Evaluation of the Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma (BAX326) in Previously Treated and Naïve Patients with Severe or Moderately Severe Hemophilia B: A Continuation Study

Abstract Introduction: The severe or moderately severe deficiency of coagulation factor IX (FIX) in patients with hemophilia B causes frequent and potentially serious bleeding, whereby joint bleeding can be one of the more serious complications. Management of bleeding episodes (BE) involves on-demand or prophylaxis replacement therapy for FIX. This study evaluated the safety profile and efficacy of a recombinant FIX, nonacog gamma (BAX326, RIXUBIS®, Shire, Lexington, MA, USA), for treatment of bleeding in adults and children with severe (FIX level <1 IU/dL) or moderately severe (FIX level 1-2 IU/dL) hemophilia B. Methods: This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) comprised patients from a phase 1/3 pivotal study (NCT01174446), a phase 2/3 pediatric study (NCT01488994), and naïve patients aged 2-70 years at screening. Nonacog gamma treatment was administered at the discretion of the investigator. Patients who transferred from earlier studies received on-demand treatment or prophylaxis, while naïve patients received only prophylaxis. Prophylactic dosing was standard (SP; 40-60 IU/kg in patients ≥12 years of age or 40-80 IU/kg in patients <12 years of age, twice weekly), modified (MP; ≤100 IU/kg, as determined by the investigator), or tailored to the patient's pharmacokinetic profile (PK; ≤120 IU/kg). One dose (75 ± 5 IU/kg) was given at each of the study visits to assess incremental recovery of nonacog gamma over time. The primary outcome measure was the occurrence of adverse events (AE) and serious AEs (SAE), regarded as possibly or probably related to nonacog gamma. Secondary outcomes included additional safety, annualized bleeding rate (ABR), hemostatic efficacy rating at resolution of bleed, and number of infusions per bleeding episode. Results: The study enrolled 117 patients, from 40 sites in 16 countries, of which 115 patients (74 patients with severe hemophilia, and 41 patients with moderately severe hemophilia) received treatment with nonacog gamma. All patients were male, with 21 patients <12 years of age and 94 patients ≥12 years of age.These included 65 patients from the phase 1/3 pivotal study, 20 patients from the phase 2/3 pediatric study and 30 naïve patients. Of 115 patients included in the full ananlysis set, 110 were treated with a prophylaxis regimen (SP, 108 patients; MP, 26 patients; PK, 3 patients ) and 13 patients received nonacog gamma on demand. Patients could switch between treatment regimens and may therefore be included in more than one regimen. A total of 459 AEs were reported in 85 (73.9%) patients; 443 nonserious AEs in 85 patients and 16 SAEs in 9 patients. The most commonly reported AEs included: nasopharyngitis (55 in 25 patients), arthralgia (48 in 15 patients), and pyrexia (23 in 14 patients). Only 2 nonserious AEs (positive antibody (Ab) tests to rFurin) in 2 patients, were considered nonacog gamma-related. These tests were negative by the time of study completion and considered transient. None of the SAEs were deemed related to nonacog gamma. No patients developed Abs to FIX, there were no thrombotic events or severe allergic reactions during or after treatment, and no significant treatment-related changes in vital signs. Clinical efficacy of nonacog gamma was rated as excellent or good in 991 (89%) of 1112 BEs. For all BEs, a mean (± SD) number of 1.8 (± 1.65) infusions were required until bleed resolution (Table 1). For on-demand treatment, the median ABR was 16.5 (n=13), whereas for overall prophylaxis the median ABR was 1.3 (n=108) (Table 2). Disclosures Windyga: Alnylam, Baxalta, Bayer, Novo Nordisk, Octapharma, Rigel Pharmaceuticals, Roche, Sanofi, Shire, SOBI: Research Funding; Alexion, Baxalta, Bayer, CSL Behring, Ferring Pharmaceuticals, Novo Nordisk, Octapharma, Rigel Pharmaceuticals, Roche, Sanofi, Shire, Siemens, SOBI, Werfen: Membership on an entity's Board of Directors or advisory committees. Stasyshyn:CSL Behring, Novonordisk, Shire: Honoraria; Novonordisk, Pfiser , Shire: Speakers Bureau. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

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Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma in Patients With Severe or Moderately Severe Hemophilia B: A Continuation Study

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620950836 ◽

2020 ◽

Vol 26 ◽

pp. 107602962095083

Author(s):

Jerzy Windyga ◽

Oleksandra Stasyshyn ◽

Toshko Lissitchkov ◽

Vasily Mamonov ◽

Margit Serban ◽

...

Keyword(s):

Prophylactic Treatment ◽

Phase 1 ◽

Factor Ix ◽

Hemophilia B ◽

Severe Hemophilia ◽

On Demand ◽

Treatment Standard ◽

Pediatric Study ◽

Bleeding Episodes ◽

Hemostatic Efficacy

This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes. NCT01286779, EudraCT: 2010-022726-33

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

Blood ◽

10.1182/blood.v114.22.2719.2719 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2719-2719 ◽

Cited By ~ 2

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.

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A Phase I Study of Midostaurin (PKC412) Investigating Cardiac Interval Effects In Healthy Subjects

Blood ◽

10.1182/blood.v116.21.4362.4362 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4362-4362

Author(s):

Adam del Corral ◽

Catherine Dutreix ◽

Alice Huntsman Labed ◽

Sumita Rai ◽

Kai Grosch ◽

...

Keyword(s):

Healthy Subjects ◽

Trough Level ◽

Phase 1 ◽

Peak Level ◽

Qtc Interval ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Equity Ownership ◽

Time Point

Abstract Abstract 4362 Midostaurin (PKC412) is a multi-targeted tyrosine kinase inhibitor (TKI) of several receptors, including wild-type and mutant variants of KIT and the FMS-like tyrosine kinase 3 (FLT3) receptor, and has known roles in hematopoiesis and leukemia. Midostaurin has demonstrated activity in acute myeloid leukemia (AML) and myelodysplastic syndrome in phase 1 and 2 trials, and is currently under investigation in a randomized phase 3 AML study at 50mg twice daily (bid) in combination with chemotherapy and a phase 2 monotherapy study of aggressive systemic mastocytosis (ASM) at 100mg bid. Despite the absence of specific midostaurin-related cardiac toxicity issues, we conducted a dedicated phase 1 study to directly investigate the effect of midostaurin on QTc interval. Healthy subjects were randomized to 3 treatment arms: placebo; midostaurin administered orally at 75mg bid on days 1 and 2 and once daily (od) on day 3; or an active control arm of moxifloxacin administered orally at 400mg od on day 3. The primary variable was QTcF interval on day 3 corrected for baseline and placebo in the midostaurin and moxifloxacin treatment arms. Drug exposure levels at each time point were confirmed for moxifloxacin, midostaurin, and its two metabolites – CGP62221 and CGP52421. Of 192 subjects enrolled, 166 completed the study. 24 of 80 subjects discontinued in the midostaurin arm: 19 (23%) due to adverse events (AEs), 17 of which encompassed expected gastrointestinal events. No patients were discontinued for AEs in the other 2 treatment groups. Discontinued patients were not included in the ECG analysis. In time-matched analysis of QTcF interval change, the maximum mean change in the midostaurin arm corrected for baseline and placebo was 0.72ms with a 90% confidence interval (CI) upper bound of 4.71ms, which excluded 10ms. At each nominal time point, the mean change from baseline placebo-corrected for midostaurin was <0ms. The QTcF change point estimate corrected for time-averaged baseline and placebo also showed a lack of QTc prolongation for midostaurin. Moxifloxacin had a maximum mean change corrected for baseline and placebo of 10.7ms with a lower unadjusted 90% CI of 6.4ms 1 hour post-dose on day 3. Plasma concentration vs QTcF change from baseline analysis confirmed a negative or lack of QT effect by midostaurin but a positive correlation for moxifloxacin. No symptomatic, clinically significant new post-baseline morphological abnormalities were identified in the study. 3 patients in the midostaurin group at a single time point or evaluation experienced new post-baseline T-wave abnormalities, as did 1 and 4 patients in the placebo and moxifloxacin groups, respectively, some at multiple time points. No subject had a new >30ms or >480ms change from baseline for QTcF or QTcI. For QTcB the only occurrences of change were in the 30–60ms category: 1 (1.3%) of the subjects on midostaurin met this non-specific outlier criterion; 7 (15.9%) on moxifloxacin; and 1 (1.5%) on placebo. 1 new U-wave abnormality was noted in the moxifloxacin group. The peak plasma concentration of midostaurin achieved in the present study (mean 2273ng/mL) covered the peak and trough plasma exposure observed at 50mg bid (2220ng/mL and 1005ng/mL, respectively) in AML patients. The peak level achieved for midostaurin was also above the steady-state trough level of 1060ng/mL, but below the peak concentration of 3500ng/mL, for the 100mg bid dose. Midostaurin was safe and generally well tolerated: 97% of the AEs noted in subjects while on study drug (n=61; 40%) were reported as grade 1. No grade 3/4 AEs were reported. While some TKIs exert pharmacologic effects on QTc interval, this carefully conducted trial demonstrates that midostaurin at 75mg bid has no effect on heart rate, AV conduction, or cardiac depolarization. The midostaurin exposure achieved in this study exceeds the peak and trough levels for the 50mg bid dose regimen under investigation in the AML phase 3 trial. The midostaurin exposure achieved also exceeds the steady state trough level, but not the peak level, of the 100mg bid dose regimen under investigation in the phase 2 ASM trial. Further, the effects of the long-acting metabolite CGP52421 cannot be fully addressed by this short study. Due to the lack of QT prolongation observed in this trial, we recommend reduced but continued ECG monitoring and omission of QT-related exclusion criteria in future midostaurin clinical trials. Disclosures: del Corral: Novartis Pharmaceuticals Corporation: Employment. Dutreix:Novartis Pharmaceuticals Corporation: Employment. Huntsman Labed:Novartis Pharmaceuticals Corporation: Employment. Rai:Novartis Pharmaceuticals Corporation: Employment. Grosch:Novartis Pharmaceuticals Corporation: Employment. Morganroth:eResearchTechnology Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Wang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

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Ex Vivo Pharmacologic Modulation in a Nutrient-Rich Medium to Accelerate Engraftment of Human Umbilical Cord Blood

Blood ◽

10.1182/blood.v124.21.3807.3807 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3807-3807

Author(s):

Corey S Cutler ◽

Daniel Shoemaker ◽

Peter Westervelt ◽

Daniel R. Couriel ◽

Sumithra Vasu ◽

...

Keyword(s):

Gene Expression ◽

Umbilical Cord Blood ◽

Ex Vivo ◽

Phase 1 ◽

Fold Increase ◽

Phase 2 ◽

Employment Equity ◽

Phase 2 Trial ◽

Equity Ownership ◽

Neutrophil Engraftment

Abstract Umbilical cord blood (UCB) offers many potential advantages as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation, including ease of collection, rapid availability, flexibility of HLA-matching, lower rates of GvHD and potentially lower relapse rates. However, the low HSC content of UCB compared to other graft sources results in a prolonged time to engraftment, and higher rates of graft failure and early mortality. Pulse ex vivo exposure of HSCs to 16,16-dimethyl PGE2 (FT1050) has been demonstrated to enhance HSC engraftment potential, which could benefit clinical UCB transplant. FT1050 modulation promotes multiple mechanisms, including increased proliferation, reduced apoptosis, and improved migration and homing [North 2007&2009; Hoggatt 2009]. Improved HSC homing is mediated by induction of CXCR4 gene expression leading to increased cell surface CXCR4. Further optimization of the UCB modulation process demonstrated that incubation with 10µM FT1050 for 2 hrs at 37C resulted in a maximal biological response of the FT1050-UCB (ProHema®). A Phase 1 trial was performed to evaluate the safety of FT1050-UCB paired with an unmanipulated UCB unit in reduced-intensity double UCBT (dUCBT) [Cutler 2013]. We observed durable, multi-lineage engraftment of FT1050-UCB with acceptable safety. Earlier neutrophil engraftment was observed relative to historical controls (median 17.5 vs. 21 days (historical control), p=0.045), coupled with preferential engraftment of the FT1050-UCB unit in 10 of 12 subjects. A Phase 2 multi-center clinical trial of FT1050-UCB in adult patients undergoing dUCBT for hematologic malignancies was then initiated. Subjects are randomized 2:1 to FT1050-UCB-containing vs. standard dUCBT after high-dose conditioning. The primary endpoint is a categorical analysis of neutrophil engraftment using a pre-specified control median. Data on the initial 11 subjects, of which 8 were randomized to receive FT1050-UCB, continue to demonstrate acceptable safety with adverse events attributed to FT1050-UCB limited primarily to common infusion-related side effects. Of the 8 FT1050-UCB subjects, 1 died prior to neutrophil engraftment, with the remaining 7 subjects engrafting at a median of 28 days vs. 31 days for the 3 control subjects. With median overall follow-up of 16.1 months, 4 of 8 subjects on the FT1050-UCB arm are alive with a median survival not reached (> 11.0 months). 1 of 3 control subjects is alive with median survival of 6.0 months. During the clinical translation process, the media used during FT1050 modulation of UCB was identified as a key variable. Standard UCB washing media, consisting of a nutrient-free saline solution of low molecular weight dextran and human serum albumin (LMD/HSA), is used clinically to stabilize fragile cells post-thaw by reducing lysis. This media was used in the Phase 1 trial and to initiate Phase 2. Early during the Phase 2 trial, we identified a novel cell-stabilizing nutrient-rich formulation (NRM), containing glucose, amino acids and other HSC-supporting nutrients that promoted full FT1050 modulation of UCB and increased cell viability. The expression of key FT1050-pathway genes was significantly higher with NRM compared to intermediate levels observed with LMD/HSA. Modulation of human CD34+ (hCD34+) cells with FT1050 in NRM led to an 8-fold increase over LMD/HSA in induced CXCR4 gene expression (20-fold total), which translated to significantly increased surface CXCR4 protein. In vivo homing models demonstrated that UCB CD34+ cells modulated with FT1050 in NRM resulted in a 2.2-fold homing increase relative to vehicle (p < 0.001) compared to a 1.6-fold increase with LMD/HSA (p = 0.002), with a significant difference between the two media conditions (p = 0.04). A xenotransplantation study in NSG mice with hCD34+ cells modulated with FT1050 in either NRM or LMD/HSA demonstrated a 2-fold increase in circulating hCD45+ cells 12-weeks post-transplant with NRM (p = 0.007; unpaired t-test). These findings supported the incorporation of NRM into the FT1050-UCB manufacturing process in order to further improve its clinical engraftment potential. Enrollment of a 60-patient Phase 2 trial has been initiated that incorporates this manufacturing change. Disclosures Shoemaker: Fate Therapeutics: Employment, Equity Ownership. Rezner:Fate Therapeutics: Employment. Guerrettaz:Fate Therapeutics: Employment. Robbins:Fate Therapeutics: Employment. Medcalf:Fate Therapeutics: Employment. Wolchko:Fate Therapeutics: Employment, Equity Ownership. Ferraro:Fate Therapeutics: Employment. Multani:Fate Therapeutics: Employment.

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Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: Updated Results from a Phase 1 and Phase 1/2 Extension Study in Patients with Inhibitors

Blood ◽

10.1182/blood.v128.22.1397.1397 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1397-1397 ◽

Cited By ~ 9

Author(s):

K John Pasi ◽

Pencho Georgiev ◽

Tim Mant ◽

Toshko Lissitchkov ◽

Michael Desmond Creagh ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Thrombin Generation ◽

Hemophilia A ◽

Phase 1 ◽

Extension Study ◽

Severe Hemophilia ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Development of inhibitory antibodies, also known as "inhibitors," to replacement factor is considered the most serious unmet need in hemophilia and occurs in up to 30% of persons with severe hemophilia A, and 3-5% of persons with severe hemophilia B. Once inhibitors are present in high titer, treatment or prevention of bleeding can become more difficult due to the decreased responsiveness to factor concentrates, requiring bypassing agents (BPA) for bleed management. Current BPAs have a short half-life and are sub-optimally effective. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting the endogenous anticoagulant antithrombin (AT) as a means to improve thrombin generation and promote hemostasis in patients with hemophilia. Preliminary data from an ongoing Phase 1, multi-center, study showed that fitusiran was generally well tolerated in patients with hemophilia A or B with and without inhibitors and that administration of once-monthly SC doses of fitusiran led to dose-dependent AT lowering, thrombin generation increase, and decrease in bleeding frequency (Pasi KJ, et al. Haemophilia 2016, 22[Suppl 4]). Here we report the updated safety, pharmacodynamic (PD) effect, and clinical activity of fitusiran in patients with hemophilia with inhibitors as well as long term data from the Phase 1/2 extension study. Methods: We are conducting a multi-center Phase 1, four part (Part A: healthy volunteers; Parts B and C: patients with moderate to severe hemophilia A or B; Part D: patients with hemophilia A or B with inhibitors) study (NCT02035605) followed by a multi-center Phase 1/2 extension study (NCT02554773). Primary endpoints include safety and tolerability; secondary endpoints include AT activity, thrombin generation and exploratory evaluation of bleed pattern. In Part D, patients with inhibitors received once-monthly SC fixed doses of 50 or 80mg fitusiran. After receiving 3 monthly doses in the Phase 1 study, all patients were eligible to continue monthly dosing in the Phase 1/2 extension study. Utilization of BPA for breakthrough bleed management was permissible in these patients. Results: Part D of the Phase 1 study included 12 hemophilia A or B patients with inhibitors in 2 dosing cohorts (50mg SC, qM dosing cohort, n=6; 80mg SC, qM dosing cohort, n=6). Within the 50mg dosing cohort there were five patients with severe hemophilia A with inhibitors and one patient with severe hemophilia B with inhibitors; mean age: 33 ± 7 years; mean weight: 73 ± 17kg. Previously reported safety data from the 50mg dosing cohort demonstrated fitusiran was generally well tolerated in hemophilia A or B patients with inhibitors and that there were no serious adverse events related to study drug and no thromboembolic events. Monthly administration of fitusiran at the 50mg dose led to a mean maximal AT lowering of 81 ± 2% and mean maximal thrombin generation increase of 368 ± 113%. A preliminary, post-hoc analysis suggested a 49-100% reduction in bleeding frequency at the lower dose of 50mg during initial follow-up in the Phase 1 study. As of July 2016, the 80mg dose cohort has been fully enrolled and includes 6 patients with hemophilia A with inhibitors; mean age: 39 ± 15 years; mean weight: 75 ± 19kg, and 5 of the 6 patients in the initial 50mg cohort have transitioned to the Phase 1/2 extension study. Follow-up in the Phase 1, 80mg cohort and Phase 1/2 extension study is ongoing. Updated safety, tolerability and clinical activity from the Phase 1 and Phase 1/2 extension studies among all 12 patients with inhibitors will be presented. Conclusions: Emerging clinical data suggest that targeting AT is generally safe and could be a promising approach for promoting hemostasis in patients with hemophilia with inhibitors. Furthermore, the potential for low volume SC administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make fitusiran a potentially encouraging investigational therapy. Disclosures Pasi: Biogen: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Georgiev:Alnylam Pharmaceuticals: Consultancy. Chowdary:Bayer: Honoraria; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ragni:Novo Nordisk: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding; SPARK: Research Funding; Baxalta: Research Funding; CSL Behring: Research Funding; Shire: Consultancy; Vascular Medicine Institute: Research Funding; Tacere Benitec: Consultancy; OPKO: Research Funding. Soh:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Sorenson:Alnylam Pharmaceuticals: Employment, Equity Ownership.

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Indoximod Combined with Standard Induction Chemotherapy Is Well Tolerated and Induces a High Rate of Complete Remission with MRD-Negativity in Patients with Newly Diagnosed AML: Results from a Phase 1 Trial

Blood ◽

10.1182/blood-2018-99-117433 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 332-332

Author(s):

Ashkan Emadi ◽

Vu H. Duong ◽

Jeremy Pantin ◽

Mohammad Imran ◽

Rima Koka ◽

...

Keyword(s):

Dose Level ◽

Induction Chemotherapy ◽

Residual Disease ◽

Phase 1 ◽

Phase 2 ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Background Successful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML. Methods In this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a "3+3" design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT. Results As of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD <0.02% (MRD-neg). Eleven of 19 pts (58%) received ≥1 cycle of HiDAC and 5 (26%) received maintenance indoximod. All 11 patients who received HiDAC #1 became MRD-neg. Median relapse-free and overall survival have not been reached. IDO Composite Scores in bone marrow were calculated by multiplying percentage of stained mononuclear cells by grade of staining intensity determined by 3 independent pathologists. Median composite IDO1 score in tested pt samples (n=11) was 0.76 (range, 0.1-2.2). Expression of IDO1 mRNA at baseline varied significantly among patient samples analyzed (fold changes (FC) range: 0.1-84, normalized to β-Actin expression). IDO1 mRNA was significantly upregulated in post-induction samples compared to baseline (FC range: 1.7-248) in 10 out of 12 paired samples. Conclusions Indoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. Disclosures Emadi: NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Once-Weekly Carfilzomib with Dexamethasone Demonstrated Promising Safety and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma Regardless of Age and Prior Bortezomib Exposure

Blood ◽

10.1182/blood.v128.22.2129.2129 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2129-2129

Author(s):

Jesus G. Berdeja ◽

Robert M. Rifkin ◽

Roger Lyons ◽

Hui Yang ◽

Anita Zahlten-Kuemeli ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Phase 1 ◽

Secondary Analysis ◽

Phase 2 ◽

Efficacy And Safety ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Background: The multicenter phase 1/2 CHAMPION-1 study (NCT01677858) showed that once-weekly carfilzomib and dexamethasone was well tolerated and active in patients with relapsed or refractory multiple myeloma (MM) (Berenson et al. Blood. 2016;127:3360−3368). We present a secondary analysis of the efficacy and safety of once-weekly carfilzomib with dexamethasone in the CHAMPION-1 study according to prior bortezomib (BTZ) exposure and age. Methods: Patients with relapsed or refractory MM (1−3 prior therapies) were eligible. The primary objectives were to determine the maximum tolerated dose (MTD) of once-weekly carfilzomib with dexamethasone (phase 1) and to determine the overall response rate (ORR; phase 2). Secondary objectives included assessment of safety and tolerability, and evaluation of the clinical benefit rate and progression-free survival (PFS) in the phase 2 portion. Patients received carfilzomib as a 30-minute, intravenous (IV) infusion on days 1, 8, and 15 of 28 day cycles. Patients received carfilzomib at 20 mg/m2 on cycle 1, day 1; subsequent doses were escalated to 45, 56, 70, or 88 mg/m2, using a standard 3+3 escalation schema to determine the MTD. In the phase 2 portion, patients received carfilzomib at the MTD. All patients received dexamethasone 40 mg (IV or orally) on days 1, 8, 15, and 22 of 28 day cycles for cycles 1−8; dexamethasone was omitted on day 22 for cycles ≥9. The MTD of once-weekly carfilzomib (30-min IV infusion) with dexamethasone was established to be 70 mg/m2 (Berenson et al. Blood. 2016;127:3360−3368). In this secondary analysis, the efficacy and safety of once-weekly carfilzomib at this dose were evaluated by prior BTZ exposure (no prior exposure vs exposed but not refractory vs refractory) and age (<65 vs 65−74 vs ≥75 years). Results: The data cutoff date for this analysis was Nov 5, 2015.A total of 104 patients (phase 1 and 2; <65 years, n=34; 65-74 years, n=41; ≥75 years, n=29) received carfilzomib at a dose of 70 mg/m2 (no prior BTZ exposure, n=17; prior BTZ exposure but not BTZ-refractory, n=33; BTZ-refractory, n=54). The ORR for all 104 patients receiving the 70 mg/m2 dose was 77%; the median PFS was 14.3 months. Efficacy by prior BTZ exposure is presented in Table 1. The ORRs were 94%, 91%, and 63% for patients with no prior BTZ exposure, those exposed but not refractory to BTZ, and BTZ-refractory patients, respectively. The proportions of patients who achieved a complete response (CR) or better were 35% (no prior BTZ exposure), 21% (exposed to but not refractory to BTZ), and 9% (BTZ-refractory). The median PFS durations were 21.0, 19.4, and 5.3 months in these subgroups, respectively. The median treatment durations by age were 6.4 months (<65 years), 6.2 months (65-74 years), and 9.9 months (≥75 years); mean cumulative doses of carfilzomib received were 1876.8, 1846.5, and 2156.1 mg/m2, respectively. Efficacy and safety outcomes by age are shown in Table 2. The median PFS durations were 7.4 and 10.2 months for patients aged <65 and 65−74 years, respectively; the median PFS was not reached for those aged ≥75 years. The ORRs were 79%, 73%, and 79% for patients aged <65 years, 65−74 years, and ≥75 years, respectively. The ≥CR rates were 26% (<65 years), 15% (65-74 years), and 10% (≥75 years). Overall rates of treatment discontinuation were similar among age subgroups (Table 2). The rates of treatment discontinuation due to adverse events were 3% (<65 years), 17% (65−74 years), and 21% (≥75 years). The proportions of patients with at least one grade ≥3 adverse event were 56% (<65 years), 61% (65−74 years), and 76% (≥75 years). Rates of grade ≥3 adverse events of interest by age are shown in Table 2. Conclusions: Once-weekly carfilzomib (70 mg/m2) with dexamethasone was safe and active for patients with relapsed or refractory MM, regardless of prior BTZ exposure or age. As expected, the median PFS durations in the BTZ-naïve or -sensitive patients were longer relative to that in the BTZ-refractory patients. Although there were higher incidences of grade ≥3 adverse events and treatment discontinuations due to adverse events in older patients (≥65 years) relative to younger patients (<65 years), median PFS was not negatively affected by increasing age. Overall, once-weekly carfilzomib with dexamethasone had a favorable benefit-risk profile in patients with relapsed or refractory MM, irrespective of prior BTZ exposure or age. Disclosures Berdeja: Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Rifkin:Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Yang:Amgen Inc.: Employment, Equity Ownership. Aggarwal:Amgen: Employment, Equity Ownership. Iskander:Amgen Inc: Employment, Equity Ownership. Berenson:Amgen Inc: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Weekly Carfilzomib with Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma: Updated Results from the Phase 1/2 Study Champion-1 (NCT01677858)

Blood ◽

10.1182/blood.v126.23.373.373 ◽

2015 ◽

Vol 126 (23) ◽

pp. 373-373 ◽

Cited By ~ 2

Author(s):

James Berenson ◽

Alan Cartmell ◽

Roger Lyons ◽

Wael Harb ◽

Dimitrios Tzachanis ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

The United States ◽

Primary Objective ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Carfilzomib is an irreversible proteasome inhibitor that is approved as a single agent in the United States and other countries for the treatment of relapsed and refractory multiple myeloma (MM); carfilzomib in combination with lenalidomide (LEN) and dexamethasone is also approved in the United States for the treatment of relapsed MM. The approved dose and schedule of carfilzomib is a twice-weekly, 10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (starting dose: 20 mg/m2 [days 1 and 2 of cycle 1]; escalated to a target dose of 27 mg/m2 thereafter). Here we present updated results from the multicenter, phase 1/2 study CHAMPION-1 (NCT01677858), which evaluated the safety and efficacy of once-weekly carfilzomib with dexamethasone (Kd) in patients with relapsed or refractory MM. Methods: Patients with relapsed or refractory MM (1-3 prior lines of therapy) were eligible. Patients received carfilzomib as a 30-min IV infusion on days 1, 8, and 15 of 28-day cycles. The phase 1 portion of the study utilized a standard 3+3 dose-escalation scheme. All patients received carfilzomib at 20 mg/m2 on day 1 of cycle 1; patients received 45, 56, 70, or 88 mg/m2 beginning on day 8 of cycle 1 in successive dose-level cohorts until the maximum tolerated dose (MTD) was reached. All patients received dexamethasone 40 mg (IV or oral administration) on days 1, 8, 15, and 22 of cycles 1-8; dexamethasone was omitted on day 22 in cycles ≥ 9. In the phase 2 portion, patients received carfilzomib at the MTD (carfilzomib dose of 20 mg/m2 on cycle 1, day 1; escalating to the MTD for subsequent doses) and dexamethasone at the same dose and schedule. Kd was administered until unacceptable toxicity or disease progression. The primary objective of the phase 1 portion was to determine the MTD of carfilzomib in the Kd regimen; the primary objective of the phase 2 portion was to determine the overall response rate (ORR [≥partial response]). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Results: A total of 27 patients were enrolled in phase 1; the MTD of carfilzomib was determined to be 70 mg/m2. Results are presented for all patients treated with Kd at the carfilzomib MTD in both the phase 1b (n=15) and phase 2 (n=89) portions of the study. Among these 104 patients, median patient age was 68.5 years (range, 41-88). Patients received a median of 1 prior line of therapy (range, 1-3); 83% of patients had received prior bortezomib (BTZ), 49% of patients were BTZ-refractory, 27% were LEN-refractory, and 16% were refractory to both BTZ and LEN. Median carfilzomib treatment duration was 7.7 months (range, 0.03-24.2). The ORR was 77% (95% confidence interval [CI]: 68%-85%); the clinical benefit rate (≥minimal response) was 84% (95% CI: 75%-90%). Kaplan-Meier median progression-free survival was 12.6 months (95% CI: 9.0-not estimable). Twelve patients (12%) discontinued treatment due to an adverse event. The most common adverse events of any grade and of grade ≥3 are shown in the Table. Five patients died on study: 1 patient each had cause of death reported as disease progression, acute respiratory distress syndrome, acute respiratory failure, acute kidney injury, and cardiopulmonary arrest. The mean area under the curve and maximum concentration following a 70-mg/m2 carfilzomib dose was 1050 ng×h/mL and 2510 ng/mL, respectively. At 1 hour post dosing of carfilzomib 70 mg/m2, the activity of the predominant chymotrypsin-like proteasome catalytic subunit in peripheral blood mononuclear cells (ie, low molecular mass polypeptide 7) was strongly inhibited (97% inhibition as determined by an enzyme-linked immunosorbent assay [ProCISE]; 93% inhibition as determined by a fluorogenic substrate assay). Conclusions: CHAMPION-1 is the first clinical study to evaluate carfilzomib on a weekly dosing schedule. Once-weekly carfilzomib (70 mg/m2) with dexamethasone demonstrated acceptable safety and tolerability with promising efficacy for patients with relapsed or refractory MM. The dose and schedule of carfilzomib used in the CHAMPION-1 study (20/70 mg/m2) is currently being compared with the regulatory-approved carfilzomib dose and schedule (20/27 mg/m2 administered twice-weekly) in the ongoing, phase 3, superiority study ARROW (NCT02412878). Disclosures Lyons: Amgen: Consultancy, Honoraria; Insyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Harb:Onyx Pharmaceuticals: Consultancy. Boccia:Incyte Corporation: Honoraria. Moss:Onyx: Honoraria, Research Funding. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schupp:Amgen: Employment, Equity Ownership. Dixon:Onyx/Amgen: Employment, Equity Ownership. Ou:Onyx/Amgen: Employment, Equity Ownership. Anderl:Onyx/Amgen: Employment, Equity Ownership. Berdeja:Abbvie: Research Funding; BMS: Research Funding; Acetylon: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Onyx: Research Funding; Janssen: Research Funding; Novartis: Research Funding; MEI: Research Funding; Array: Research Funding; Curis: Research Funding.

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A Phase 1/2 Study of the Oral Novel JAK1 Inhibitor INCB052793 As Monotherapy and in Combination with Standard Therapies in Patients with Advanced Hematologic Malignancies

Blood ◽

10.1182/blood.v130.suppl_1.640.640 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 640-640

Author(s):

Amer M. Zeidan ◽

Rachel J. Cook ◽

Rodolfo Bordoni ◽

Ekaterine Asatiani ◽

Gongfu Zhou ◽

...

Keyword(s):

Combination Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Hematologic Malignancies ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Background: The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies. INCB052793, a small molecule JAK1 inhibitor, is being evaluated in an ongoing phase 1/2 study of INCB052793 as monotherapy or in combination with standard therapies in patients with advanced hematologic malignancies. Preliminary safety and efficacy data are reported. Methods: Phase 1 consisted of a monotherapy dose escalation (phase 1a) and combination therapy dose expansion (phase 1b). In phase 1a, patients with advanced hematologic malignancies received INCB052793 monotherapy (25, 35, and 50 mg QD). Phase 1b evaluated INCB052793 (25 and 35 mg QD) in patients with advanced multiple myeloma (MM) in combination with dexamethasone (DEX); or in patients with advanced acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes in combination with azacitidine (AZA). The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous 21-day (monotherapy) or 28-day (combination therapy) cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity. Phase 2 is evaluating INCB052793 combination therapy in patients with AML and high-risk MDS who failed prior therapy with hypomethylating agents (HMAs). Primary study objectives included safety, tolerability, and dose selection for expansion of INCB052793 monotherapy and combination therapy (phase 1) and safety and efficacy of INCB052793 combination therapy in patients with AML and higher-risk MDS (phase 2). Responses were recorded according to malignancy-specific criteria. Results: We report data on the first 39 patients with hematological malignancies enrolled in the study.At data cutoff (June 19, 2017),11 patients (MDS/MPN, n=4; MM, n=3; diffuse large B-cell lymphoma, n=2; chronic lymphocytic leukemia, n=1; Hodgkin's lymphoma, n=1) received INCB052793 monotherapy. INCB052793+DEX combination therapy was received by 7 patients with MM; 21 patients received INCB052793+AZA combination therapy (AML, n=12; MDS, n=7; MDS/MPN, n=2). Prior HMA treatment was received by 0 patients in the INCB052793+DEX group and 71.4% (15/21) of patients in the INCB052793+AZA group. The median (range) duration of treatment was as follows: INCB052793 monotherapy, 104 (14‒528) days; INCB052793+DEX, 51 (15‒96) days; INCB052793+AZA, 125 (15‒456) days. Grade ≥3 adverse events (Table 1) were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793+DEX (most common: anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia), and 95% of patients receiving INCB052793+AZA (most common: febrile neutropenia, anemia, neutropenia, and thrombocytopenia). Most patients discontinued treatment (INCB052793 monotherapy, 91%; INCB052793+DEX, 100%; INCB052793+AZA, 90%), with the primary reasons being disease progression (INCB052793 monotherapy, 55%; INCB052793+DEX, 57%) or adverse event (INCB052793+AZA, 24%). Of 11 patients who received INCB052793 monotherapy, 1 with MDS/MPN had complete response (CR) and remains on study at data cutoff; 2 with MDS/MPN had partial remission (PR; Table 2). Of 7 patients with MM in the INCB052793+DEX group, 2 had a minimal response with a reduction in M protein. The overall response rate (ORR) was 67% (8/12) for patients with AML treated with INCB052793+AZA, with 1 CR, 1 morphologic leukemia-free state, and 6 PRs. The ORR was 56% (5/9) for patients with MDS or MDS/MPN who received INCB052793+AZA. Of 7 patients with MDS in the INCB052793+AZA group, 3 had CR. Of 2 patients with MDS/MPN in the INCB052793+AZA group, 1 had CR and 1 had PR. Conclusion: Preliminary findings from this phase 1/2 trial indicate that INCB052793 has encouraging clinical activity, especially in combination with AZA, in patients with advanced myeloid malignancies, including those who previously failed HMAs. These data indicate that INCB052793 might (re)-sensitize HMA-refractory or relapsed patients to the effects of HMAs. Preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrolment is ongoing in phase 2 and expanded data, including PK/PD, will be presented. Disclosures Zeidan: Otsuka: Consultancy; Takeda: Speakers Bureau; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria. Cook: Syros Corporation: Membership on an entity's Board of Directors or advisory committees. Bordoni: Merck: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Asatiani: Incyte Corporation: Employment, Equity Ownership. Zhou: Incyte Corporation: Employment, Equity Ownership. Faivre: Incyte Corporation: Employment, Equity Ownership. Byrne: Karyopharm: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Savona: Sunesis: Research Funding; Incyte Corporation: Consultancy, Research Funding; Takeda: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

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Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽

10.1182/blood-2019-127893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1848-1848

Author(s):

Maria Karvouni ◽

Heyue Zhou ◽

Arnika Kathleen Wagner ◽

Qiangzhong Ma ◽

Alamdar H. Baloch ◽

...

Keyword(s):

Multiple Myeloma ◽

Nk Cells ◽

Therapeutic Potential ◽

Ex Vivo ◽

Phase 1 ◽

Employment Equity ◽

Multiple Myeloma Patient ◽

Myeloma Cells ◽

Car T ◽

Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

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