scholarly journals Assessment of Romiplostim Immunogenicity in Adult Patients in Clinical Trials and in a Global Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2427-2427 ◽  
Author(s):  
Troy E. Barger ◽  
Andy Boshier ◽  
Vibha Jawa ◽  
June Kim ◽  
Daniel T. Mytych ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Platelet Count ◽  
Research Funding ◽  
Phase 1 ◽  
Adult Patients ◽  
Employment Equity ◽  
Lower Baseline ◽  
Increased Risk ◽  
Equity Ownership ◽  
Global Registry

Abstract Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing. Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted. Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result. Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2). Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO. Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs. Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy. Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. Disclosures Barger: Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: 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.

scholarly journals Phase 1 Results of ZUMA-3: KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 888-888
Author(s):  
Bijal D. Shah ◽  
Wendy Stock ◽  
William G Wierda ◽  
Olalekan Oluwole ◽  
Houston Holmes ◽  
...  
Keyword(s):  
T Cells ◽  
Research Funding ◽  
Phase 1 ◽  
Adult Patients ◽  
Employment Equity ◽  
Efficacy Analysis ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3

Abstract Background : Approximately 45% of new ALL cases occur in adults ≥ 20 years of age (Howlader et al. SEER Cancer Statistics. 2015), and approximately 50% of adult patients relapse with poor subsequent outcomes (Oriol et al. Haematologica. 2010; Basson et al. JCO. 2011). Promising early efficacy and manageable safety were previously reported with anti-CD19 CAR T cells (KTE-C19) in adult patients with R/R ALL (Shah et al. ASCO 2017. #3024). Here we report updated results of the ZUMA-3 trial. Methods : Adult patients (≥ 18 years of age) with R/R ALL (Philadelphia+ eligible), > 5% bone marrow (BM) lymphoblasts; Eastern Cooperative Oncology Group performance status (ECOG) 0-1; and adequate renal, hepatic, and cardiac function were eligible. Patients with active graft-versus-host disease or clinically significant infection were not eligible. Patients received a target dose of 1 × 106 CAR T cells/kg or 2 × 106 CAR T cells/kg after lymphodepletion with 25 mg/m2/day fludarabine for 3 days and 900 mg/m2/day cyclophosphamide given on the last day. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence of adverse events (AEs), incidence of minimal residual disease-negative (MRD-) responses, duration of remission (DOR), relapse-free survival (RFS), and overall survival (OS). Exploratory endpoints included levels of anti-CD19 CAR T cells in blood and levels of cytokines in serum. Results : As of the data cut-off date (DCO; April 26, 2017), 22 patients have been enrolled, and 16 patients received KTE-C19 on study. Four patients had not received treatment by the DCO, 1 patient did not receive KTE-C19 due to an AE after conditioning, and 1 patient received KTE-C19 under compassionate use. All 16 patients who received KTE-C19 prior to the DCO were included in the safety analysis, and all patients who had the opportunity to be followed for 8 weeks prior to the DCO were included in the efficacy analysis (n = 11). Of the 16 patients dosed with KTE-C19, 63% were male, 56% had ECOG 1, and 50% had received ≥ 2 previous lines of treatment, including 3 patients with prior blinatumomab. Nineteen percent of patients had undergone prior allogeneic stem cell transplant, 31% had R/R to ≥ second-line therapy, 31% had primary refractory disease, and 19% experienced first relapse within 12 months of first remission. Most patients (81%) had baseline BM blasts ≥ 60%. Six patients received the 2 × 106 cells/kg dose and 10 received the 1 × 106 cells/kg dose. No DLTs were observed. One patient experienced a grade 5 event of cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose, and no other KTE-C19-related grade 5 AEs were observed. In the 16 patients who received KTE-C19, all of whom were followed for at least 4 weeks, the most common grade ≥ 3 AEs were hypotension (56%), anemia (50%), pyrexia (50%), and decreased platelet counts (44%). Grade ≥ 3 CRS and neurologic events (NE) were reported in 25% and 63% of patients, respectively. Tocilizumab (toci) or steroids were given for AE management in 94% and 75% of patients, respectively. In the 11 patients eligible for the efficacy analysis, objective response rate was 82%, including 8 (73%) patients with a complete remission (CR or CR with partial hematopoietic recovery), and 1 (9%) with blast-free BM. All remissions were MRD- as determined by flow cytometry. All 5 (100%) of the other patients who were too early for inclusion in the efficacy analysis had MRD- bone marrow with varying degrees of count recovery at the time of the DCO. Median follow-up was 6.8 months; 4 patients relapsed 63 - 168 days after treatment with KTE-C19. Efficacy was comparable between patients who recieved KTE-C19 doses of 1 × 106 and 2 × 106 CAR T cells/kg. Data from additional patients, including those treated with a lower dose of 0.5 × 106 CAR T cells/kg, as well as updated safety, efficacy, biomarker, and product characteristic analyses across dosing groups will be presented. Conclusions : In this ongoing phase 1 study, KTE-C19 has shown promising efficacy in adult patients with R/R ALL. The safety profile was generally manageable and additional approaches to improve the benefit:risk profile are being explored. ZUMA-3 continues to enroll additional patients at the 0.5 × 106 CAR T cells/kg dose level. Disclosures Wierda: AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Juno: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding. Oluwole: Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Schiller: Kite Pharma: Research Funding. Topp: Regeneron: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Celgene: Other: Travel; Macrogenics: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Research Funding. Kersten: Kite Pharma: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millenium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Mojadidi: Kite Pharma: Employment, Equity Ownership. Xue: Kite Pharma: Employment, Equity Ownership. Mardiros: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Shen: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Stout: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Jain: Kite Pharma: Employment, Equity Ownership.

scholarly journals TNB383B.0001: A Multicenter, Phase 1, Open-Label, Dose-Escalation Andexpansion Study of TNB-383B, a Bispecific Antibodytargeting BCMA in Subjects with Relapsed or Refractorymultiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1874-1874 ◽  
Author(s):  
Ben Buelow ◽  
Anita D'Souza ◽  
Cesar Rodriguez ◽  
Ravi Vij ◽  
Rajneesh Nath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
T Cells ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Open Label ◽  
Employment Equity ◽  
High Affinity ◽  
Equity Ownership

Introduction Multiple myeloma (MM) is an incurable plasma cell malignancy with an estimated incidence in 2019 of ~32,000 in the United States. Although median survival is greater than 8 years, treatment options are limited for patients who relapse on or are refractory to standard treatment regimens containing proteasome inhibitors, immune-modulating drugs and anti-CD38 antibodies (triple refractory). Novel therapies are critical to the treatment of these patients. Chimeric antigen receptor T cells (CAR-Ts) and T-cell redirecting Bispecific Antibodies (T-BsAbs) targeting B-cell maturation antigen (BCMA) -a protein found exclusively on the surface of plasma cells- have shown efficacy against relapsed/refractory MM in early phase clinical trials. However, toxicity from over-activation of T-cells still hinders these approaches. Utilizing Teneobio's proprietary next generation sequencing (NGS)-based discovery tool incorporating in silico analysis of heavy chain only/fixed light chain antibody sequences (HCA/Flic, respectively) to enrich for antigen specific antibodies, we made a high affinity αBCMA HCA and a library of αCD3 Flic antibodies that showed a >2 log range of EC50s for T cell activation in vitro. TNB-383B combines a high affinity αBCMA HCA with a low-activating αCD3 Flic; in preclinical studies TNB-383B showed equivalent anti-tumor efficacy but significantly reduced cytokine secretion compared to BCMA-targeted T-BsAbs incorporating a strongly-activating αCD3 (similar in strength to the αCD3s used in other T-BsAbs currently in clinical trials). A Phase 1 study investigating the safety, pharmacokinetics, and preliminary activity of TNB-383B in patients with relapsed/refractory multiple myeloma (RRMM) is ongoing and described. This trial represents, to the best of our knowledge, the first reported clinical trial of a HCA/Flic hybrid antibody in humans. Study Design TNB383B.0001 (NCT03933735) is an open-label, multi-center study of TNB-383B in patients with RRMM. The study is divided into escalation (Arm A, N=24) and expansion (Arm B, N=48) arms. Subjects who have received 3 or more prior lines of therapy with exposure to a PI, an IMiD, and an anti-CD38 antibody are eligible for this study. Documentation of BCMA expression by tumor cells is not required for entry, although prior treatment with a BCMA-targeted agent is an exclusion criterion. Other key inclusion/exclusion criteria include EGFR of >30ml/min, ANC ≥1000/mm3 and platelets ≥50,000/mm3 and minimal bone marrow biopsy requirements on-study. Subjects must be admitted for 48 hours following the 1st dose in Cycle 1 (21-day cycle length), but TNB-383B may be administered on an outpatient basis thereafter. Dose Escalation TNB-383B is administered as an intravenous infusion. Dose escalation is proceeding via a 3+3 design with fixed (as opposed to weight based) doses per protocol. Arm B will be initiated once the maximum tolerated dose (MTD, or recommended phase 2 dose, RP2D) has been selected. Patients will be treated until progression, unacceptable toxicity, or other discontinuation criteria are met. One patient has been enrolled thus far. Statistical Methods and Study Endpoints In Arm A occurrence of dose limiting toxicities (DLTs) will drive identification of the MTD (or RP2D in line with standard practices. In Arm B accrual will be suspended if more than 33% of subjects experience a DLT event. Adverse events, laboratory profiles, physical exams, and vital signs will be assessed throughout the study. Adverse events will be graded according to the NCI CTCAE, version 5.0. Concentrations of TNB-383B and Anti-Drug Antibodies (ADA) will be determined at designated time points throughout the study. Values for standard pharmacokinetic parameters of TNB-383B including the maximum observed serum concentration (Cmax), the time to Cmax, area under the concentration-time curve, clearance, and terminal half-life will be determined using non-compartmental methods. The activity endpoints (determined using the IMWG uniform response criteria) include overall response rate, progression-free survival and overall survival. The relationship between biomarkers, including soluble BCMA and A Proliferation Inducing Ligand (APRIL; the endogenous ligand for BCMA), and activity will be assessed. Disclosures Buelow: Teneobio, Inc.: Employment, Equity Ownership. Rodriguez:Takeda, Amgen: Consultancy, Speakers Bureau. Vij:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Genentech: Honoraria; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria; Sanofi: Honoraria. Nath:Teneobio, Inc.: Consultancy. Snyder:Teneobio, Inc.: Consultancy. Pham:Teneobio, Inc.: Employment, Equity Ownership. Patel:Teneobio, Inc.: Employment, Equity Ownership. Iyer:Teneobio, 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 >-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 Comparison of CD22 Expression between Baseline, End of Treatment, and Relapse Among Patients Treated with Inotuzumab Ozogamicin Who Responded and Subsequently Relapsed in Two Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2699-2699 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Wendy Stock ◽  
Ryan D. Cassaday ◽  
Daniel J. DeAngelo ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Complete Remission ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Inotuzumab Ozogamicin ◽  
Phase 3 ◽  
Expression Levels ◽  
End Of Treatment ◽  
Equity Ownership

Abstract Introduction: Downregulation or loss of B-cell ALL surface antigens (most notably CD19) in patients with acute lymphoblastic leukemia (ALL) targeted by various therapeutic modalities including CART and bi-specific T-cell engagers (BiTEs) has been implicated in acquired resistance to those therapies. Inotuzumab Ozogamicin (InO) is a calicheamicin-conjugated antibody targeting CD22 on ALL blast cells. In the Phase 3 INO-VATE trial, patients with refractory (R/R) ALL who received InO vs standard of care chemotherapy (SC) achieved greater remission, MRD negativity, and improved survival. This study reports CD22 expression levels at baseline, end of treatment (EOT) and relapse in R/R ALL patients who received InO or SC as salvage therapy and subsequently relapsed; the goal of this analysis was to understand if relapse was associated with changes in CD22 expression. Methods: The study population consisted of R/R ALL patients who were treated with InO or SC as part of two clinical trials: Phase 1/2 Study 1010 (NCT01363297; Phase 1, Expansion Phase, + Phase 2 at a dosage of 1.8 mg/m2) and Phase 3 Study 1022 (NCT01564784). This analysis incorporated CD22 expression levels at baseline, at end of treatment, and at relapse. Central laboratory flow cytometry was used to assess CD22 expression, which was quantified as % CD22-positive leukemic blasts and as Molecules of Equivalent Soluble Fluorochrome (MESF), a quantitative measure of CD22 density on leukemic blasts. Outcomes are reported in InO (Study 1022 or 1010) and SC patients who responded to treatment (patients who achieved complete remission/complete remission with incomplete hematologic recovery [CR/CRi]) and subsequently relapsed. CR was defined by <5% marrow blasts and the absence of peripheral blood leukemic blasts; with recovery of hematopoiesis. Results: 25 InO patients (Study 1022, n=19; Study 1010, n=6) and 11 SC patients who responded to treatment and subsequently relapsed were evaluable for central-lab CD22 analysis at baseline. Among InO patients who responded to treatment, the majority had leukemic blasts that were ≥90% CD22-positive at baseline (Study 1022, 66.7%; Study 1010, 66.7%); of the evaluable patients at EOT (Study 1022, n=4; Study 1010, n=0), leukemic blast CD22-positivity was >0-<70%. At relapse, all evaluable InO patients had leukemic blasts with detectable CD22-positivity; with blasts that were predominately <90% CD22 positive (Study 1022, n=6/7; Study 1010, n=5/6 [Table 1]). In contrast, the majority of evaluable subjects who received SC and achieved CR/CRi exhibited CD22 positivity that remained ≥90% at EOT and at relapse When CD22 expression was quantified as MESF, a similar trend was evident (Table 2). In Study 1022, InO patients had a median CD22 MESF of 4085.0 at baseline, which declined to 94.0 at EOT and 418.0 at relapse. In contrast, the median CD22 MESF at EOT and at relapse (3738.0 and 3738.0, respectively) was similar to baseline (4065.0) for SC patients. Conclusions: Among R/R ALL patients who responded to InO treatment and subsequently relapsed, a decrease in CD22 positivity and receptor density was evident from baseline to EOT and relapse, but emergent CD22 negativity was not evident. These results suggest that recurrent disease is associated with decreased CD22 expression, but is not generally attributable to the outgrowth of CD22-negative clones. Disclosures Stock: Jazz Pharmaceuticals: Consultancy. Cassaday:Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Kite Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. DeAngelo:Pfizer Inc: Consultancy, Honoraria; BMS: Consultancy; Glycomimetics: Research Funding; Shire: Honoraria; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Takeda: Honoraria; Incyte: Consultancy, Honoraria. Jabbour:Novartis: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. O'Brien:Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Alexion: Consultancy; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy; Acerta: Research Funding; Abbvie: Consultancy; Astellas: Consultancy; Kite Pharma: Research Funding. Stelljes:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria. Wang:Pfizer: Employment, Equity Ownership. Liau:Pfizer: Employment, Equity Ownership. Nguyen:Navigate BioPharma Services, Inc., a Novartis Subsidiary: Employment. Sleight:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Neuhof:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Advani:Novartis: Consultancy; Amgen: Research Funding; Glycomimetics: Consultancy; Pfizer: Honoraria, Research Funding.

A Phase 1 Study of TTI-621, a Novel Immune Checkpoint Inhibitor Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1812-1812 ◽  
Author(s):  
Stephen Ansell ◽  
Robert W Chen ◽  
Ian W. Flinn ◽  
Michael B. Maris ◽  
Owen A. O'Connor ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Dose Dependent

Abstract Introduction The phagocytic activity of macrophages is regulated by activating ("eat") and inhibitory ("do not eat") signals. Under normal physiologic conditions, the ubiquitously expressed cell surface antigen CD47 suppresses phagocytosis by binding to signal regulatory protein alpha (SIRPα) on macrophages. It is hypothesized that overexpression of CD47 by cancer cells enables immune evasion. Blockade of CD47 results in phagocytosis of cells bearing "eat" signals and primes effective anti-tumor T cell responses. TTI-621(SIRPαFc)is a soluble recombinant fusion proteinconsisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1designed to both: 1) block the CD47 "do not eat" signal, and 2) engagemacrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.In vitro, TTI-621 binds to normal human cells, platelets, a wide range of human primary tumor cells and cell lines, but only minimally to human erythrocytes. TTI-621 selectively promotes macrophage-mediated phagocytosis of hematologic and solid tumors over that observed with normal monocytes, and exhibits antitumor activity in xenograft mouse models. Methods A first-in-human, phase 1, open label, multicenter study (NCT02663518) is ongoing to evaluate the safety and tolerability, and to identify the maximum tolerated dose of TTI-621 in patients (pts) with relapsed/refractory lymphomas using a 3+3 dose-escalation design. Once the optimal dose has been determined in the dose-escalation phase, multiple expansion cohorts will be enrolled comprising pts with various relapsed/refractory hematologic malignancies. Assessments include peripheral receptor occupancy, serum cytokine levels, pharmacokinetics, and immunogenicity. Eligible pts are adults with advanced, measurable, hematologic malignancies, who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are required to have baseline hemoglobin ≥10 g/dL, platelets ≥75 x 109/L, and be transfusion- and growth factor-independent. Pts with cutaneous T-cell lymphoma, high-grade lymphoma, and acute promyelocytic leukemia are excluded. TTI-621 is administered IV once weekly at protocol-defined doses. Treatment may continue until disease progression or unacceptable toxicity. Results Eleven pts (6M/5F, age 21-72 years) have been enrolled as of the data cut-off date of 28 July 2016. Lymphoma diagnoses included Hodgkin (N=4), diffuse large B cell (DLBCL) (N=4), follicular (N=2), and mantle cell (N=1). Treatment has been reasonably well tolerated by pts in the 0.05 mg/kg (N=3), 0.1 mg/kg (N=3), and 0.3 mg/kg (N=5) dose cohorts. The majority of pts experienced mild to moderate infusion-related events. Hemoglobin levels have remained stable or improved with treatment. Transient, dose-dependent decreases in platelets and leukocytes occurred in the hours following infusion in all pts without clinical sequelae. The 0.3 mg/kg dose was associated with reversible, dose-limiting toxicity (DLT) in 2 of 5 pts: one pt with G3 elevated ALT/AST and G4 platelet count, and a second pt with G4 platelet count who was transfused. Dosing at 0.2 mg/kg is now being explored. Aside from the DLTs and 2 non-DLT G3 platelet count (all in 0.3 mg/kg cohort), treatment-related adverse events have been ≤G2. CD47 receptor occupancy increased with each cohort, peaking at the end of infusion and remaining detectable 24 hrs after the 1st infusion in Cohort 3. Macrophage-associated cytokines, including MIP-1α and MIP-1β, increased during the 4 hrs after infusion. Six pts continue to receive weekly infusions of TTI-621; one pt with DLBCL and another with FL have experienced progression-free intervals of 161 and 70 days, respectively. Conclusions TTI-621 has been reasonably well tolerated. Pts retained stable hemoglobin levels consistent with minimal drug binding to erythrocytes. Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets. TTI-621 binds to CD47+ cells in a dose-dependent manner, potently yielding increases in cytokines associated with augmented phagocytic activity. Enrollment continues at the 0.2 mg/kg dose level; updated data will be provided at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. O'Connor:Bristol Myers Squibb: Research Funding; Spectrum: Research Funding; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; TG Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sievers:Seattle Genetics: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership; MEI Pharma: Consultancy.

scholarly journals Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Acute Leukemia and Highly Aggressive Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 963-963 ◽  
Author(s):  
Amir T Fathi ◽  
Robert Chen ◽  
Tanya M. Trippett ◽  
Maureen M. O'Brien ◽  
Daniel J DeAngelo ◽  
...  
Keyword(s):  
B Cell ◽  
Interim Analysis ◽  
Research Funding ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Adult Patients ◽  
Aggressive Lymphoma ◽  
Weekly Schedule ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background CD19, a B cell-specific marker, is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma. SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This first-in-human, phase 1, open-label, dose-escalation study is investigating the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in adult and pediatric patients with relapsed or refractory B-cell leukemia or highly aggressive lymphoma (NCT 01786096). Eligible patients must have B-cell acute lymphoblastic leukemia (B-ALL) or lymphoma (B-LBL), Burkitt leukemia or lymphoma, and be relapsed or refractory to at least 1 prior systemic regimen. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation for both pediatric and adult patients. The study is evaluating 2 schedules of IV SGN-CD19A administration: weekly (Days 1 and 8 of 21-day cycles; 0.3-4.5 mg/kg) or every 3weeks (q3week; 0.5-6 mg/kg). Results To date, 49 patients with relapsed or refractory leukemia (n=40) or lymphoma (n=9) have been treated. Median age of adult (n=38) and pediatric patients (n=11) was 37 and 11 years (range, 18-74 and 1-16), respectively. Patients received a median of 2 prior therapies (range 1-9); 14 patients (29%) previously received an allogeneic stem cell transplant. On the weekly schedule, 39 patients (28 adult, 11 pediatric) have been treated, and the median number of cycles is 2.5 (adults; range, 1-12) or 1 (pediatric; range, 1-4). On the q3week schedule, 10 adult patients have been treated, and the median number of cycles is 2.5 (range, 1-4) to date. Six patients remain on study treatment (3 on each schedule), and enrollment is ongoing. The toxicity profiles were similar across both dosing schedules (0.3-2.3 mg/kg weekly and 4-5 mg/kg q3week) and across adult and pediatric patients. The most frequently reported drug-related AEs included pyrexia, nausea, chills, vomiting, blurred vision, and dry eye. Frequent infusion-related reactions were observed early in the study, and recommendation for premedication was instituted. Ocular events were also observed and treated with ophthalmic steroids; steroid eye drop prophylaxis was instituted with each dose. Corneal findings consistent with superficial microcystic keratopathy were observed in 13 adult patients (34%) and in 1 pediatric patient (9%). Grade 3/4 corneal AEs have been observed in 4 adult patients; the majority of these events have resolved or improved to Grade 1 or 2. Steroid eye drop prophylaxis has reduced the incidence of Grade 3/4 events at this interim analysis. Three DLTs were observed: acidosis in a pediatric patient at 1 mg/kg weekly, cytokine release syndrome in an adult patient at 2 mg/kg weekly, and asymptomatic Grade 4 AST elevation in an adult patient at 5 mg/kg q3week. MTD has not yet been determined. SGN-CD19A ADC pharmacokinetic profiles indicate target-mediated drug disposition in patients with leukemia. Plasma ADC exposures generally increased with doses and were lower than those in patients with lymphoma. To date, no objective responses were observed in 9 efficacy-evaluable pediatric patients or in 3 adult patients with Burkitt lymphoma/leukemia. However, in efficacy-evaluable adult patients with B-ALL/B-LBL, objective responses were observed in 6 of 25 patients treated on the weekly schedule (3 CR, 2 CRp, 1 PR), and in 4 of 8 patients treated on the q3week schedule (2 CR, 2 CRp). Of 8 B-ALL patients with CR/CRp, 6 were MRD negative. Conclusions MTDs have not yet been identified, and dose escalation continues on weekly and q3week schedules. SGN-CD19A has been generally well tolerated. At this interim analysis, objective responses were observed in 30% (10 of 33) of heavily pretreated adult B-ALL/B-LBL patients dosed weekly or q3week. Evidence of activity in relapsed/refractory patients and lack of overlapping toxicities suggest opportunities for combination with conventional anti-leukemic therapies in lymphoblastic malignancies. Disclosures Fathi: Ariad: Consultancy; Exelixis: Research Funding; Takeda pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. O'Brien:Seattle Genetics, Inc.: Research Funding. DeAngelo:Seattle Genetics, Inc.: Research Funding. Shah:Pharmacyclics: Consultancy; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Consultancy. Cooper:Seattle Genetics, Inc.: Research Funding. Foran:Seattle Genetics, Inc.: Research Funding. Hale:Seattle Genetics, Inc.: Research Funding. Pressey:Seattle Genetics, Inc.: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Tibes:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Albertson:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Borate:Genoptix: Consultancy; Seattle Genetics, Inc.: Research Funding.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
Donna Weber ◽  
Sheeba Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Employment Equity ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

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

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

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

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