scholarly journals Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. LBA-6-LBA-6 ◽  
Author(s):  
Franco Locatelli ◽  
Michael B. Jordan ◽  
Carl E. Allen ◽  
Simone Cesaro ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Diagnostic Criteria ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Null Hypothesis ◽  
Research Funding ◽  
Response Rate ◽  
Study Entry ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, genetic life-threatening syndrome characterized by hyper-inflammation that is mainly driven by high production of interferon (IFN)-𝛾, leading to the development of fever, splenomegaly, cytopenias and coagulopathy. There are currently no approved treatments for HLH, and recent attempts to improve the dexamethasone/etoposide-based regimen (HLH-94) did not show a significant improvement in overall probability of survival. Emapalumab (NI-0501) is a fully human, anti-IFN-𝛾 monoclonal antibody that binds to and neutralizes IFN-𝛾 and is in development for treatment of HLH. Methods: This open-label pivotal study (NCT01818492) includes patients ≤18 years with a diagnosis of pHLH based on genetic confirmation, family history, or the presence of ≥5 of the 8 HLH-2004 diagnostic criteria. Patients were either treatment-naïve or had failed previous conventional HLH therapy prior to study entry. The emapalumab initial dose was 1 mg/kg given intravenously every 3-4 days. Subsequent doses could be increased up to 10 mg/kg based on the evolution of clinical and laboratory response parameters. Emapalumab was administered concomitantly with 5 to10 mg/m2/day of dexamethasone which could be tapered during the study. Treatment duration was 8 weeks (with possible shortening to a minimum of 4 weeks). Treatment could be extended up to allogeneic hematopoietic stem cell transplantation (HSCT) whenever needed. The primary efficacy endpoint of the study was overall response at end of treatment assessed by pre-defined objective parameters. Overall Response Rate (ORR) was assessed as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrogen and/or D-Dimer levels, central nervous system (CNS) abnormalities, with no sustained worsening of sCD25 serum levels. The primary analysis used an exact binomial test to evaluate the null hypothesis that ORR be at most 40% at a one-sided 0.025 significance level. Data presented are from 34 patients of whom 27 entered the study after failing conventional HLH therapy. Following completion of the main study patients entered into an extension phase (NCT02069899). The data cut-off applied is July 20 2017. Results: Patient characteristics are summarized in Table 1. Disease presentation at study entry was consistent with the broad spectrum of pHLH abnormalities, both in terms of HLH-2004 diagnostic criteria and other known HLH features; over 30% of patients had signs and/or symptoms of CNS disease. Efficacy results are summarized in Table 2. ORR was significantly higher than the pre-specified null hypothesis of 40%; thus the primary endpoint was met. The response rate based on investigator's clinical judgement was 70.6% and 70.4% in the two groups. Emapalumab infusions were in general well tolerated, with mild to moderate infusion-related reactions reported in 27% of patients. The observed safety events pre-HSCT conditioning mostly included HLH manifestations, infections or toxicities due to other administered drugs. Infections caused by pathogens potentially favored by IFN-𝛾 neutralization occurred in 1 patient during emapalumab treatment (Disseminated histoplasmosis), and resolved with appropriate treatment. No off-target effects were observed. Conclusions: This is the first prospective HLH study that reports response rates based on pre-defined objective criteria. Our results indicate that emapalumab should be considered as a new therapeutic option in pHLH thanks to its targeted mode of action. Treatment with emapalumab was able to control HLH activity with a favorable safety and tolerability profile in a very fragile population. The majority of patients proceeded to HSCT with favorable outcome. Disclosures Jordan: Novimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allen:Novimmune: Membership on an entity's Board of Directors or advisory committees. Sevilla:Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties; Novimmune: Other: currently participating in and have participated in Novimmune-sponsored clinical trials within the past two years . Grom:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AB2Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; NovImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Benedetti:Novartis: Consultancy, Research Funding; SOBI: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; UCB: Consultancy; Eli-Lylli: Consultancy; Abbvie: Research Funding; Novimmune: Research Funding; Pfizer: Research Funding. Ferlin:Novimmune: Employment, Equity Ownership, Patents & Royalties. Ballabio:Novimmune: Employment, Equity Ownership. De Min:Novimmune: Employment, Equity Ownership.

scholarly journals Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2883-2883
Author(s):  
Matthew S. Davids ◽  
Andrew W. Roberts ◽  
William G. Wierda ◽  
Kathryn Humphrey ◽  
Debbie J Alter ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Study Drug ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Equity Ownership

Abstract Introduction: Venetoclax is a selective, oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway. The dose-escalation phase 1 study of venetoclax in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) enrolled 106 patients from June 2011, and the overall response rate across the entire NHL cohort was 44%. The highest response rate (75%) was seen in the 28 patients with mantle cell lymphoma (MCL) (Davids et al., J Clin Oncol. 2017). Here, we report longer-term outcomes for those patients, now with a median of 27 months (range: 0.2 - 59) follow up. Methods: Venetoclax was administered in dose cohorts ranging from a maximum dose of 300-1200 mg and continued until progressive disease (PD) or unacceptable toxicity; intra-patient dose escalation was allowed. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and responses were assessed using 2007 Cheson IWG response criteria, utilizing CT scans beginning at week 6. The data cut off for this analysis was June 4th, 2018. Results: For the 28 patients with MCL, the median age was 72 years (range: 35 - 85). They had received a median of 3 (range: 1 - 7) prior treatments; 5 patients received prior PI3K inhibitor (but no prior ibrutinib). The median time from the preceding treatment to start of venetoclax was 13 months (range: 2 - 148). The median dose of venetoclax was 400 mg/day; 25/28 received at least 400mg/day. Median time on study drug was 11 months (range: 0.2 - 59). Three patients have been on therapy for over 4 years. The overall response rate was 75%, with 6 (21%) patients achieving complete remission (CR) and 15 (54%) partial response (PR). The median duration of response was 16 months (95% CI: 4, 30) and median progression free survival was 11 months (95% CI: 5, 21) for all patients (Figure). The 2 year PFS estimate was 30% (95% CI: 14%, 47%) for all patients, 83% (95% CI: 27%, 97%) for patients who achieved CR and 14% (95% CI: 2%, 37%) for patients who achieved PR. One patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last protocol defined follow-up (24 months after coming off study). Three patients developed progressive disease after receiving venetoclax for more than two years of therapy (time to progression: 31, 33, and 33 months). Two patients with CR continue on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy. The most common (≥25% of patients with MCL) all grade treatment emergent AEs were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%) and upper respiratory infection (25%). The most common (≥10% of patients with MCL) grade 3/4 AEs were neutropenia (14%), anemia (14%), pneumonia (11%), and thrombocytopenia (11%). Biochemical tumor lysis syndrome (TLS), without accompanying clinical features, was reported in one patient considered high risk for TLS. Specific interventions were not required, and the patient continued on study drug. Conclusions: Venetoclax monotherapy leads to durable remission in a meaningful proportion of patients with pretreated MCL. Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including a Phase 3 randomized study with ibrutinib (SYMPATICO, NCT03112174). Disclosures Davids: Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Alter:AbbVie, Inc: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Buss:Abbvie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Seymour:Janssen: Honoraria, Research Funding; Celgene: Consultancy; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding.

scholarly journals Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4471-4471 ◽  
Author(s):  
Michael Wang ◽  
Andre Goy ◽  
Peter Martin ◽  
Rod Ramchandren ◽  
Julia Alexeeva ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Dreamm-5: Platform Trial Evaluating Belantamab Mafodotin (a BCMA-directed Immuno-conjugate) in Combination with Novel Agents in Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1857-1857 ◽  
Author(s):  
Paul G. Richardson ◽  
Swethajit Biswas ◽  
Beata Holkova ◽  
Nicola Jackson ◽  
Thelma Netherway ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Cell Surface Receptor ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Patients with RRMM who have relapsed through multiple prior lines of therapy need novel, effective, targeted agents. B-cell maturation antigen (BCMA) is a cell-surface receptor required for plasma cell survival that is ubiquitously expressed on MM cells, but virtually absent on naïve and memory B cells. Belantamab mafodotin (GSK2857916) is a BCMA-directed immuno-conjugate with an afucosylated, humanized anti-BCMA monoclonal antibody (mAb) conjugated by a protease-resistant cysteine linker to a microtubule disrupting agent, monomethyl auristatin F (MMAF). Belantamab mafodotin specifically binds to BCMA, eliminating MM cells by a multimodal mechanism including delivering MMAF to BCMA-expressing malignant cells, enhancing antibody-dependent cellular cytotoxicity, and leveraging immunogenic cell death. In an open-label, phase 1 study (DREAMM-1), belantamab mafodotin monotherapy had a manageable safety profile and demonstrated rapid, deep and durable clinical response (60% overall response rate, 14.3 months duration of response) with significant progression free-survival (PFS; 12 months) in patients with heavily pretreated MM. Belantamab mafodotin is being evaluated in clinical trials in various lines of MM therapy, either as monotherapy or in combination. The DREAMM-5 platform trial is a phase 1/2 study that incorporates an efficient design with 1 master protocol, wherein multiple belantamab mafodotin-containing combinations will be evaluated in separate substudies to identify effective doublet combinations versus a shared belantamab mafodotin monotherapy control arm. Initial substudies will include combinations with the T-cell activating checkpoint mAbs GSK3359609 (an IgG4 inducible T-cell costimulatory [ICOS] agonist antibody that is Fc optimized to selectively enhance T-cell function to enable antitumor responses), GSK3174998 (a humanized wild-type IgG1 anti-OX40 agonistic mAb), and a gamma-secretase inhibitor, Nirogacestat (PF-03084014, SpringWorks Therapeutics). Furthermore, as treatment paradigms evolve, including potential genomic subsets of patients with RRMM and actionable mutations, other control arms may be introduced. The combination agent for evaluation in each substudy will be selected based on scientific rationale and/or results of preclinical experiments with the selected agent in combination with belantamab mafodotin. Methods: Patients with RRMM will be eligible if they have received ≥3 prior lines of therapy (consisting of an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 mAb), have measurable disease (as measured by M-protein and free light chain), and acceptable hematologic and vital organ functions. Participants previously treated with an anti-BCMA targeted therapy are eligible except for prior belantamab mafodotin treatment and chimeric antigen receptor (CAR) T-cell therapy within 3 months of screening. Each substudy will have 2 sequential phases to evaluate safety and efficacy (Figure). The dose exploration (DE) phase will evaluate the safety and tolerability of belantamab mafodotin administered in combination with a partner agent. Each DE phase will consist of multiple dosing cohorts (N≤10 per cohort), 1 cohort per doublet combination. The primary objective is to identify a recommended phase 2 dose for each doublet combination based on safety and preliminary efficacy. Once a substudy is selected for the cohort expansion (CE) phase (N=35 per substudy), the objective is to compare the response rate between the doublet combination and the shared belantamab mafodotin monotherapy control arm. Secondary objectives in CE are to assess AEs, durability of response, PFS, and overall survival. Exploratory objectives include assessment of PK for belantamab mafodotin with each partner agent, bone marrow minimal residual disease status, and plasma soluble BCMA levels as candidate prognostic and predictive biomarkers. DREAMM-5 is designed to efficiently identify novel, highly effective belantamab mafodotin-containing doublet combinations for evaluation in pivotal trials against current standard-of-care MM agents. Acknowledgments: Editorial assistance provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd and funded by GSK. Study funded by GSK (208887); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Biswas:GSK: Employment, Equity Ownership. Holkova:GlaxoSmithKline: Employment, Equity Ownership. Jackson:GlaxoSmithKline: Employment, Equity Ownership. Netherway:GlaxoSmithKline: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Ferron-Brady:GlaxoSmithKline: Employment, Equity Ownership. Yeakey:GlaxoSmithKline: Employment, Equity Ownership. Shelton:GlaxoSmithKline: Employment, Equity Ownership. Montes De Oca:GlaxoSmithKline: Employment. Ahlers:GlaxoSmithKline: Employment, Equity Ownership. Franco:GlaxoSmithKline: Employment, Equity Ownership. Ballas:GlaxoSmithKline: Employment, Equity Ownership; Bristol-Myers Squibb: Equity Ownership; AstraZeneca: Patents & Royalties: Uncompensated copyrights. Paul:GlaxoSmithKline: Employment, Equity Ownership. Luptakova:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

scholarly journals Phase 1b Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3986-3986 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Vincent Ribrag ◽  
Craig H. Moskowitz ◽  
Jean-Marie Michot ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Employment Equity ◽  
Advisory Committees ◽  
Humanized Monoclonal Antibody ◽  
Heavily Pretreated ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Like classical Hodgkin lymphoma (cHL), PMBCL frequently harbors genetic alterations of the 9p24.1 locus, leading to overexpression of the PD-1 ligands, PD-L1 and PD-L2. This provides a possible mechanism of immune evasion and suggests that PMBCL could have a genetically determined vulnerability to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands. Pembrolizumab has already demonstrated robust antitumor activity in advanced solid tumors and in cHL. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b trial testing the safety and preliminary efficacy of pembrolizumab in patients with hematologic malignancies. Based on its genetics, PMBCL was included as an independent cohort in this trial. Here we report the preliminary results in this patient population. Methods: The PMBCL cohort of KEYNOTE-013 is enrolling patients with relapsed/refractory (R/R) disease who have relapsed after or are ineligible for autologous stem cell transplant (ASCT). Pembrolizumab is administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or unacceptable toxicity. The primary end points are safety and antitumor activity. Response is being evaluated using computed tomography (CT) and positron emission tomography (PET) at week 12 and every 8 weeks thereafter, using IHP 2007 criteria. Other end points include complete remission (CR) rate, duration of response (DOR), and exploratory biomarker analyses. Results: As of July 23, 2015, 10 patients with R/R PMBCL with a median age of 28 (23-62) years have been enrolled in this cohort. Patients were heavily pretreated: 40% had ≥4 prior lines of therapy, and 60% had prior radiation. Six patients (60%) experienced at least 1 adverse event (AE) of any grade related to study treatment. These treatment-related AEs, all grade 1/2, were: hypothyroidism and decreased appetite (2 patients each), and diarrhea, nausea, vomiting, fatigue, edema, weight loss, and arthralgia (1 patient each). There were no grade 3-5 treatment-related AEs. Two patients experienced a serious AE (grade 3 infectious pneumonia) unrelated to study drug. No patient discontinued for toxicity. Nine patients were evaluable for response (1 discontinued treatment based on clinical progression before week 12). The objective response rate (ORR) was 44% (4/9), with 1 patient achieving a CR and 3 patients achieving a partial response. The intent-to-treat ORR was 40%. With a median follow-up of 144 days, the median DOR has not been reached (1+ to 291+) days, with all 4 responses ongoing at the time of data cutoff. Six of 10 patients have discontinued study treatment because of disease progression, and 4 patients remain on study. Conclusion: The preliminary results of KEYNOTE-013 indicate that PD-1 blockade with pembrolizumab is associated with a tolerable safety profile and a promising response rate in heavily pretreated patients with R/R PMBCL. Those patients often have a very poor outcome with conventional therapy, justifying further studies of pembrolizumab in this population. Disclosures Zinzani: Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Ribrag:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Karyopharm: Honoraria. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Snyder:Merck: Employment, Equity Ownership. Marinello:Merck: Employment, Equity Ownership. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Armand:Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; BMS: Research Funding.

Use of Rituximab in a Study Comparing the Thrombopoietin Mimetic Romiplostim with Standard of Care (SOC) in Patients with Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3282-3282
Author(s):  
Jeffrey Wasser ◽  
Ralph Vincent V. Boccia ◽  
Roger M. Lyons ◽  
Romeo Mandanas ◽  
Ingrid Pabinger ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Term Response

Abstract Abstract 3282 Background/Methods: The relative safety and efficacy of romiplostim and rituximab in ITP have not been compared in clinical trials. In an open-label 52-week trial of SOC (N = 77) and romiplostim (N = 157) in ITP patients without prior splenectomy (Kuter et al, NEJM 2010), treatment failure was lower with romiplostim vs SOC (11% vs 30%, P<0.001). Within the SOC arm, 16 patients (21%) received rituximab; most (11/16) at QW × 4 (dose: 219–363 mg/m2), other rituximab dosing regimens varied considerably. We examine here outcomes of those 16 patients as compared with the romiplostim arm (in which 1 patient received rituximab) and the SOC arm as a whole. Results: All 3 groups had comparable age, sex, and baseline platelet count (Table). Median ITP duration was somewhat shorter for romiplostim-treated patients and the SOC arm vs. SOC-rituximab patients (2.1, 2.3 vs 3.4 years). More romiplostim patients completed the 52-week treatment phase vs SOC-rituximab patients and the SOC arm (78% vs 44%, 56%). Fewer romiplostim patients vs. SOC-rituximab and SOC patients experienced treatment failure (4% vs 13%, 13%). Adverse events (AE), serious AE (SAE), treatment-related AE, and treatment-related SAE rates were similar for all 3 groups. Platelet response rates (platelet count >50×109/L, excluding 8 weeks after rescue medication) were higher with romiplostim than with SOC-rituximab or SOC as a whole (Graph). When comparing concomitant ITP medications prior to rituximab and during or after rituximab treatment in the SOC-rituximab patients, there was no change in the proportion of patients receiving ITP medications (9/16 vs 10/16) or the number of medications per patient [median (range) of 1 (0, 3) vs 1 (0, 4)]. The most common prior to rituximab treatment were prednisone (7/16), IVIg (3/16) and anti-D (2/16); during or after rituximab treatment, the most common were prednisone (6/16), IVIg (4/16), anti-D (2/16), and methylprednisone (2/16). Conclusion: This post hoc non-randomized comparison indicates that romiplostim may have greater effects on platelet responses than SOC-rituximab or SOC, with similar safety profiles. However, different treatment goals – ongoing use of romiplostim to maintain platelet response as opposed to one or more courses of rituximab which may result in a long-term response in the absence of other therapies (∼20% response rate at 5 years, Patel, ASH 2010) – makes efficacy comparisons problematic, particularly as the long-term response rate was not measured in this one-year study. Also not analyzed was how the use of concomitant ITP medications changed over the course of the study. As splenectomy and many immunosuppressive ITP medications are associated with significant morbidity and mortality over time, this is an important consideration. Most importantly, patients were selected for rituximab treatment by the investigators in a non-random way, as evidenced by the longer duration of ITP, making any generalizations difficult. Prospective controlled studies of romiplostim and rituximab in patients with ITP would be needed to provide further information. Disclosures: Wasser: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Rituximab is not indicated for ITP. Boccia:Amgen: Equity Ownership, Speakers Bureau. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mandanas:Amgen: Membership on an entity's Board of Directors or advisory committees. Pabinger:Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Michel:Roche: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Viallard:Amgen: Consultancy. Wang:Amgen: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

Preliminary Evidence Of Anti Tumor Activity Of Selinexor (KPT-330) In a Phase I Trial Ofa First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) In Patients (pts) With Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 90-90 ◽  
Author(s):  
John Kuruvilla ◽  
Martin Gutierrez ◽  
Bijal D. Shah ◽  
Nashat Y. Gabrail ◽  
Peter de Nully Brown ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Study Entry ◽  
Mrna Levels ◽  
Tumor Shrinkage ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background Exportin 1 (CRM1/XPO1) is the exclusive transporter of the majority of Tumor Suppressor Proteins (TSP) out of the nucleus, rendering these TSPs non-functional. Selinexor (KPT-330) is a potent, oral SINE XPO1 antagonist, forcing the nuclear retention and activation of >10 TSPs resulting in NHL and CLL cell death in vitro, while sparing normal lymphocytes and other hematopoietic cells. Oral Selinexor has marked activity in murine models of NHL and CLL including R-CHOP resistant tumors. Dogs with spontaneous B- and T-cell lymphomas exposed to the related SINE Verdinexor demonstrate potent anti tumor effect and good tolerability. Methods Patients (pts) with advanced NHL or CLL relapsed/refractory to all available drug classes were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a Phase 1 trial in hematological malignancies (NCT01607892). Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were obtained. Response evaluation was performed every cycle. Results 18NHL/CLL pts with median age 66.5yrs; ECOG PS 0/1: 8/10; median number of prior regimens: 4.5 [range 2-11], received KPT-330 across 6 dose levels (3 to 30 mg/m2). Ten pts experienced drug-related grade 3/4 Adverse Events (AEs) including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), fatigue (n=1). The most common grade 1/2 toxicities were: anorexia (10/18pts; 56%), fatigue (9/18; 50%), diarrhea (6/18; 33%), vomiting (6/18; 33%), neutropenia (5/18; 28%), malaise (3/18; 17%), anemia (3/18; 17%) and weight loss (3/18; 17%). These adverse events were manageable with supportive care. 23mg/m2, one case of Grade 4 thrombocytopenia for >5 days without bleeding was reported as a DLT for the cohort; this patient with refractory follicular NHL was continued on therapy at the same dose and schedule with intermittent platelet support with SD for 83 days on study.Dose escalation continues.There were no clinically significant cumulative toxicities or major organ dysfunction and pts have remained on therapy for ≥6 cycles. Maximum tolerated dose has not been reached; dosing at 35 mg/m2 twice weekly is ongoing.PK analysis at doses of 3-35 mg/m2demonstrated a dose proportional increase in Cmax and AUC with increasing dose. Elimination half-life was independent of dose and ranged from 4.7-7.0 hours. Significant increases (2-20x) in total leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction.Evaluation of lymph node biopsies from 2 pts confirms Selinexor-induced nuclear localization of multiple TSPs as well as apoptosis of tumor cells. Response was evaluable in 15pts; Selinexor treatment induced tumor shrinkage or disease stabilization in 80%(n=12) of pts with relapsed/refractory NHL/CLL who had progressive disease on study entry (Figure 1). 20% (n=3) of pts had clinical progression. One patient with ibrutinib-refractory CLL with Richter's transformation who progressed on chemotherapy achieved a rapid 60% reduction in lymph nodes in Cycle 1 and was referred for transplantation. A patient with DLBCL refractory to R-CHOP and bone marrow transplantation achieved a near CR (93% tumor shrinkage) and remains on study >11 months. Conclusions Oral Selinexor is generally well tolerated, with favorable PK andPDn parameters. In this cohort of heavily pretreated, refractory/refractoryNHLand CLL with progressive disease on study entry, single agent oral Selinexor induced tumor shrinkage in the majority of pts. Disclosures: Kuruvilla: Seattle Genetics: Consultancy, Honoraria, Research Funding; Hoffman LaRoche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shah:Seattle Genetics, Inc.: Research Funding; NCCN: Membership on an entity’s Board of Directors or advisory committees; SWOG: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau. Garzon:Karyopharm: Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Speakers Bureau. Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Rashal:Karyopharm Therapeutics: Employment, Equity Ownership. Yau:NPM Pharma Inc: NPM Pharma hired Ozmosis Research as CRO for this trial Other. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. McCartney:Karyopharm Therapeutics: Employment, Equity Ownership. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therapeutics: Employment. Pond:Ozmosis Research: Consultancy. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Mirza:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals X4P-001: A Novel Molecularly-Targeted Oral Therapy for Whim Syndrome

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 995-995
Author(s):  
David Dale ◽  
Audrey Anna Bolyard ◽  
Emily Dick ◽  
Merideth L. Kelley ◽  
Vahagn Makaryan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Exposure Period ◽  
Study Entry ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Whim Syndrome ◽  
Equity Ownership

Abstract Background: WHIM syndrome (WHIMs; Warts, Hypogammaglobulinemia, Infections, Myelokathexis) is a rare autosomal dominant immunodeficiency disease attributable to mutations in CXCR4 . Most patients have severe neutropenia and lymphocytopenia with total white blood cell counts (WBC) &lt;1.0 x 109/L. In general, children have more frequent and more severe infections than adults. Adults are at risk of human papilloma virus (HPV)-associated malignancies. There are no treatments approved for WHIMs although immunoglobulin and G-CSF are used to treat clinical symptoms of the disease. CXCR4 antagonists are being evaluated as a treatment for patients with WHIMs. Methods: We have begun the phase 2, dose-titration portion of a phase 2/3 study of a novel, orally bioavailable, selective, CXCR4 antagonist, X4P-001, in adult patients with genetically confirmed WHIMs to evaluate safety and tolerability of X4P-001 and determine the dose for a phase 3 study. All patients were required to be off chronic immunoglobulin and/or G-CSF treatment while on study. Patients receive increasing doses of X4P-001 ranging from 50 mg to 300 mg orally once daily with periodic monitoring of serial blood counts and intra-patient dose escalation is based on 24-hour serial area-under-the-curve (AUC) measurements of absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) with prespecified thresholds. Results: As of July 10, 2017, 4 patients (2 females, 2 males; age range 19 to 57 years; 3 with R334X and 1 with E343X mutation) have been enrolled. The study entry screening WBC was 0.775 x 109/L +/-0.16 (mean +/- SEM); ANC was 0.125 x 109/L +/- 0.027; and ALC was 0.588 x 109/L +/- 0.155. All patients had mild hypogammaglobulinemia; the mean levels were: Immunoglobulin G 766 +/- 130 (SEM), IgA 50 +/- 17, IgM 74 +/- 13. In the 6 months prior to study entry, these adult patients had up to 6 episodes of infections, primarily upper respiratory and skin infections. Patients 1 and 2 have escalated through 50 mg/day and 100 mg/day to 150 mg/day over a total exposure period of 169 days. Patients 3 and 4 have escalated from 100 mg/day to 200 mg/day with an exposure period of 62 and 54 days, respectively. All patients have demonstrated a dose-dependent increase in ANC and ALC from screening values, with ALC increasing in greater proportion than ANC. At the 100 mg dose level, the pre-dose WBC was 1.24 x 109/L +/- 0.469 (mean +/- SEM) with peak levels of 2.8 x 109/L +/- 0.721 (increase=2.3 fold), the pre-dose ANC was 0.385 x 109/L +/- 0.178) with peak levels of 0.58 x 109/L +/- 0.202 (increase=1.5 fold) and pre-dose ALC was 0.728 x 109/L +/- 0.276 with peak levels of 2.143 x 109/L +/-0.513 (increase=2.9 fold). The increases in the pre-dose levels of both neutrophils and lymphocytes above the study entry screening values after 1-3 months on treatment suggest a continuing effect of daily exposure to this drug. However, the ANC and ALC responses thus far are below the targeted AUC for ANC and ALC, so dose escalation continues. Thus far, X4P-001 has been well tolerated and the most common treatment-related adverse events are mild dyspepsia and dry eyes. Patients have not required antibiotic treatment for infections during the cumulative 15 months on X4P-001, except for Patient 1 who had an infection at the start of the study. Conclusion: Preliminary data suggests X4P-001 is a promising oral agent for treating WHIM syndrome. Disclosures Dale: Sanofi Aventis: Consultancy, Editor, Current Opinions in Hematology, Honoraria; Cellerant: Membership on an entity's Board of Directors or advisory committees; Genzyme (now owned by Sanofi-Aventis): Consultancy, Patents & Royalties, Research Funding; Genkyotex: Other: DSMB (work completed 6/2015); Hospira: Consultancy; Prolong: Consultancy; Boheringer-Ingelheim: Consultancy; Coherus: Consultancy; Omeros: Other: DSMB; Shire: Other: Independent Review Board; X4Pharma: Research Funding; Philips: Research Funding; Wolter Kluwer: Other: Editor, Current Opinions in Hematology; WedMD/Medscape: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding; University of Washington: Employment, Research Funding; American College of Physicians: Other: Editor and author; GlaxoSmithKline: Equity Ownership; Johnson&Johnson: Equity Ownership; Amgen: Consultancy, Research Funding. Johnson: X4 Pharmaceuticals: Employment. Gan: X4 Pharmaceuticals: Employment, Equity Ownership. Parasuraman: X4 Pharmaceuticals: Employment, Equity Ownership.

Overall Survival Advantage and Acceptable Safety Profile with Fludarabine In Combination with Alemtuzumab (FluCam) In Previously Treated Patients with Advanced Stage Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 919-919 ◽  
Author(s):  
Andreas Engert ◽  
Liana Gercheva ◽  
Galina Pilipenko ◽  
Tadeusz Robak ◽  
Jingyang Wu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Stage Iii ◽  
Advanced Stage ◽  
Employment Equity ◽  
Advisory Committees ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 919 Background: Patients (pts) with Rai Stage III/IV CLL have a shorter median survival compared to Rai Stage I/II pts. We previously reported significant improvement in progression-free survival (PFS) with FluCam compared to single-agent fludarabine (Flu) in pts with previously treated CLL (Engert ASH 2009; EHA 2010). Here we report the efficacy and safety of FluCam and Flu in a subset of these pts with advanced stage CLL. Methods: In a Phase 3, multi-center, controlled trial, pts with relapsed/refractory CLL were randomized to receive either IV Flu 25 mg/m2 on days 1–5 every 28 days or IV alemtuzumab (Cam) in combination with IV Flu (FluCam). Prior to cycle 1, FluCam pts were required to undergo Cam escalation (3 mg, 10 mg, 30 mg); once the 30 mg dose was tolerated, pts began cyclic administration of Flu 30 mg/m2 IV and Cam 30 mg IV on days 1–3 every 28 days. Pts could receive up to 6 cycles of either therapy depending on response and toxicity. Randomization was accomplished utilizing the minimization method to ensure balance between treatment arms with respect to study center, disease status, prior therapy, Rai Stage, age, gender, and lymph node size. All pts received prophylaxis with cotrimoxazole and famciclovir until CD4+ counts were >200 cells/mcL. The primary endpoint of the study was PFS with FluCam compared to Flu. A pre-specified subgroup analysis in Rai Stage III/IV pts compared PFS, overall response rate (ORR=CR + PR), complete response rate (CR), overall survival (OS) and safety in FluCam vs Flu treated pts. Differences in PFS between the 2 treatment arms were tested using the log-rank test. Results: Of the 335 pts enrolled in this study, 123 (37%) were Rai Stage III or IV (61 FluCam pts, 62 Flu pts). For the overall study population, FluCam significantly prolonged PFS compared with Flu (24.1 months (mos) vs 15.4 mos, respectively; p = 0.002; HR: 0.618; 95% CI 0.46–0.83). Data presented herein focus on the subgroup of CLL pts with Rai Stage III/IV disease. Demographics for this subset of FluCam vs Flu treated pts include: median age (65 yrs [36-80] vs 64 yrs [46-80]); gender (70% male vs 61% male); and prior Flu exposure (10% vs 8%) respectively. Pts received a median of 6 cycles in the FluCam arm and a median of 5 cycles in the Flu arm. FluCam significantly prolonged PFS compared with Flu (24.5 mos vs 11.8 mos, respectively; p < 0.001; HR 0.46; 95% CI 0.29–0.73). Similarly, the ORR (77% vs 56%; p = 0.016) and CR (16% vs 3%; p = 0.014) improved significantly with FluCam compared to Flu. With a median follow-up of 21 mos, pts treated with FluCam had significantly improved median OS compared with those treated with Flu (not reached vs 23.5 mos, respectively, p = 0.005 HR 0.44; 95% CI 0.24–0.79), representing a 56% reduction in the risk of death (Figure 1). Treatment-related adverse events (AE) occurred in 97% and 88% of Rai Stage III/IV pts receiving FluCam (n=59) and Flu (n=60) arms, respectively. There were no clinically relevant differences in the AE profile in pts with Rai Stage III/IV between arms. In the Rai Stage III/IV subgroup, the AEs that occurred ≥10% and more frequently in the FluCam arm relative to the Flu arm included infusion-related events and leukopenia. Reported all-cause grade 3/4 hematologic AEs in the FluCam vs Flu arms were neutropenia (47% vs 48%), leukopenia (29% vs 8%), thrombocytopenia (15% vs 20%), and anemia (7% vs 23%), respectively. The total frequency of treatment-emergent infections was 42% in the FluCam arm vs 52% in the Flu arm. No CMV infections were reported in either arm in this subset of pts. All-cause serious AEs (SAE) occurred in 37% and 45% in the FluCam and Flu arms, respectively. The most commonly reported all-cause SAEs in ≥5% of pts in either arm were pyrexia (5% vs 2%), neutropenia (3% vs 5%), febrile neutropenia (2% vs 8%) and anemia (0% vs 8%) for FluCam vs Flu respectively. Deaths occurring on therapy or within 30 days after last dose were 3% on the FluCam arm vs 8% on the Flu arm. Conclusion: Data presented in this subset analysis of Rai Stage III/IV CLL pts demonstrate a survival advantage, longer PFS and improved ORR/CR in pts treated with FluCam compared to Flu. The safety profile of FluCam in pts with advanced stage was acceptable and in most respects, comparable to the Flu alone arm. Overall, FluCam is a compelling treatment option in pts with previously treated advanced CLL. Disclosures: Engert: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Alemtuzumab (Campath, MabCampath) is indicated for the treatment of CLL. This trial examined the use of alemtuzumab in combination with fludarabine monophospate. Gercheva:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pilipenko:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Robak:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wu:Genzyme: Employment, Equity Ownership. Sirard:Genzyme: Employment, Equity Ownership. Elter:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase 1/2 Trial of TH-302 and Dexamethasone without or with Bortezomib (TBorD) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2142-2142
Author(s):  
Jacob P. Laubach ◽  
Noopur S. Raje ◽  
Andrew J. Yee ◽  
Philippe Armand ◽  
Robert L. Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxic conditions. TH-302 has demonstrated anti-myeloma activity in preclinical models both in vitro and in vivo, as well as synergistic cytotoxic activity with bortezomib (Bor) in vitro. An ongoing Phase 1/2 study (NCT01522872) investigates TH-302 with dexamethasone (dex) without Bor or with Bor (TBorD) in patients (pts) with relapsed/refractory multiple myeloma (RR MM). The maximum-tolerated dose (MTD) of TH-302 plus dex was previously established at 340 mg/m2. We report preliminary results from pts treated at the MTD of TH-302 plus dex; enrollment in the TBorD arm is ongoing. Methods: The Phase 1/2 open-label multicenter study investigates IV TH-302 (240-480 mg/m²) plus PO dex (40 mg) with or without Bor (1.3 mg/m2) on Days 1, 4, 8 and 11 of a 21-day cycle. At the MTDs, Simon two-stage designs are implemented to pursue a regimen of TH-302 plus dex if ≥25% response rate or discontinue if ≤5% (90% power, 10% alpha), and pursue TBorD if ≥50% response rate or discontinue if ≤25% (85% power, 10% alpha). Treatment at the MTD of TH-302 plus dex, and establishment of the MTD of TH-302 in TBorD, is ongoing. Results: 24 pts (19 male, 5 female) with median age 65 years (range: 53 – 86) were enrolled at the 340 mg/m2 MTD of the TH-302 plus dex biweekly regimen. Ten pts had 18 severe adverse events (SAEs), of which 9 were related to TH-302, including 3 pts with cellulitis and 2 pts with pneumonia. Of 17 pts assessable for response at the time of abstract submission, 3 pts achieved a partial response (PR) and 2 pts achieved a minimal response (MR) for an overall response rate of 18% (PR) and a clinical benefit rate of 29% (PR+MR). Nine pts achieved stable disease and 3 pts had progressive disease. Eight pts are undergoing treatment; 16 pts discontinued: progressive disease (10), subject decision (4), AE (1) and alternative therapy (1). The initial dose escalation with TBorD has been completed at 240 mg/m2 TH-302, with enrollment ongoing at 340 mg/m2 TH-302. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly with dex. Preliminary clinical activity has been noted in pts with heavily pre-treated RR MM. Data from the complete cohort of pts treated with dex and initial patients treated with TBorD will be updated and presented at the meeting. Disclosures Laubach: Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Raje:Acetylon: Research Funding; Eli Lilly: Research Funding; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Schlossman:Millennium: Consultancy. Matous:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Speakers Bureau. Reynolds:Threshold: Honoraria. Shain:Onyx/Amgen: Research Funding; Celgene: Research Funding; Envision/Celgene: Speakers Bureau; L&M Healthcare/Onyx/Amgen: Speakers Bureau. Zackon:Millenium: Speakers Bureau. Mar:Threshold: Employment. Handisides:Threshold: Employment, Equity Ownership. Kroll:Threshold: Employment, Equity Ownership. Anderson:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees; JNJ: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

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

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

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

Sign in / Sign up

Export Citation Format

Share Document