent Compound ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Study Visit ◽  
Clinical Events ◽  
Patient Reported

Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a life-threatening, irreversible condition, which can lead to heart failure (HF) and, ultimately, heart transplant or death. Despite the recent approval in United States of a TTR stabilizer (VYNDAQEL®-tafamidis meglumine;VYNDAMAX™-tafamidis) for the treatment of ATTR-CM, disease progression still occurs. This study aims to determine if treatment with AKCEA-TTR-LRx (ION-682884), an antisense oligonucleotide (ASO), is safe and superior to placebo in reducing the risk of cardiovascular (CV) death or CV clinical events in patients with hereditary (hATTR-CM) or wild-type ATTR-CM (wtATTR-CM). Study Design and Methods: AKCEA-TTR-LRx (ION-682884) is a follow-on compound that incorporates the Ligand-Conjugated Antisense (LICA) technology; in this case, a triantennary N-acetyl galactosamine (GalNAc) moiety which targets the asialoglycoprotein receptors (ASGPR) expressed abundantly on the hepatocyte cell surface. In comparison to inotersen, its parent compound, ION-682884 requires a lower dose and frequency of administration (27-fold smaller; 45mg SC Q4W) to achieve a similar reduction in ATTR, providing greater patient convenience. ION-682884-CS2 (EudraCT No: 2019-002835-27) is a Phase 3 global, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of AKCEA-TTR-LRx (ION-682884) in hATTR-CM or wtATTR-CM patients receiving available background standard of care (SoC) therapy. Approximately 750 patients with a history of HF due to ATTR-CM will be randomized 1:1 to receive AKCEA-TTR-LRx (ION-682884) or placebo administered by subcutaneous injection once every 4 weeks. The main inclusion criteria include confirmed diagnosis of ATTR-CM by tissue biopsy or positive PYP/DPD scan, end-diastolic interventricular septum thickness of >12mm, NT-proBNP >600 pg/mL, NYHA class I-III and 6-minute walk distance (6MWD) >150 m. The main exclusion criteria include estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2, platelet count below the low limit of normality and urine protein/creatinine ratio (UPCR) ≥ 1000 mg/g. Patients are allowed to concomitantly receive tafamidis/tafamidis meglumine as SoC for ATTR-CM, if locally approved and available, per physician's discretion. The study consists of a 120-week Treatment Period and a 20-week Post-Treatment Evaluation Period. During each study visit, subjects will undergo laboratory tests, cardiac assessments (echocardiography), and functional evaluations. Patient-reported outcomes (PRO) will also be collected. Primary efficacy endpoint is the composite of CV mortality and frequency of CV clinical events (HF-related urgent visits requiring administration of IV diuretics and/or CV-related hospitalizations) at Week 120 study visit, analyzed by the Finkelstein-Shoenfeld method. This test is based on the principle of each patient in the study being compared with every other patient in a pairwise manner in hierarchical fashion. Secondary endpoints include the change from baseline in the 6MWD, Kansas City Cardiomyopathy Questionnaire score, rate of CV mortality, CV clinical events, and all-cause of mortality at Week 120. Additional exploratory endpoints include a change from baseline in cardiac imaging parameters, renal function, biomarkers, and PROs questionnaires and disease scores. An interim analysis on change from baseline in 6MWD is also planned at Week 60. All deaths and CV clinical events will be adjudicated by an independent, blinded Clinical Adjudication Committee, using predefined endpoint criteria. Conclusions: Despite recent advances, there is still a need for more efficacious, safe and convenient treatment options for ATTR-CM. The ION-682884-CS2 is a large Phase 3 trial designed to evaluate the clinical efficacy and safety of AKCEA-TTR-LRx (ION-682884) compared to placebo for the treatment of ATTR-CM. Figure Disclosures Falk: Ionis Pharmaceuticals: Consultancy. Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Proclara: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Benson:Ionis Pharmaceuticals: Research Funding. Buchele:Ionis Pharmaceuticals: Employment. Brambatti:Ionis Pharmaceuticals: Employment. Tsimikas:Ionis Pharmaceuticals: Employment. Viney:Ionis Pharmaceuticals: Employment. Tai:Ionis Pharmaceuticals: Employment. Monteiro:Ionis Pharmaceuticals: Employment. Yang:Ionis Pharmaceuticals: Employment. O'Dea:Akcea Therapeutics: Employment. Karwatowska-Prokopczuk:Akcea Therapeutics: Employment. Schneider:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment.

scholarly journals Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Regis Peffault De Latour ◽  
Jeffrey Szer ◽  
Austin Kulasekararaj ◽  
Jin Seok Kim ◽  
Caroline I. Piatek ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibitor ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged &gt;65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged &gt;65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or &gt;65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged &gt;65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (&gt;65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged &gt;65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the &gt;65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (&gt;65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

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

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

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.

scholarly journals Impact of Body Weight Adjusted Dose on Efficacy and Safety of Radotinib in Chronic Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3086-3086
Author(s):  
Hayeon Noh ◽  
Su Young Jung ◽  
Jae-Yong Kwak ◽  
Sung-Hyun Kim ◽  
Suk Joong Oh ◽  
...  
Keyword(s):  
Body Weight ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Fixed Dose ◽  
Efficacy And Safety ◽  
Dosing Regimen ◽  
Phase 3 ◽  
Advisory Committees

Abstract Background: Radotinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). It is typically administered as a fixed dose; however, a subanalysis of the Phase 2 study (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278) demonstrated that as the dose adjusted for body weight (Dose/BW) increased the risk of dose-limiting toxicity (DLT) significantly. Aims: To assess the impact of Dose/BW of radotinib on the occurrence of DLT as well as on the achievement of major molecular response (MMR) using the clinical data obtained from the Phase 3 study Methods: The Phase 3 study involved 160 CP-CML patients who were randomly assigned to a fixed dose of radotinib 300 mg BID or 400 mg BID regardless of BW. The authors performed a logistic regression analysis to evaluate the relationship between daily Dose/BW and the probability of achieving MMR at 12 months as well as experiencing DLT by 12 months. Chi-square test and Kaplan-Meier analysis (log-rank test) were utilized to compare the incidence of MMR and DLT, respectively, according to specific Dose/BW cut-offs. Results: Efficacy. Dose/BW of radotinib was negatively associated with the rate of MMR when controlled for gender (p = 0.033). That is, increasing Dose/BW rather decreased the likelihood of achieving MMR. More specifically, patients who received ≥13 mg/kg/d showed a significantly lower rate of MMR at 12 months (35%) than those who received <13 mg/kg/d (56%) (p = 0.045). Safety. Dose/BW of radotinib was positively associated with the rate of DLT (p = 0.003). A Dose/BW cut-off 13 mg/kg/d yielded the largest difference in the rate of DLT, such that the patients who received ≥13 mg/kg/d had a substantially higher rate of DLT (91%) than those who received <13 mg/kg/d (57%) (p <0.001). The time at which 50% of patients experienced their first DLT was also much earlier in the ≥13 mg/kg/d group (83 days) than in the <13 mg/kg/d group (194 days) (p <0.001). Conclusion: Dose adjustment of radotinib based on BW is warranted so as not to exceed 13 mg/kg/d. Therefore, a two-tier weight-based dosing regimen was developed: radotinib 300 mg BID for patients who weigh 60 kg or less, and 400 mg BID for patients who weigh more than 60 kg. A prospective clinical trial would be needed to confirm the efficacy and safety of this new dosing regimen. Disclosures Noh: Il-Yang Pharmaceutical: Research Funding. Jung:Il-Yang Pharmaceutical: Research Funding. Park:Il-Yang Pharmaceutical: Employment. Jo:Il-Yang Pharmaceutical: Employment. Shin:Il-Yang Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Lee:Il-Yang Pharmaceutical: Research Funding.

A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide Combined with Melphalan and Prednisone In Patients ≥ 65 Years with Newly Diagnosed Multiple Myeloma (NDMM): Continuous Use of Lenalidomide Vs Fixed-Duration Regimens

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 622-622 ◽  
Author(s):  
Antonio Palumbo ◽  
Michel Delforge ◽  
John Catalano ◽  
Roman Hajek ◽  
Martin Kropff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Fixed Duration ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Risk Of Progression ◽  
Grade 3

Abstract Abstract 622 Background: Lenalidomide is an oral IMiD® compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and has proven efficacy in patients with MM. The current study (MM-015) is a prospective, randomized phase 3 trial designed to evaluate the efficacy and safety of continuous lenalidomide treatment (MPR-R: melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in transplant-ineligible patients with NDMM. Methods: 459 patients aged ≥ 65 years with NDMM, stratified by age and International Staging System (ISS) stage were randomized to receive MPR-R, MPR, or MP. During double-blind treatment, patients received melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), with or without lenalidomide 10 mg/day (D1-21) for nine 28-day cycles. Following 9 cycles of MPR, patients received maintenance lenalidomide (10 mg/day; D1-21) or placebo until progression; MP patients received placebo until progression. Patients with progressive disease (PD) could enroll in the open-label extension phase (OLEP) and receive lenalidomide at 25 mg/day (D1-21) with or without dexamethasone at 40 mg/day (D1-4, 9–12, and 17–20). The primary comparison for this trial was MPR-R vs MP. Updated data from a pre-planned interim analysis at 70% of events (median follow-up of 21 months) are presented. Results: MPR-R compared with MP resulted in a higher overall response rate (ORR; 77% vs 50%, P <.001) as well as higher rates of complete response (16% vs 4%, P < .001) and very good partial response (VGPR) or better (32% vs 12%, P < .001). Responses were more rapid in patients receiving MPR-R compared with MP (median 2 vs 3 months, P < .001), and improved over time. Overall, MPR-R reduced the risk of disease progression by 58% compared with MP (hazard ratio [HR] = 0.423, P < .001) with a higher 2-year progression-free survival (PFS) rate (55% vs 16%). PFS was extended in patients receiving continuous lenalidomide therapy vs fixed-duration MP regardless of gender, ISS stage (stage I/II vs III), kidney function (creatinine clearance ≥ 60 vs < 60 mL/min), or baseline β2-microglobulin (≤ 5.5 vs > 5.5 mg/L). A landmark analysis comparing MPR-R and MPR initiated at the beginning of cycle 10 demonstrated that maintenance lenalidomide resulted in a 69% reduced risk of progression compared with placebo (HR = 0.314, P < .001). In addition, regardless of induction response (≥ VGPR or PR), patients who received maintenance lenalidomide had longer PFS compared with placebo. Importantly, patients relapsing during MPR-R had similar second-line treatment duration (median 55 weeks) compared with those relapsing while on placebo following MPR or MP (median 68 and 54 weeks, respectively). Additionally, PD rates during the OLEP were similar across all treatments (13% for each). Thus, outcomes of patients who relapse following continuous lenalidomide are similar to those who relapse following fixed-duration regimens, suggesting maintenance lenalidomide is not associated with more aggressive relapse. Follow-up remains too short to identify significant overall survival differences between the 3 groups. MPR-R had a manageable safety profile with minimal cumulative toxicities. Discontinuation rates due to adverse events (AEs) for patients treated with MPR-R and MP were 20% and 8%, respectively. Grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 71%, 38%, and 24% of patients receiving MPR-R and 30%, 14%, and 17% of those receiving MP; no grade 3/4 peripheral neuropathy was observed. Importantly, maintenance lenalidomide was as well tolerated as placebo, with few grade 3/4 AEs. During maintenance, low rates of thrombocytopenia (3% vs 2%, respectively), neutropenia (2% vs 0%), deep vein thrombosis (1% vs 0%), and fatigue (1% vs 0%) were observed. Conclusions: MPR-R achieved a higher ORR, as well as better quality and more rapid responses vs MP. Furthermore, MPR-R compared with fixed-duration regimens of MP and MPR resulted in an unprecedented reduction in the risk of progression with a manageable safety profile, and similar rates of PD in subsequent OLEP treatment. These data suggest that continuous lenalidomide therapy with MPR-R is superior to regimens of limited duration by providing sustained disease control in transplant-ineligible patients with NDMM. Disclosures: Palumbo: 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; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria. Kropff:OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Dimopoulos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Comparison of Efficacy and Safety Results in 103 Treatment-Naïve Acute Myeloid Leukemia (TN-AML) Patients Not Candidates for Intensive Chemotherapy Using 5-Day and 10-Day Regimens of Guadecitabine (SGI-110), a Novel Hypomethylating Agent (HMA)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 458-458 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Gail J. Roboz ◽  
Patricia L. Kropf ◽  
Karen W.L. Yee ◽  
Casey L. O'Connell ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Intensive Chemotherapy ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Significant Difference

Abstract Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.

scholarly journals Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 179-179
Author(s):  
Jessica K. Altman ◽  
Tsila Zuckerman ◽  
Olga Frankfurt ◽  
Selina M. Luger ◽  
Dale L. Bixby ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Standard Therapy ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Prior Exposure ◽  
Efficacy And Safety ◽  
First Line ◽  
Advisory Committees ◽  
Ongoing Phase

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3866-3866 ◽  
Author(s):  
Maria Teresa Petrucci ◽  
Igor W. Blau ◽  
Paolo Corradini ◽  
Meletios A. Dimopoulos ◽  
Johannes Drach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Bortezomib Treatment ◽  
Best Response ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3286-3286 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Bernadeta Ceglarek ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Randomized Phase II Study Evaluating the Efficacy and Safety of Deferasirox in Non-Transfusion-Dependent Thalassemia Patients with Iron Overload.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5111-5111 ◽  
Author(s):  
Ali Taher ◽  
John B. Porter ◽  
Antonis Kattamis ◽  
Vip Viprakasit ◽  
Tomasz Lawniczek ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Thalassemia Intermedia ◽  
Advisory Committees

Abstract Abstract 5111 Background Clinically mild forms of thalassemia exist that, unlike β-thalassemia major, require no or only infrequent transfusions (eg. β-thalassemia intermedia, HbH disease). However, due to increased gastrointestinal iron absorption secondary to ineffective erythropoiesis these patients may still develop iron overload. For example, thalassemia intermedia patients (n=74) within a cross-sectional study had a mean serum ferritin (SF) of 1023 ng/mL (range 15–4140) and a mean liver iron concentration (LIC) of 9 mg Fe/g dw (range 0.5–32.1) at baseline despite most being transfusion-naïve (n=20) or rarely transfused (n=45), and only nine receiving regular transfusions (2–4 times/yr) (Taher et al. ITIFPaP: 13th International TIF Conference for Thalassaemia Patients & Parents, October 8–11 2008, Singapore, poster number MON04). Non-transfusional iron overload leads to the same serious clinical sequelae as transfusional iron overload, including liver, cardiac and endocrine dysfunctions. As patients with non-transfusional iron overload are not candidates for phlebotomy due to their underlying anemia, chelation therapy is the only available option for decreasing their iron burden. However, there is currently limited data available on the use of chelation in this population. The once-daily oral iron chelator deferasirox (Exjade®) is currently approved for the treatment of iron overload in patients with transfusion-dependent anemia. This prospective, randomized, double-blind, placebo-controlled Phase II ‘THALASSA’ study will evaluate the efficacy and safety of deferasirox in patients with non-transfusion-dependent thalassemia. Methods Non-transfusion-dependent thalassemia patients aged ≥10 yrs will be randomized 2:1:2:1 to starting doses of deferasirox/placebo 5 mg/kg/day/ deferasirox/placebo 10 mg/kg/day over a planned 12-month treatment period. Doses can be doubled after 6 months should patients require a higher dose, which will be determined after 6 months of treatment. All patients are required to have a baseline LIC of ≥5 mg Fe/g dw, as measured by R2 magnetic resonance imaging, and SF levels of >300 ng/mL. Patients will be excluded if they have: anticipated regular transfusions during the study (sporadic transfusions, such as in cases of infection, are allowed); any transfusion within 6 months prior to study start, chelation within 1 month prior to study start; HbS variants of thalassemia; impaired renal and liver function. Primary efficacy endpoint is absolute change from baseline in LIC at 12 months; secondary efficacy endpoints include change from baseline in LIC after 6 months and in SF after 6 and 12 months, as well as change in hematological and iron metabolism parameters (eg hemoglobin, transferrin saturation). Safety assessments include adverse event and laboratory parameter monitoring. 156 patients are planned for inclusion. Results As of 3 August 2009, 18 sites had been activated. Sites currently activated are in Thailand (n=5), Turkey (n=4), Italy (n=3), Malaysia (n=2), UK (n=2) Lebanon (n=1). Fifty-seven patients have been randomized to either deferasirox or placebo and their demographic data are shown in Table 1. Conclusions Similar to transfusion-dependent thalassemia patients, non- transfusion-dependent thalassemia patients also develop iron overload. This ongoing study will generate prospective efficacy and safety data for the use of deferasirox in non-transfusion-dependent thalassemia patients with iron overload. To prevent long term complications due to iron overload, it is important to assess iron chelation in this patient population as they are not candidates for phlebotomy due to the underlying anemia. Disclosures Taher: Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Pereno:Novartis Pharma AG: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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