scholarly journals SGN-CD33A Plus Hypomethylating Agents: A Novel, Well-Tolerated Regimen with High Remission Rate in Frontline Unfit AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 454-454 ◽  
Author(s):  
Amir T. Fathi ◽  
Harry P Erba ◽  
Jeffrey E Lancet ◽  
Eytan M Stein ◽  
Roland B. Walter ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Remission Rate ◽  
Intensive Therapy ◽  
Advisory Board ◽  
Hypomethylating Agents ◽  
Employment Equity ◽  
Advisory Committees ◽  
Low Intensity ◽  
Equity Ownership

Abstract Background Older patients with AML who are not candidates for intensive therapy are typically treated with hypomethylating agents (HMAs) or other low intensity therapy. HMAs have been shown to upregulate CD33 and to increase sensitivity to cytotoxic chemotherapy by decreasing apoptotic threshold in tumor cells. SGN-CD33A (or 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. In preclinical studies combining 33A with an HMA (azacitidine and decitabine), synergy has been demonstrated in multidrug resistant AML models (Sutherland ASH 2014). Methods A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-leukemic activity of 33A in combination with an HMA. Eligible patients (ECOG 0-1) must have previously untreated CD33-positive AML, and have declined intensive therapy. A single dose level of 33A, 10 mcg/kg, was administered outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5 day regimen], standard dosing). Patients with clinical benefit may continue treatment until relapse or unacceptable toxicity. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003). Results To date, 24 patients (63% male) with a median age of 77 years (range, 66-83) have been treated with the combination therapy. 42% of patients had adverse cytogenetics (MRC), 23 patients were treatment naïve and 1 patient had received prior low intensity therapy for MDS. At baseline, patients had a median of 60% BM blasts (range, 2%-90%) and a median of WBC of 2.2 (range, 1-132). At the time of this interim analysis, patients were on treatment for a median of 13.5+ weeks with 17 patients continuing treatment; no DLTs have been reported. Grade 3 or higher adverse events (AE) reported in >20% of patients were fatigue (54%), febrile neutropenia (46%), anemia (25%), neutropenia (25%), and thrombocytopenia (21%). Other treatment-emergent AEs regardless of relationship to study treatment reported in ˃20% of patients were nausea (29%), decreased appetite (25%), and constipation (21%). Thirty- and 60-day mortality rates are 0% and 4% respectively with no treatment-related deaths reported. Fifteen of the 23 efficacy evaluable patients (65%) achieved CR (5) or CRi (10). Remissions were generally obtained after 2 cycles of treatment and were observed in many patients with adverse risk including underlying myelodysplasia (6/8, 75%) and adverse cytogenetics (8/9, 89%). Median OS has not been reached with 20 patients alive at the time of this data cut. Conclusions The combination of 33A with HMA appears to be well-tolerated, active, and has no identified off-target toxicities. Activity with the combination compares favorably with historical experience with HMAs alone in this patient population. The CR+CRi rate of 65% in AML patients with poor risk factors with the observed low 60-day mortality (4%) are particularly encouraging. These promising data warrant further evaluation in future trials. Disclosures Fathi: Agios Pharmaceuticals: Other: Advisory Board participation; Merck: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding. Off Label Use: SGN-CD33A is an investigational agent being studied in patients with CD33-positive AML. SGN-CD33A is not approved for use.. Erba:GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Sunesis;Pfizer; Daiichi Sankyo; Ariad: Consultancy; Millennium/Takeda; Celator; Astellas: Research Funding; Seattle Genetics; Amgen: Consultancy, Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Lancet:Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Stein:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Walter:Pfizer, Inc.: Consultancy; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy; CSL Behring: Research Funding; AbbVie, Inc.: Research Funding; Amgen: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. DeAngelo:Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Agios: Consultancy. Faderl:Celator: Research Funding; Ambit: Research Funding; BMS: Research Funding; Astellas: Research Funding; Karyopharm: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; JW Pharma: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Onyx: Speakers Bureau. Jillella:Seattle Genetics, Inc.: Research Funding. Bixby:Seattle Genetics, Inc.: Research Funding. Kovacsovics:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Stein:Amgen: Speakers Bureau.

scholarly journals Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3512-3512
Author(s):  
Rachael F. Grace ◽  
D. Mark Layton ◽  
Frédéric Galactéros ◽  
Wilma Barcellini ◽  
Eduard J. van Beers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
The Core ◽  
Equity Ownership ◽  
Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses >25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3543-3543 ◽  
Author(s):  
Alexis A. Thompson ◽  
Mark C. Walters ◽  
Janet L. Kwiatkowski ◽  
Suradej Hongeng ◽  
John B. Porter ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Board ◽  
Prior Exposure ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Defining the Incidence and Clinical Impact of Genomic Alterations Across Different Histologic Types of Lymphoma Using a Clinically Validated Comprehensive Targeted Sequencing Assay

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2668-2668
Author(s):  
Connie Batlevi ◽  
Franck Rapaport ◽  
Andrew M. Intlekofer ◽  
Anne Reiner ◽  
Craig H Moskowitz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Clinical Relevance ◽  
Research Funding ◽  
Advisory Board ◽  
Genomic Sequencing ◽  
Genomic Alterations ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Lymphoma is a clinically and molecularly heterogenous disease. Next generation sequencing of primary lymphoma samples has identified common recurring genomic alterations (GAs). The distribution and frequency of recurring GAs across lymphoma subtypes remains unknown because prior studies vary in sequencing methods, depth of coverage, and specimen source. In this study, we benchmark the distribution of GAs across different lymphoma subtypes by prospectively analyzing lymphoma cases and performing comprehensive DNA/RNA targeted sequencing of genes commonly found in hematologic malignancies using the Foundation One Heme (F1H) clinical assay. Methods: After obtaining proper consent, archived specimens from 183 samples [formalin fixed paraffin embedded (FFPE) N=141, peripheral blood N=28, BM aspirate N=14] distributed across lymphoma subtypes (including 62 DLBCL, 38 T cell lymphoma, 32 FL, 17 CLL, 13 MCL) were sequenced to high, uniform coverage averaging >600x for DNA, >20 million pairs for RNA. GAs were determined, including base substitutions, small insertions and deletions, rearrangements, and copy number alterations. Significant non-synonymous variants were identified as mutations from the COSMIC database, amplifications of established oncogenes, or homozygous deletions and/or clear loss-of-function mutations of known tumor suppressors. Fisher's exact test with Monte Carlo estimation corrected by false discovery rate was used for associations. Results: Samples from prospectively consented patients were banked for a median of 30 days prior to genomic analysis, range 1 day to 6.5 yr. Sequencing data was reported a median of 16 days from sample date receipt. GAs were identified in 95% of samples, with a median of 4 GAs/sample. The most common GAs were TP53 (29%), MLL2 (27%), BCL2 (25%), CDKN2A/B (17%) and CREBBP (14%). Alterations of chromatic modifiers (80%), BCR/NFkB components (51%), and cell cycle pathway (44%) were most common. In our group of unpaired follicular lymphoma samples (N=7 treatment naïve, N=25 treatment exposed), the number of GAs increased with treatment exposure. We found similar gene and biological signatures regardless of prior therapy; however differences emerge in genes of potential clinical relevance. Sequencing profiles augmented or altered the pathologic diagnosis in 11 of 183 (6%) of the cases. Importantly we were able to classify the GAs as actionable, potentially actionable and variants of unclear significance to better define the clinical relevance of targeted genomic sequencing. Conclusions: Integration of comprehensive next generation targeted genomic sequencing and clinical analysis in lymphoma provides an opportunity to describe the spectrum and incidence of GAs across different lymphoma subtypes and provide guidance on application of genomic profiling. This work serves to benchmark GAs across all lymphoma subtypes in a clinically relevant population and enables design of basket trials selecting patients based on shared genomic and biologic similarity instead of lymphoma subtype. To our knowledge, this is the largest repository of clinically annotated genomic sequencing in lymphoma. Table 1. Total Specimens N = 183 Median Age at Diagnosis 57 Range 21 - 84 Median Age at Biopsy 61 Range 21 - 91 Sex • Male • Female 113 70 62% 38% Biospecimen source • Paraffin embedded • Peripheral blood • Marrow aspirate 141 28 14 77% 15% 8% Patient consent • Prospective consent • Retrospective consent 145 38 79% 21% Prospectively consented patients (N=145) Median Days to Result Median Age of Sample 16 30 days 8 - 81 1 day - 6.5 yr Disclosures Palomba: Janssen: Consultancy. Gerecitano:Genentech: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board. Matasar:Spectrum: Consultancy; Genentech: Consultancy. Straus:Millenium Pharmaceuticals: Research Funding. He:Foundation Medicine, Inc.: Employment, Equity Ownership. Balasubramanian:Foundation Medicine: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine: Employment. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Younes:Celgene: Honoraria; Johnson and Johnson: Research Funding; Novartis: Research Funding; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Sanofi-Aventis: Honoraria; Seattle Genetics: Honoraria, Research Funding; Curis: Research Funding; Janssen: Honoraria; Takeda Millenium: Honoraria; Incyte: Honoraria.

scholarly journals Biomarkers of Overall Survival and Response to Glasdegib and Intensive or Non-Intensive Chemotherapy in Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2733-2733 ◽  
Author(s):  
Jorge E. Cortes ◽  
Akil Merchant ◽  
Catriona Jamieson ◽  
Daniel A Pollyea ◽  
Michael Heuser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Board Of Directors ◽  
Research Funding ◽  
Intensive Therapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Expression Levels ◽  
Biomarker Analysis ◽  
Cytokine Levels ◽  
Equity Ownership

Abstract Background: In a previously reported Phase 2 randomized study of patients with acute myeloid leukemia (AML), addition of the investigational agent glasdegib (PF-04449913) to low-dose cytarabine (LDAC) improved overall survival (OS) when compared with LDAC alone. In a non-randomized study arm, glasdegib together with 7+3 chemotherapy was well tolerated and associated with clinical activity. We used a comprehensive biomarker analysis, evaluating gene expression, circulating cytokine levels, and gene mutations, to identify molecular drivers that predict overall response (OR) and OS. Methods: In this Phase 2 multicenter study (NCT01546038), patients with AML who were suitable for non-intensive therapy were randomized (2:1) to LDAC + glasdegib 100 mg QD or LDAC alone, and patients suitable for intensive therapy were assigned 7+3 plus glasdegib 100 mg QD. Whole blood, serum, and bone marrow aspirate samples were collected at baseline, and used to assess 19 genes for expression analysis, 38 analytes for circulating cytokine levels, and 109 genes for mutation analysis. Gene expression was analyzed using TaqMan Low Density Array Cards (TLDCs), cytokine levels were analyzed using quantitative, multiplexed immunoassays (Myriad RBM), and mutation analysis was performed using the Illumina® MiSeq instrument (San Diego, CA). All correlations were performed either for OS or for OR. For gene expression and cytokine analysis, a cut-off value above or below the median expression level for each treatment arm was used to separate samples into two subgroups (< or ≥ the median value) to explore the relationship of expression levels with OS data. Criteria for significance in the non-intensive cohort required one subgroup to have a p-value of <0.05 in the between-treatment arms comparison and the HR difference between the two subgroups to be ≥2 fold. Responses were defined as patients with a complete remission (CR), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, partial remission (PR), or PRi. For response correlations, genes or cytokines were considered to be differentially expressed if they had a p-value <0.05 and were differentially expressed by ≥2-fold. Results: Within the non-intensive arm (LDAC + glasdegib, n=68; LDAC alone, n=30), expression levels of several genes correlated with improved OS with glasdegib plus LDAC. Lower levels of expression of FOXM1 and MSI2, and higher expression levels of BCL2 and CCND2 correlated with improved OS with the combination. Additionally, lower levels of the cytokines 6CKINE (CCL21), ICAM-1, MIP-1α, and MMP-3 correlated with improved OS. An analysis of correlations of gene expression and cytokine levels with OR could not be completed due to the low number of responders in the LDAC only group (n=2). In the intensive treatment arm (glasdegib and 7+3, n=59), higher PTCH1 expression correlated with improved OS (p=0.0219, median OS 10.8 versus 39.5 months). In this cohort, lower levels of IL-8 (p=0.0225) and MIP-3β (p=0.0403) correlated with lower OS. Expression levels of no genes or cytokines significantly correlated with OR in this arm. We also examined correlations between gene mutation status and OS in both study arms. In the non-intensive arm (LDAC + glasdegib, n=58; LDAC alone, n=25), no genes mutated in at least 5 patients correlated with OS. In the intensive treatment arm (n=47), mutations in FLT3, TP53, CEP170, NPM1, and ANKRD26 correlated with OS (all p<0.05). Patients in this arm with FLT3 mutations responded better than patients with wild type FLT3 (p=0.0336, median OS of 13.1 months versus unreached for FLT3 mutant). Conclusions: In this biomarker analysis, we found that expression levels of a select number of genes and circulating cytokines implicated in AML correlated with OS in the non-intensive and the intensive arms. The improved response for patients with FLT3 mutations and high PTCH1 expression levels in the intensive arm deserves further investigation. These findings need to be verified in larger controlled studies, which are ongoing. Disclosures Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Pollyea:Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Astellas: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding. Chan:Pfizer: Employment, Equity Ownership. Wang:Pfizer: Employment, Equity Ownership. Ching:Pfizer Inc: Employment, Equity Ownership. Johnson:Pfizer Inc: Employment, Equity Ownership. O'Brien:Pfizer Inc: Employment, Equity Ownership.

Results from Phase 1/2 Trial of Tagraxofusp in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3145-3145 ◽  
Author(s):  
Paul G. Richardson ◽  
Myo Htut ◽  
Cristina Gasparetto ◽  
Jeffrey A. Zonder ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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 . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .

scholarly journals Flotetuzumab (FLZ), an Investigational CD123 x CD3 Bispecific Dart® Protein-Induced Clustering of CD3+ T Cells and CD123+ AML Cells in Bone Marrow Biopsies Is Associated with Response to Treatment in Primary Refractory AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1410-1410 ◽  
Author(s):  
John E. Godwin ◽  
Carmen Ballesteros-Merino ◽  
Nikhil Lonberg ◽  
Shawn Jensen ◽  
Tarsem Moudgil ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Refractory Aml

Introduction The infiltration of immune cells into tumors has been associated with therapeutic effects in preclinical models and patients with cancer. In AML, we have previously reported that immune infiltrated TME is predictive of failure to cytotoxic chemotherapy, but associated with response to immunotherapy, specifically FLZ (Uy ASH 2018, Rutella ASH 2018). Furthermore, FLZ also affects immune infiltration in the TME (Rutella ASH 2018). NK cells play an important role in AML control (Ruggieri Science 2012). FLZ (MGD006/S80880) is a humanized DART® molecule that bridges CD123 on AML with CD3 on T cells and mediates anticancer activity via T-cell activation and cytolytic activity against the bound cancer cell. While this is well described in vitro, little evidence of this interaction is available in vivo. Methods Patients (pts) were treated on the recommended phase 2 dose (RP2D) of FLZ (multi-step lead-in dose followed by 500ng/kg/day, in 28-day cycles). We studied the bone marrow (BM) tissue samples for 6 primary refractory pts at baseline and after treatment. Response assessment was performed at day 25±3 days of each cycle. Serial BM samples were evaluated using 2 different staining panels (PD-L1, FoxP3, CD8, CD3, CD103 / CD123, CD3, CD57, CD16) on consecutive slides. Slides were stained using a Leica BondRx autostainer and fluorescence imaged using a Polaris Vectra 3 and analyzed using inForm software. A density-based clustering algorithm developed and run in QuPath was used to quantify CD3+ T cell clusters. Results Six pts with primary refractory AML were included in this report. Pts were heavily pretreated (median prior lines of therapy was 3, range 2-9), and had adverse cytogenetic risk (ELN 2017). Three pts had a complete remission (CR) after 1 cycle of therapy (CR, CRh, CRi), two went on the receive allogeneic stem cell transplant (HSCT). In baseline BM samples, CD3 and CD8 cell infiltrates were higher in CR vs non-responders (CD3+ 18.3% ±6.9 vs 9.3% ±1.8; CD8+ 9.4% ±3.5 vs 4.8% ±1.2; mean±SEM). Two of the three CR patients, who underwent HSCT, developed clusters (Figure 1) in their on-treatment biopsies with 65 and 22 clusters of an average of 34 and 17 T cells per cluster, respectively. All clusters in CR pts were found on or adjacent to CD123+ cells. The BM biopsy of the CR pt with no detected clusters had no unequivocal evidence of residual/recurrent leukemic blasts. This pt had their dose interrupted early due to non-treatment related AE (infectious complication) and did not receive a full cycle of treatment; the response was transient and the pt relapsed shortly thereafter. NK cells (CD57+CD16+) were increased in post treatment biopsies of CR vs non-responders (0.93 ±0.31 vs 0.27 ±0.13; mean±SEM) with the largest fold increase in CR (28 vs 9). Lastly, post treatment biopsy PD-L1 expression was higher in non-responders than CR (23% vs 16%) with non-responders exhibiting the largest fold change in total PD-L1+ cells (10.9 vs 2.2). Summary Consistent with its proposed mechanism of action, these data highlight for the first time, the dynamic induction of an increase in T-cell infiltration, and clustering around CD123 AML cells in the bone marrow microenvironment of two AML patients that responded to FLZ. In pts with resistance to FLZ (non-responders) PD-L1 induction was significantly higher indicating that in some pts treatment with sequential check point inhibitor could obviate this mechanism of resistance A trial combining FLZ with sequential administration of a PD-1 inhibitor (MGA012) is currently recruiting pts. Figure 1. Baseline and on-treatment IHC of BM biopsies of a FLZ-treated CR pt showing cluster formation following treatment. Disclosures Bifulco: Ventana: Other: advisory board; PrimeVax: Equity Ownership, Other: ScientificBoard; BMS: Other: Advisory Board; Providnece: Patents & Royalties: Imaging processing; Halio Dx: Other: advisory board. Wigginton:macrogenics: Employment, Equity Ownership; western oncolytics: Consultancy, Other: consultancy. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. Fox:Akoya: Research Funding; Bristol Myers Squibb: Research Funding; Definiens: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Research Funding; Ultivue: Membership on an entity's Board of Directors or advisory committees.

A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 551-551 ◽  
Author(s):  
K John Pasi ◽  
Pencho Georgiev ◽  
Tim Mant ◽  
Michael Desmond Creagh ◽  
Toshko Lissitchkov ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Educational Support ◽  
Monthly Dosing ◽  
Equity Ownership

Abstract Background: Hemophilia A and B are bleeding disorders characterized by a profound defect in thrombin generation (TG). Furthermore, in the presence of normal levels of endogenous anticoagulants a deficiency in factor VIII and IX results in major hemostatic imbalance and a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin (AT) that aims to restore the hemostatic balance by increasing TG. Methods: We are conducting a phase 1 multi-center study (NCT02035605) in healthy volunteers and patients with moderate to severe hemophilia A or B. Part A of this study has been completed and assessed a single ascending dose study in healthy volunteers. Parts B and C are multiple ascending dose studies in patients with hemophilia who are receiving weekly or monthly dosing, respectively. Primary endpoints are safety and tolerability. Secondary endpoints include PK, AT knockdown; change in thrombin generation and whole blood clot formation as measured by Calibrated Automated Thrombin generation and ROTEM thromboelastometry. Exploratory endpoints include evaluations of bleed pattern and control. Results: Part A enrolled 4 healthy volunteers, randomized (3:1) to 30 mcg/kg ALN-AT3 or placebo; no serious adverse events (SAE) or injection site reactions were observed. A total of 12 patients with severe hemophilia (10 hemohilia A; 2 hemophilia B) were enrolled in Part B and received 3 weekly subcutaneous doses of ALN-AT3 at 15 (n=3), 45 (n=6), and 75 (n=3) mcg/kg. Similar to part A, weekly administration of ALT-AT3 was generally safe and well tolerated in patients with hemophilia; no SAEs, discontinuations, clinical thromboembolic events or clinically significant D-dimer increases were reported. In the 75 mcg/kg dosing cohort, the mean maximum AT knockdown was 59% (p<0.05, relative to baseline), with nadir levels achieved between days 28 and 42. Maximum plasma AT knockdown of 86% was achieved, resulting in thrombin generation increases that correlated with AT knockdown and a bleed-free period of 114 days in the patient achieving the highest level of AT knockdown. The association between AT KD and TG was assessed in a post hoc exploratory analysis in which AT KD was categorized into tertiles. Part C aims to enroll several cohorts (n=3 per cohort) and will assess a monthly dosing schedule (x3 doses) of ALN-AT3. Patients in cohort 1 and 2 were dosed at 225 and 450 mcg/kg, respectively. Up to 4 additional cohorts may be enrolled within Part C. Updated safety, PK, AT knockdown, TG results as well as bleed patterns from Parts B and C will be presented. Conclusions: Emerging clinical data suggest that targeting AT could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make ALN-AT3 a potentially encouraging investigational therapy. Disclosures Pasi: Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Mant:Quintiles: Employment, Equity Ownership. Creagh:Bayer Healthcare UK: Honoraria. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Brand:Alnylam: Honoraria. Chowdary:Bayer: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; SOBI: Consultancy. Ragni:Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dimension: Research Funding; Bayer: Research Funding; SPARK: Research Funding; Genentech Roche: Research Funding; Pfizer: Research Funding; Vascular Medicine Institute: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; CSL Behring: Research Funding. Chen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Rangarajan:Octapharma: Other: Investigator.

scholarly journals Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 591-591 ◽  
Author(s):  
Amir T. Fathi ◽  
Harry P. Erba ◽  
Jeffrey E. Lancet ◽  
Eytan M. Stein ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Survival Data ◽  
Research Funding ◽  
Intensive Therapy ◽  
Advisory Board ◽  
Hypomethylating Agents ◽  
Employment Equity ◽  
Secondary Aml ◽  
Genetics Research ◽  
Equity Ownership

Abstract Background Treatment of AML among the elderly is challenging due to intolerance of intensive therapy and greater prevalence of therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used in this setting, but yield suboptimal remission rates and modest survival (Dombret 2015, Kantarjian 2012). Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. In preclinical studies, HMA priming followed by 33A resulted in upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. Methods A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33Ain combination with an HMA. Eligible patients (ECOG status 0-1) must have had previously untreated CD33-positive AML andhad declined intensive therapy. A single dose level of 33A, 10 mcg/kg,was administered outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003). Results Fifty-three patients (median age 75 years; range, 60-87) have been treated with 33A+HMA. All patients had adverse (38%) or intermediate (62%) cytogenetic risk by MRC criteria; 40 patients (75%) were considered unfit for intensive therapy and 13 patients (25%) declined intensive therapy.Of the patients with secondary AML (23/53, 43%), median age was 77 years (range 60-87) with most of the patients ≥75 years (70%). The median treatment duration is currently 19.3 weeks (range, 2-86) with 13 patients remaining on treatment; no DLTs or infusion reactions were reported. G3 or higher AEs reported in ≥15% of patients were thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%); no G4 or 5 bleeding events were observed. Other non-hematologic treatment-emergent AEs regardless of relationship to study treatment and reported in ˃25% of patients were fatigue (58%), nausea (47%), constipation (43%), decreased appetite, peripheral edema (40% each), pyrexia (32%), dyspnea (28%), diarrhea (26%), and dizziness (25%). 30- and 60-day mortality rates were 2% and 8% with no treatment-related deaths reported. A total of 37% (90/246) of doses were delayed due to AEs primarily related to myelosuppression (neutropenia 16%, thrombocytopenia 6%, febrile neutropenia 4%).Thirty-six of the 49 efficacy evaluable patients (73%)achieved CR (21, 43%) or CRi (15, 31%); an additional 4 patients were not efficacy evaluable by protocol definition, due to death (n=2) or withdrawal of consent (n=2) before a response assessment marrow could be obtained. Remissions were achieved after a median of 2 cycles (range, 1-4) and were observed in most of the patients with adverse risk disease including antecedent myelodysplasia (16/22, 73%), adverse cytogenetics (15/18, 83%), FLT3/ITD (5/5, 100%), and patients≥75 years (17/26, 65%). Seventeen of 22 efficacy-evaluable patients with secondary AML (77%) achieved CR (11, 50%) or CRi (6, 27%). Of all responding patients, 17 of 36 (47%) achieved MRD negativity by flow cytometry. The median relapse-free survival was 9.1 months (range, 0.1-16.5+) andOS continues to evolve with22 patients (42%) alive with a median follow-up of 10 months. Conclusions The combination of 33A+HMA is well tolerated with no identified pattern of off-target toxicity. Activity with the combination appears markedly improved when compared to the historical experience of HMA monotherapy in this patient population (Table 1). The CR+CRi rate of 73% in older AML patients with poor risk factors in the setting of low early mortality is particularly encouraging. Activity was maintained even in the highest risk patient groups (adverse risk cytogenetics, underlying myelodysplasia, secondary AML, FLT3/ITD). Survival data are evolving and compare favorably to historical controls. CASCADE, a phase 3 trial investigating 33A+HMA v. HMA alone in older AML patients is now enrolling (NCT02785900). Disclosures Fathi: Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding. Erba:Gylcomimetics: Other: DSMB; Millennium Pharmaceuticals, Inc.: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Celator: Research Funding; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Stein:Celgene: Other: Advisory Board, Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding; Novartis: Consultancy. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. DeAngelo:Baxter: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Kovacsovics:Seattle Genetics: Research Funding. Jillella:Seattle Genetics: Research Funding. Levy:Seattle Genetics: Research Funding; Jansen: Speakers Bureau; Amgen: Speakers Bureau; Millennium: Speakers Bureau. O'Meara:Seattle Genetics: Employment, Equity Ownership. Ho:Seattle Genetics: Employment, Equity Ownership. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding.

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