scholarly journals Medically Ill Patients with Moderate Renal Insufficiency Have More Thrombotic and Bleeding Events Than Those with Normal Renal Function: Insights from the Magellan and Mariner Trials of Extended Thrombprophylaxis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1236-1236
Author(s):  
Jeffrey I. Weitz ◽  
Gary E. Raskob ◽  
Alex C. Spyropoulos ◽  
Alexander T Cohen ◽  
Theodore E. Spiro ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Insufficiency ◽  
Research And Development ◽  
Board Of Directors ◽  
Normal Renal Function ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Equity Ownership ◽  
Moderate Renal Insufficiency

Abstract Background: Hospitalized medically ill patients are at risk for venous thromboembolism (VTE) for at least 45 days after discharge. This observation prompted the MAGELLAN and MARINER trials, which evaluated the efficacy and safety of rivaroxaban for extended thromboprophylaxis. In MAGELLAN, rivaroxaban (10 mg once daily) started in hospital and continued for 35 days was compared with a 10±4 day course of enoxaparin (40 mg once daily) followed by placebo. In MARINER, a 45-day course of rivaroxaban (10 mg once daily for those with creatinine clearance [CrCl] ≥50ml/min and 7.5 mg once daily for those with CrCl 30-<50ml/min) started at discharge was compared with placebo. The goals of this analysis were: (i) to compare rates of VTE (total or symptomatic) and VTE related death and major or clinically relevant bleeding in patients with moderate renal insufficiency (CrCl 30-<50ml/min) and those with normal renal function (CrCL ≥50ml/min), and (ii) to determine if revised criteria for selecting patients for extended thromboprophylaxis are associated with reduced bleeding, particularly in those with moderate renal insufficiency. Methods: We evaluated key efficacy and safety outcomes in patients with moderate renal insufficiency and those with normal renal function from days 1 to 35 in the MAGELLAN study and in a MARINER-like subpopulation of MAGELLAN using the criteria defined a priori for patient exclusion used in the MARINER study. These criteria were: 1) active gastroduodenal ulcer within 3 months of randomization or currently symptomatic, 2) any bleeding within 3 months prior to randomization or during index hospitalization prior to randomization, 3) active cancer at randomization, 4) medical history of severe bronchiectasis or pulmonary cavitation, or 5) dual antiplatelet therapy at baseline. These criteria excluded approximately 20% of subjects in MAGELLAN at high risk of bleeding. Results: The rates of VTE and VTE related death in both the rivaroxaban and enoxaparin/placebo groups were approximately twofold higher in subjects with renal impairment than in those with normal renal function, but the relative risk reduction with rivaroxaban treatment (10mg) compared with enoxaparin/placebo was similar in both renal function subgroups. Rates of major and clinically relevant bleeding in the rivaroxaban group were approximately 50% higher in patients with renal impairment compared with those with normal renal function. In the MARINER like subpopulation, the relative risk reductions for efficacy outcomes were maintained in both renal subgroups, whereas the increase in major bleeding with rivaroxaban was reduced by approximately 50%. Conclusions: Medically-ill patients with renal impairment given extended thromboprophylaxis are at increased risk for both VTE and major bleeding. Use of the MARINER criteria to exclude patients at increased risk of bleeding appears to reduce the major bleeding risk without compromising the efficacy of 10mg daily of rivaroxaban. Figure Figure. Disclosures Weitz: Novartis: Honoraria; Servier: Honoraria; Janssen: Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria. Raskob:Janssen: Consultancy; Bayer: Consultancy; BMS: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy. Spyropoulos:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Colorado Prevention Center - ATLAS: Consultancy; Portola: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cohen:Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Medscape: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Portola: Consultancy, Speakers Bureau; AbbVie: Consultancy; ACI Clinical: Consultancy; Boston Scientific: Consultancy; CLS Behring: Consultancy; GLG: Consultancy; Guidepoint Global: Consultancy; Leo Pharma: Consultancy; McKinsey: Consultancy; Sanofi: Consultancy; Navigant: Consultancy; ONO: Consultancy; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy. Spiro:Bayer: Employment, Equity Ownership. De Sanctis:Bayer: Employment, Equity Ownership. Xu:Janssen Research and Development LLC: Employment, Equity Ownership. Suh:Janssen Research and Development LLC: Employment, Equity Ownership. Lu:Janssen Research and Development LLC: Employment. Lipardi:Janssen Research and Development LLC: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership.

Safety and Efficacy of Dasatinib Versus Imatinib by Baseline Cardiovascular Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2286-2286 ◽  
Author(s):  
Giuseppe Saglio ◽  
Andreas Hochhaus ◽  
Jorge E. Cortes ◽  
Hagop Kantarjian ◽  
Michele Baccarani ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Initial Treatment ◽  
Qtc Interval ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Safety And Efficacy ◽  
Lv Dysfunction ◽  
Equity Ownership ◽  
Artery Disease

Abstract Abstract 2286 Background: BCR-ABL kinase inhibitors dasatinib, nilotinib and imatinib have become the therapeutic mainstay for patients (pts) with CML-CP. It has been suggested that baseline comorbid conditions be considered in choosing BCR-ABL inhibitors as second-line treatment for pts with CML post-imatinib failure. Cardiovascular (CV) disease is an important comorbid condition in some pts with CML-CP (median age, ∼ 60 years) and can play a critical role in treatment decisions. The DASISION trial is a large Phase 3 study comparing dasatinib with imatinib as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of dasatinib after a minimum of 12 months (mos) of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260-70). We assessed if baseline CV conditions impacted the efficacy and safety of these agents when used as initial treatment for CML-CP. Methods: Five hundred nineteen pts with newly diagnosed CML-CP (median disease duration of 1 mo) were randomized to either dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed in pts with CV conditions and in those without. Pts with myocardial infarction (MI) within 6 mos, uncontrolled angina within 3 mos, congestive heart failure (CHF) within 3 mos, congenital prolonged QT syndrome, QTc interval of > 450 msec or ventricular arrhythmias were excluded. Pts with CV conditions including hypertension, MI > 6 mos prior to the start of treatment, uncontrolled angina > 3 mos prior to the start of treatment, CHF > 3 mos prior to the start of treatment, unstable angina (UA), left ventricular (LV) dysfunction, coronary artery disease (CAD), peripheral artery disease (PAD), transient ischemic attack (TIA), stroke and QTc interval of ≤ 450 msec were not excluded. Results: Across the 2 treatment arms, there were 85 pts (16%) with ≥ 1 baseline CV condition, 42 of whom had ≥ 2. Of the 85 pts, 69 (35 dasatinib; 34 imatinib) reported having baseline hypertension and 16 (8 dasatinib; 8 imatinib) reported other baseline CV conditions (some pts reported more than 1 CV condition) including LV dysfunction (n = 6), CAD (including clinically documented CAD, prior MI and unstable angina; n = 15), PAD (n = 11), and cerebral artery disease (including prior stroke and TIA, n = 8). The distribution of CV conditions was balanced across the 2 treatment arms. Safety profiles of dasatinib and imatinib in pts with baseline CV conditions were generally similar to those in pts without (Table). Notably, fluid retention including superficial edema and pleural effusion appeared to have occurred more frequently in pts with baseline CV conditions compared to those without. Pleural effusions were all grade 1 or 2, and manageable by dose interruption and/or reduction. In both arms, the 12-mo rates of CCyR and MMR in pts with baseline CV comorbidities were similar to the corresponding rates in pts without (Table). Safety and efficacy profiles of pts with hypertension and pts with CV conditions other than hypertension were also generally similar to those in pts without any CV condition. Conclusions: Although fluid retention and cardiac AEs were more common in patients with any baseline CV condition, overall these data show no substantial impact of baseline CV conditions on the general safety and efficacy of dasatinib or imatinib as initial treatment for CML-CP. Disclosures: Saglio: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani: Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Shah: Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees.

Effect of the Cytochrome P450 3A4 Inducers, Rifampicin and Dexamethasone, on the Pharmacokinetic, Pharmacodynamic and Safety Profile of Bortezomib In Patients with Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3983-3983
Author(s):  
Andrzej Hellmann ◽  
Simon A. Rule ◽  
Jan Walewski ◽  
Ofer Shpilberg ◽  
Huaibao Feng ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Proteasome Inhibition ◽  
Employment Equity ◽  
Advisory Committees ◽  
Time Curve ◽  
Once Daily ◽  
Cyp3a4 Inducer ◽  
Equity Ownership ◽  
The Mean

Abstract Abstract 3983 Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: 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, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

An Expanded Multicenter Phase I/II Study of CYT387, a JAK- 1/2 Inhibitor for the Treatment of Myelofibrosis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3849-3849 ◽  
Author(s):  
Animesh Pardanani ◽  
Jason Gotlib ◽  
Vikas Gupta ◽  
Andrew W Roberts ◽  
Martha Wadleigh ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Multicenter Study ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Safety And Efficacy ◽  
Equity Ownership ◽  
Grade 3 ◽  
Study Sites

Abstract Abstract 3849 Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria. Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1. The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study. CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3–4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3–4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%. Conclusions: When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Gupta: Incyte: 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. Smith:YM Biosciences: Employment, Equity Ownership. Bavisotto:YM Biosciences: Consultancy. Kowalski:YM Biosciences: Employment, Equity Ownership.

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability Of Pomalidomide + Low-Dose Dexamethasone In Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5393-5393 ◽  
Author(s):  
Jeffrey Matous ◽  
David S. Siegel ◽  
Hien K. Duong ◽  
Claudia Kasserra ◽  
Min Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Adverse Events ◽  
Board Of Directors ◽  
Impaired Renal Function ◽  
Low Dose ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background Pomalidomide (POM) is indicated for patients (pts) with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Renal impairment (RI) is a common comorbidity in multiple myeloma (MM), occurring in > 40% of pts. POM is extensively metabolized, with < 5% eliminated renally as the parent drug. Thus, renal function may not substantively affect exposure of the active parent compound. POM + low-dose dexamethasone (LoDEX) has shown efficacy in pts with relapsed/refractory MM (RRMM) with moderate RI in phase 2 and phase 3 trials. However, pts with severe RI were excluded from these trials. MM-008 is an active multicenter, open-label, phase 1 study designed to prospectively assess the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function. Methods Pts with RRMM and ≥ 1 prior therapy were eligible for enrollment. Pts in Cohort A (creatinine clearance [CrCL] ≥ 60 mL/min) served as the control population and received POM 4 mg on days 1-21 of each 28-day cycle. Pts in Cohort B (CrCL < 30 mL/min but not requiring dialysis) followed a standard 3 + 3 dose-escalation design, receiving POM 2 mg on days 1-21 of each 28-day cycle and based on results, escalating to 4 mg. Dosing for Cohort C (CrCL < 30 mL/min and requiring dialysis) was informed by the results from Cohort B. All cohorts received dexamethasone 40 mg (20 mg for pts aged > 75 years) on days 1, 8, 15, and 22. Pts were not permitted to enroll in more than 1 cohort. Granulocyte colony-stimulating factor for management of neutropenia was not permitted in cycle 1, but could be started on day 1 of the next cycle at the physician’s discretion. Treatment was continued until disease progression or unacceptable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (V 4.0). PK samples were obtained pre- and post-POM dose on days 1, 2, and 3 (after single doses) and days 21, 22, and 23 (after multiple doses) of cycle 1 for cohorts A and B. PK data were dose-normalized for comparison across cohorts by dividing the measured exposure by the POM dose in milligrams. Results As of April 1, 2013, 11 pts have been treated (8 in Cohort A; 3 in Cohort B at 2 mg). At screening, median age (range) was 68 years (46-71 years) and 64 years (57-64 years) while median CrCL (range) was 85 mL/min (53.1- 114.8 mL/min) and 18.4 mL/min (12.5-25.7 mL/min) in cohorts A and B, respectively. The most common grade ≥ 3 adverse events were neutropenia (Cohort A: 4 pts; Cohort B: 1 pt), infections (Cohort A: 2 pts; Cohort B: 2 pts), and anemia (Cohort A: 2 pts; Cohort B: 1 pt). No dose-limiting toxicities in cycle 1 have been reported. Median duration of treatment and relative dose intensity were similar between cohorts A and B, 4.1 months (range, 1.8-5.1 months) vs 3.9 months (range, 1.8-8.5 months) and 1.0 (range, 0.5-1.1) and 1.1 (range, 1.0-1.1), respectively. Only 1 pt (Cohort A) discontinued treatment due to adverse events. Five pts remain on study (Cohort A: 3 pts; Cohort B: 2 pts). Initial PK analyses showed that mean dose-normalized AUC024 in Cohort B was approximately 20% lower than in Cohort A. Mean dose-normalized Cmax in Cohort B was approximately 30% lower than that in Cohort A after a single dose but comparable after multiple doses. Based on these results, additional pts in Cohort B and pts in Cohort C will receive POM 4 mg. Updated PK and adverse event data will be presented at the meeting. Conclusion MM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with severe RI. Preliminary data suggest that dose-normalized exposure in pts with RRMM with severe RI is similar to that in pts with normal to mildly impaired renal function. No dose-limiting toxicities have been reported, and early tolerability data are encouraging. Disclosures: Matous: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Approved in the US but not in Europe. Siegel:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Kasserra:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Doerr:Celgene: Employment, Equity Ownership. Sternas:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Shah:Celgene: Consultancy, Research Funding.

Safety and Efficacy of Dasatinib (DAS) Vs. Imatinib (IM) by Baseline Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3421-3421 ◽  
Author(s):  
H. Jean Khoury ◽  
Jorge E. Cortes ◽  
Hagop Kantarjian ◽  
Michele Baccarani ◽  
Neil P. Shah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Age Groups ◽  
Initial Therapy ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Safety And Efficacy ◽  
Equity Ownership

Abstract Abstract 3421 Background: BCR-ABL kinase inhibitors DAS, nilotinib and IM have become the primary treatment modality for patients (pts) with CML-CP. Pre-treatment comorbid conditions have been proposed to help select a second-line BCR-ABL inhibitor for IM-resistant CML-CP. The DASISION trial is a large Phase 3 trial comparing DAS with IM as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of DAS 100 mg once daily after a minimum follow-up of 12 months (Kantarjian, H, et al. N Engl J Med 2010;362:2260). This analysis assessed the impact of baseline comorbidities on safety and efficacy of these agents when used as initial therapy for CML-CP. Methods: 519 pts with newly diagnosed CML-CP were randomized to either DAS 100 mg once daily (n = 259) or IM 400 mg once daily (n = 260). Key exclusion criteria included serious uncontrolled medical disorders or active infections; uncontrolled or serious cardiovascular disease; prior or concurrent malignancy; inadequate hepatic or renal function; and ECOG performance status of ≥ 3. Pts were analyzed according to the number (0, ≥ 1 and ≥ 2) and type of baseline comorbidity (allergic, dermatologic, diabetes, endocrine-metabolic, gastrointestinal, hematologic-lymphatic, hepatobiliary, hyperlipidemia, musculoskeletal, renal and respiratory), and age (< 46, 46–65 and > 65 y). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed across these groups. Cardiovascular comorbidities were analyzed separately and are not included here. Results: Across the 2 treatment arms, 74% of the pts had 31 baseline comorbidity and 47% had 32. The distribution of comorbidities including allergic (n = 61), dermatologic (n = 62), diabetes (n = 31), endocrine/metabolic (n = 98), gastrointestinal (n = 176), hematologic/lymphatic (n = 57), hepatobiliary (n = 56), hyperlipidemia (n = 41), musculoskeletal (n = 150), neoplasia (n = 17), renal (n = 33) and respiratory (n = 72) was balanced across the 2 arms. Proportions of pts across 3 Hasford risk groups were similar between pts with baseline comorbidity and those without. Safety profiles of DAS and IM in pts with and without baseline comorbidities were comparable (Table). Proportions of pts with at least 1 dose interruption or dose reduction were also similar with or without any comorbidity (Table). Pts with 32 comorbidities and pt grouped by comorbidity type including diabetes mellitus, hepatobiliary conditions and hyperlipidemia also had generally similar safety profiles. In both arms, the 12-mo rates of CCyR and MMR were similar (Table). In DAS-treated pts with diabetes (n = 18), hepatobiliary conditions (n = 32) and hyperlipidemia (n = 22), CCyR rates were 67, 78 and 96%, respectively; the respective MMR rates were 44, 56 and 59%. IM pts with diabetes (n = 13), hepatobiliary conditions (n = 24) and hyperlipidemia (n = 19) had CCyR rates of 69, 75 and 79%, respectively; and MMR rates of 15, 29 and 32%, respectively. In DAS-treated pts, CCyR rates were 88% for pts aged < 46 y (n = 128), 78% for those aged 46–65 y (n = 111) and 85% for those aged > 65 y (n = 20); the corresponding MMR rates were 45, 47 and 50%, respectively. The corresponding IM age groups (n = 111, 125 and 24, respectively) had CCyR rates of 70, 70 and 83%, respectively; and MMR rates of 26, 30, 29%, respectively. Safety profiles were generally similar across age groups in both treatment arms, except that fluid retention rates in pts aged < 46, 46–65 and > 65 y were 13, 25 and 35%, respectively, for DAS; and 34, 45 and 67%, respectively, for IM. Conclusions: The presence of baseline comorbidities appeared to have no effect on the safety and efficacy of either DAS or IM as initial therapy for CML-CP. Disclosures: Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani:Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin:Bristol-Myers Squibb: Employment, Equity Ownership. Hochhaus:Brostol-Myers Squibb, Novartis: Consultancy, Research Funding.

CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2510-2510 ◽  
Author(s):  
Tara L. Lin ◽  
Laura F. Newell ◽  
Robert K. Stuart ◽  
Laura C. Michaelis ◽  
Stephen E. Rubenstein ◽  
...  
Keyword(s):  
Renal Function ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Dose Adjustment ◽  
Cardiac Repolarization ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar ratio. It is highly effective in patients with high-risk acute myeloid leukemia (AML). This study evaluated the impact of CPX-351 (100 units/m2) on cardiac repolarization. Methods: This open-label, Phase II, pharmacokinetic (PK) and pharmacodynamic (PD) study entered AML and acute lymphocytic leukemia (ALL) patients with good risk hepatic function (Child-Pugh scores <7), and normal cardiac function (LVEF≥50%, QTcF<470 ms). Cardiac repolarization changes were assessed using conventional ECG and Holter monitor recordings. PK was assessed during the first 21 days for total cytarabine, daunorubicin, Ara-U and daunorubicinol. The relationship between CPX-351 PK, QTcF, and renal function using the equation to calculate the estimated glomerular filtration rate (eGFR) was evaluated. Results: Twenty-six patients entered the study and 21 were evaluable for QT interval change from baseline. Evidence that CPX-351 prolongs the QTcF interval was not observed. The largest absolute and mean change from time-matched baseline was 12.56 and 8.03 ms, respectively (Day 1, hour 4). Mean QTcF change on Day 5 was unchanged from baseline. QTcF intervals >480 ms were never observed and no consistent QTcF intervals >450 ms were noted. Absolute QTcF increases between 30 and 60 ms were present in 4 of 25 patients and no changes >60 ms were observed. CPX-351 plasma concentration vs. time curves for day 1 and 5 exhibited a volume of distribution approximately equal to the plasma volume with prolonged single-exponential elimination half-lives for cytarabine and daunorubicin of ≥24 hours. The PK of CPX-351 was independent of renal function. Patients with moderately impaired (eGFR=30-59 mL/min/1.73m2) renal function exhibited similar drug exposure as those with mild and normal renal function. Table 1. Impact of renal function impairment on Day 5 CPX-351 PK parameters (mean, %CV): Analyte Renal Function Cmax (ng/mL) AUClast (ng*hr/mL) AUCinf (ng*hr/mL) T1/2 (hr) Cytarabine Normal (n=3) Mean 59333 2893146 2902641 42.5 %CV 28.7 68.8 69 34.1 Mild (n=7) Mean 58071 3599512 3606695 41.0 %CV 31.9 52.4 52.4 21.8 Moderate (n=3) Mean 57333 3149303 3156738 38.0 %CV 46.6 50.7 50.6 21.9 Daunorubicin Normal (n=3) Mean 25967 754646 870861 24.9 %CV 23.1 63 65.3 56.0 Mild (n=7) Mean 28686 865034 1021420 30.5 %CV 43.9 43.5 43.6 25.3 Moderate (n=3) Mean 21933 671542 814732 35.4 %CV 50.9 35.9 33.5 31.2 Table 2 summarizes response and transplant outcomes. One of two ALL patients achieved CR and was transplanted. Among AML patients there were 7 CR and 2 CRi of which three went on to transplant. An additional four patients became morphologically leukemia free (MLF) and were transplanted before full documentation of CR was achieved. A large majority of patients given first-line treatment with CPX-351 responded or became suitable for transplant (10/13, 77%). Table 2. 206 Study Efficacy Diagnosis n ResponseCR/CRi Transplanted in CR/CRi Induced MLF and Transplanted No Response ALL-Relapsed 2 1/0 1/0 0 1 AML-First Line de novo 8 5/0 0 1 2 AML-First Line sAML 5 1/2 1/1 1 1 AML-Salvage 11 1/0 1/0 2 8 Conclusions: Clinically relevant prolongation of QTcF is not a feature of CPX-351 treatment. CPX-351 exposure was independent of renal function, indicating no need for dose adjustment when renal function is impaired. The high rate of complete remission and referral for transplant corroborate the high level of efficacy observed in earlier studies with CPX-351. Disclosures Stuart: Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Pentikis:Celator Pharmaceuticals: Consultancy. Alvarez:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Mayer:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership.

scholarly journals A Phase 2a Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 556-556 ◽  
Author(s):  
Kristen Pettit ◽  
Aaron T. Gerds ◽  
Abdulraheem Yacoub ◽  
Justin M. Watts ◽  
Maciej Tartaczuch ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Equity Ownership

Ruxolitinib (Jakafi®) is the one approved therapy for myelofibrosis (MF) based on reduction of splenomegaly and symptoms but JAK inhibition has not proven to significantly modify disease progression. There remains the need for novel therapies with distinct modes of action that can improve the patient experience of MF and impact progression. Lysine-specific demethylase, LSD1, is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors. LSD1 bound to GFI1b permits maturation of progenitors to megakaryocytes and enables their normal function. IMG-7289 (bomedemstat) is an orally available LSD1 inhibitor. In mouse models of myeloproliferative neoplasms (MPN), IMG-7289 reduced elevated peripheral cell counts, spleen size, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting its clinical development. IMG-7289-CTP-102 is an ongoing, multi-center, open-label study that recently transitioned from a Phase 1/2a dose-range finding study to a Phase 2b study of IMG-7289 administered orally once-daily in adult patients with intermediate-2 or high-risk MF resistant to or intolerant of ruxolitinib. The key objectives are safety, PD, changes in spleen volume (MRI/CT) and total symptoms scores (TSS) using the MPN-SAF instrument. Inclusion criteria included a platelet count ≥100K/μL. Bone marrow (BM) biopsies and imaging studies (both centrally-read) were conducted at baseline and during washout (post-Day 84). The MPN-SAF was self-administered weekly. Phase 1/2a patients were treated for 84 days followed by a washout of up to 28 days. Patients demonstrating clinical benefit could resume treatment for additional 12 week cycles. Dosing was individually tailored using platelet count as a biomarker of effective thrombopoiesis. Patients were started at a presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL. This preliminary analysis includes 20 patients; 18 enrolled in the Phase 1/2a study, 2 in the Phase 2b portion. 50% had PMF, 35% Post-ET-MF, 15% Post-PV-MF. The median age was 65 (48-89) with 70% males. The median baseline platelet count was 197 k/μL (102-1309k/μL). 12 patients (56%) were transfusion-dependent at baseline. Sixty percent were IPSS-classified as high risk, the remainder, intermediate risk-2. 71% had more than 1 mutation of the 261 AML/MPN genes sequenced of which 63% were high molecular risk (ASXL1, U2AF1, SRSF2) mutations; 31% had abnormal karyotypes. Sixteen patients completed the first 12 weeks; 4 patients withdrew, one due to fatigue (Day 33), one for progressive disease (Day 39), one due to physician decision (Day 76), one for an unrelated SAE of cellulitis (Day 83). All patients were up-titrated from the starting dose 0.25 mg/kg to an average daily dose of 0.89 mg/kg ± 0.20 mg/kg, the dose needed to achieve the target platelet count range; 17 achieved the target platelet range in a mean time of 45 days. Of patients evaluable for response after cycle 1 in Phase1/2a (N=14), 50% had a reduction in spleen volume from baseline (median SVR: -14%; -2% to -30%). Further, 79% (N=11) recorded a reduction in TSS (mean change -28%; -13% to -69%); for 21% of patients (N=3), the change was &gt;-50%. Improved BM fibrosis scores at Day 84 were observed in 2/13 patients. Two patients had improvement in transfusion requirements. Plasma IL-8 levels were significantly elevated in 6/14 patients at baseline and dropped in a dose-dependent manner over 21 days in 5/6 patients. The mean duration of treatment is 166 days (14-539) at the census point in this ongoing study. Nineteen patients (95%) reported 358 AEs of which 22 were SAEs. Of the SAEs, 2 were deemed by investigators as possibly related: painful splenomegaly and heart failure. There have been no safety signals, DLTs, progression to AML, or deaths. This is the first clinical study of an LSD1 inhibitor in patients with MPNs. Once-daily IMG-7289 was well-tolerated in a heterogeneous population of patients with advanced MF and limited therapeutic options. Despite under-dosing and slow dose escalation, IMG-7289 improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients. The Phase 2b 24-week expansion study with more aggressive dosing aimed at preserving safety and enhancing efficacy is open for enrollment in the US, UK and EU. Figure Disclosures Pettit: Samus Therapeutics: Research Funding. Gerds:Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy. Yacoub:Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Natsoulis:Imago BioSciences: Consultancy, Equity Ownership. Jones:Imago BioSciences: Employment, Equity Ownership. Talpaz:Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding. Peppe:Imago BioSciences: Employment, Equity Ownership. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rienhoff:Imago Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Renal Response in Carfilzomib (K)- Versus Bortezomib (V)-Treated Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM) in the Real-World Practice Setting

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3253-3253
Author(s):  
Shaji K. Kumar ◽  
Alan Fu ◽  
Khalid Mezzi ◽  
Megan Braunlin ◽  
Christopher Kim ◽  
...  
Keyword(s):  
Renal Function ◽  
Board Of Directors ◽  
Research Funding ◽  
Post Treatment ◽  
Rank Test ◽  
Employment Equity ◽  
Advisory Committees ◽  
Renal Response ◽  
Log Rank Test ◽  
Equity Ownership

Abstract Introduction: Renal impairment (RI) is a classic clinicopathological feature of MM, is associated with poor prognosis and shorter survival (Eleutherakis-Papaiakovou Leuk Lymphoma 2007), and can complicate drug dosing and limit treatment options. In clinical trials, the proteasome inhibitors K and V have demonstrated efficacy in RRMM pts with RI, with superior efficacy observed in K-treated pts (Dimopoulos Blood 2017). K and V have also been observed to improve renal function in RRMM pts (Dimopoulos Clin Lymphoma Myeloma 2009; Dimopoulos Blood Advances 2017). However, few studies have investigated the real-world effectiveness of K- and V-based regimens in renal rescue. This study aimed to describe and compare renal response rates in RRMM pts treated with K + dexamethasone (Kd) and V + dexamethasone (Vd) in oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database (Lau Clin Epidemiol 2011) contains electronic medical records (EMR) from community- and hospital-affiliated oncology clinics in the United States. MM pts aged ≥18 who entered an OSCER clinic Jan 2012‒Feb 2018; initiated Kd or Vd treatment as line 2 (2L), 3L, or 4L; and had baseline renal impairment (Modification of Diet in Renal Disease Study estimated glomerular filtration rate [eGFR] <50 mL/min from the most recent baseline serum creatinine measurement) were included. Index date was the date of Kd or Vd initiation. The baseline period was 60 d prior to index to 30 d post-index. Follow-up was 30 d after index date to 60 d after completion of the same line. Primary outcome was renal response during follow-up. Renal response was defined according to the International Myeloma Working Group criteria (Dimopoulos J Clin Oncol 2016): complete response (RCR; baseline eGFR <50 mL/min and best post-treatment eGFR ≥60 mL/min), partial response (baseline eGFR <15 mL/min and best post-treatment eGFR 30‒59 mL/min), minor response (baseline eGFR <15 mL/min and best post-treatment eGFR 15‒29 mL/min, or baseline eGFR 15‒29 mL/min and best post-treatment eGFR 30‒59 mL/min). Renal response rates in Kd- and Vd-treated pts were evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and RCR using multivariate Cox proportional hazard models adjusted for baseline covariates (demographics, Eastern Cooperative Oncology Group Performance Status, International Staging System stage, baseline renal function, V use in 1L, time from MM diagnosis to line initiation, use of intravenous bisphosphonates, and baseline serum calcium, serum free light chain ratio, lactate dehydrogenase, and whole blood hemoglobin measurements). Missing baseline values were estimated by multiple imputations. Results: 543 Kd-treated and 1005 Vd-treated pts were included. Baseline characteristics were similar between cohorts, with no difference in baseline eGFR stages. More Kd pts were <65 yrs of age at MM diagnosis. Median time from diagnosis to line initiation was longer in Kd pts (Kd: 17.1 mos; Vd 16.1 mos). V-based regimens were the most common therapies in 1L. Median (interquartile range) treatment duration was 4.4 (2.3-8.3) mos for Kd and 4.3 (2.1-8.3) mos for Vd. Pts treated with Kd at 2L were more likely than those treated with Vd to achieve both ROR (51.4% [178/346] vs 39.6% [327/825]; log-rank test p<0.0001) and RCR (26.6% [92/346] vs 22.2% [183/825]; log-rank test p=0.0229). This pattern persisted when 3L and 4L pts were included, (ROR: 48.4% [263/543] vs 39.8% [400/1005]; log-rank p<0.0001; RCR: 26% [141/543] vs 22.1% [222/1005]; log-rank p=0.0084) (Figures 1A and 1B). Following adjustment for potential baseline confounders, 2L Kd pts were 45% more likely to achieve ROR (IRR, 95% CI: 1.45, 1.18‒1.78) and 68% more likely to achieve RCR (1.68, 1.24‒2.28) vs 2L Vd pts (Figure 2). Kd pts in 2‒4L were 36% more likely to achieve ROR (1.36, 1.15‒1.62) and 52% more likely to achieve RCR (1.52, 1.19‒1.94). Conclusions: Using one of the most complete oncology EMR databases available, we found that RRMM pts with baseline RI treated with Kd had higher rates of overall and complete renal response, and were more likely to have a renal response, compared with pts treated with Vd. A limitation of the study is that we could not account for all concomitant medications or comorbidities that affect renal function, as some may not be captured in OSCER. Disclosures Kumar: AbbVie: 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, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fu:Amgen: Employment, Equity Ownership. Mezzi:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Kim:Amgen: Employment, Equity Ownership. Iskander:Amgen: Employment, Equity Ownership. Niesvizky:Amgen Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Boccia:Sandoz: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; BMS: Research Funding; Pfizer: Consultancy; AstraZeneca: Research Funding, Speakers Bureau. Raje:Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; BMS: Consultancy; Amgen Inc.: Consultancy.

scholarly journals Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Fold Change ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document