Exposure-Response Relationship of the SMART-Ig Anti-hC5 Antibody Crovalimab (SKY59): Results from the Umbrella Phase 1/2 Composer Trial in Healthy Volunteers and PNH Patients

Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017) 7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL - 4mL) in C5 mediated diseases. We aimed at characterizing the exposure-response relationship of crovalimab used to define the minimum concentration of crovalimab achieving complete terminal inhibition. To establish pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, and optimal dose of crovalimab, we conducted a four-part adaptive clinical trial (Figure 1): Part 1: 15 healthy subjects were enrolled. 3 received 75 mg RO7112689 IV, 3 received 125 mg RO7112689 IV, 3 received 100 mg RO7112689 SC, and 6 received placeboPart 2: 10 treatment-naïve PNH patients were enrolled in Part 2 to receive increasing IV doses of 375mg, 500mg, and 1000mg on days 1, 8 and 22, respectively, followed by weekly doses of 170mg SC starting on day 36Part 3: 19 eculizumab pre-treated PNH patients were enrolled in Part 3 to receive 1000mg IV before randomization into 3 different arms: Arm A: 680mg SC Q4W (N=7)Arm B: 340mg SC Q2W (N=6)Arm C: 170mg SC QW (N=6) SC dosing was initiated on day 8 after the IV dose in all the dosing groups. Part 4: 5 eculizumab pre-treated PNH patients and 5 treatment-naïve PNH patients are planned to be enrolled to receive IV dose of 1000mg on Day 1 followed by SC dose of 340mg on Day 2, Day 8, Day 15, Day 22 followed by SC dose of 680mg given Q4W from Day 29 Crovalimab concentrations and free C5 were measured using a validated ELISA. A population PK model was developed using all the available data to describe the crovalimab concentration-time profiles. Crovalimab PD was assessed by evaluating the extent and duration of terminal complement inhibition, quantified using a validated, functional ex vivo liposome immunoassay (LIA) (http://www.wakodiagnostics.com/r_ch50.html). Relationships between crovalimab PK and PD were analyzed using graphical analysis. The PK was best described by a two-compartment open model with first-order elimination and absorption. To describe the PK in eculizumab pre-treated patients, elimination of crovalimab was modeled as a combination of the first-order elimination used for naïve patients and a faster clearance which decreases exponentially over time. Body weight was introduced using allometry on the clearance and volume of the distribution. After SC administration, bioavailability is estimated at 100% and terminal half-life around 30 days. In all PNH patients, complete complement inhibition (defined as LIA <10 U/ml, the LLOQ of the assay) was achieved immediately after end of infusion following the initial dose and maintained across the different dosing intervals investigated in the majority of the patients (Figure 2). Complete inhibition of free C5 (defined as free C5 <0.05μg/mL) was also achieved after end of infusion and maintained throughout the dosing intervals reflecting the LIA profiles. By pooling all the PK and PD data from the 3 parts of the COMPOSER study, crovalimab was shown to induce a concentration-dependent inhibition of serum hemolytic activity and of free C5 which closely correlates with terminal complement inhibition. Collectively, these data indicate that approximately 100μg/mL of crovalimab are required to achieve complement inhibition (Figure 3). At the target concentration of crovalimab between 80-100ug/mL, patients achieve complete terminal complement inhibition. Data collected in the ongoing Part 4 of COMPOSER will be used to confirm the target concentration of crovalimab. Exposure-response characterization demonstrated the potential of crovalimab as an infrequent, subcutaneous therapy for PNH. Disclosures Sostelly: F. Hoffmann-La Roche: Employment. Buatois:F. Hoffmann-La Roche: Employment. Soubret:F. Hoffmann-La Roche: Employment, Equity Ownership. Klughammer:F. Hoffmann-La Roche Ag: Employment, Equity Ownership. Hsu:Roche/Genentech: Employment, Equity Ownership. Jordan:Roche Diagnostics GmbH: Employment; F. Hoffmann-La Roche: Equity Ownership. Bucher:F. Hoffmann-La Roche: Employment. Charoin:F. Hoffmann-La Roche: Employment. Gotanda:Chugai Pharmaceutical Co., Ltd.: Employment. Shinomiya:Chugai Pharmaceutical Co., Ltd.: Employment, Patents & Royalties: (WO2018143266) A PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OR PREVENTION OF A C5-RELATED DISEASE AND A METHOD FOR TREATING OR PREVENTING A C5-RELATED DISEASE. Nagy:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Panse:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Yoon:Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Yuhan Pharma: Research Funding; Janssen: Consultancy. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees. Röth:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Honoraria.

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Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial

Blood ◽

10.1182/blood.v124.21.3201.3201 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3201-3201

Author(s):

Srdan Verstovsek ◽

Jean-Jacques Kiladjian ◽

Ruben Mesa ◽

Mark M Jones ◽

Shui He ◽

...

Keyword(s):

Polycythemia Vera ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Jak2 Inhibitor ◽

Equity Ownership ◽

To Receive ◽

Response Trial

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control. Methods: Phlebotomy-dependent PV pts with splenomegaly, aged ≥18 years, and resistant to or intolerant of HU were enrolled. Pts were required to have HCT between 40%−45% 14 days prior to randomization; those who did not could enter a phlebotomy control period to achieve a HCT in this range within 14 days of randomization. Eligible pts were randomized 1:1 to RUX or BAT. BAT pts could cross over to receive RUX from Wk 32 if they had not met the primary endpoint, or after Wk 32 due to protocol-defined disease progression. The primary composite endpoint comprised HCT control and a ≥35% reduction from baseline in spleen volume (SV) at Wk 32. HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In pts who were HCT control non-responders (HCT-N) as defined by protocol, time to second phlebotomy eligibility was evaluated. For this analysis, pts without phlebotomy eligibility were excluded and phlebotomies in the first 8 wks were not considered. Patient-reported outcomes were evaluated in both HCT control responders (HCT-R) and HCT-N, including the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the Patient Global Impression of Change (PGIC). Results: Of 222 randomized pts (RUX, n=110; BAT, n=112), most were male (RUX, 60%; BAT, 71%) and the median age (range) was similar between treatment arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]). Although pts had a HCT between 40% and 45% within 14 days prior to randomization (with or without phlebotomy), 24% of pts had a HCT >45% on Day 1 (similar between treatment arms) illustrating that many pts have poor HCT control over short intervals of observation. RUX treatment resulted in long-term benefits on HCT levels, even in pts who did not achieve protocol-defined HCT control through Wk 32. Among the RUX HCT-R group, the probability of maintaining HCT response was 97% at 48 wks and 87% at 80 wks. Most BAT pts crossed over to receive RUX immediately after the Wk 32 visit (84% between Wks 32 and 48). In the RUX HCT-N pts, the median time to subsequent phlebotomy eligibility was 52 wks, compared with 21 wks for BAT HCT-N pts (Figure). Compared with the entire BAT group, more RUX-R and RUX-N pts had a ≥50% improvement in the MPN-SAF total symptom score at Wk 32 (RUX-N, 38%; RUX-R, 40%; BAT, 4%). Median changes from baseline at Wk 32 in key symptoms such as tiredness (RUX-N; −50%; RUX-R, −49%; BAT, −4%), itching (RUX-N, −88%; RUX-R, −97%; BAT, −2%), and night sweats (RUX-N, −100%; RUX-R, −97%; BAT, 4%) were also greater among RUX-R and RUX-N pts than BAT pts. RUX-N and RUX-R pts were also more likely to consider their symptoms to be “much improved” or “very much improved” on the PGIC compared with BAT pts (RUX-N, 57%; RUX-R, 74%; BAT, 13%). Conclusion: Among pts receiving RUX who did not achieve protocol-defined HCT control, the median time to subsequent phlebotomy eligibility was 1 year. In contrast, pts on BAT had a median time to subsequent phlebotomy eligibility of 21 wks. Furthermore, pts in the RUX arm achieved meaningful improvements in PV-related symptoms, regardless of meeting the endpoint of HCT control, while pts treated with BAT showed worsening or no improvement. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy

Blood ◽

10.1182/blood-2019-130635 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3919-3919

Author(s):

William B. Donnellan ◽

Ehab L. Atallah ◽

Adam S. Asch ◽

Manish R. Patel ◽

Jay Yang ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Slow Release ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Refractory Aml

Background: Aurora kinases (AurK) represent potential targets for anticancer therapy in hematological malignancies and solid tumors. AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of AurKB, when given as 2-4hr IV on days 1 and 4, offers a prolonged drug exposure in vivo, mimicking the AZD1152 7-day continuous IV infusion. This is an update on the first-in-man dose-escalation study of AZD2811NP in pts with relapsed/refractory AML/MDS or treatment-naïve patients (pts) not eligible for intensive induction therapy (NCT03217838). The primary objectives are to determine the Maximum Tolerated Dose (MTD) and safety profile of AZD2811NP monotherapy and in combination with azacitidine. The secondary objectives are to evaluate the pharmacokinetic (PK) profile, Biologically Effective Dose (BED), and preliminary efficacy (CR, CRi, PR, 6 month OS). Methods: Pts received a 2-hour IV infusion on Day 1 and 4 of each 28-day cycle (Cy) for doses up to 600mg, extending to a 4 h IV infusion for dosages > 600 mg. In the ongoing dose escalation, 3-6 pts have been sequentially enrolled in cohorts ranging from 100 mg to 800 mg per infusion (Day 1 & 4), i.e. from 200 mg to 1,600 mg per cycle in monotherapy setting, according to a modified continuous reassessment method (mCRM) dose escalation design. AZD2811NP was also combined with azacitidine (75 mg day 1 to 7 or the 5-2-2 schedule) starting at an AZD2811NP dose of 400 mg D1 and D4 every 4 weeks. Study treatment was continued until disease progression, intolerability, or when discontinuation criteria were met. Results: Currently, 30 pts have enrolled of which 29 pts (12 females and 17 males) received study treatment in 5 monotherapy cohorts and 2 azacitidine combination cohorts, with ages ranging from 53 to 85 years. Nineteen pts had relapsed/refractory AML, 9 pts had MDS and 1pt had MDS/MPN. Monotherapy cohort 5 (800 mg D1 & D4) and combination cohort 4c (600mg D1 & D4 + Azacitidine) are currently enrolling. Of the 19 pts in monotherapy cohorts 1-5, 18 pts discontinued (due to consent withdrawal [2], early disease related deaths [2], other reason [1], or completed follow up [13; 11 pts after Cy1, 2 pts after Cy2]) and 1 pt is still on therapy. Nine pts were treated in combination with azacitidine, and of these, 3 pts are still on therapy and 6 pts have discontinued AZD2811NP (due to death [1], consent withdrawal [2], or completed follow up [3; 2 pts after Cy2, 1 pt after Cy4]). Adverse events that occurred in ≥ 20% of pts were mainly myelotoxicity, nausea and fatigue. One dose-limiting toxicity (DLT) has been observed in the monotherapy arm (esophageal infection) and one DLT in the combination setting (late neutropenia recovery). Two deaths were due to the underlying disease and 1 due to a serious adverse event of Gr 5 sepsis not related to study drug. AZD2811 total and released blood PK exposure appears broadly dose proportional with a terminal t1/2 of ~ 30-50 hours. Released blood PK exposure is ~ 1% of total PK exposure. Conclusion: AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented. Additional dose finding and expansion cohorts of AZD2811NP in combination with venetoclax are planned. Disclosures Atallah: Pfizer: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Eghtedar:Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Borthakur:Merck: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Eisai: Research Funding; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding. Charlton:AstraZeneca: Employment; GSK: Equity Ownership. MacDonald:AstraZeneca: Employment, Equity Ownership. Korzeniowska:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment, Equity Ownership. Strickland:Sarah Cannon Development Innovations: Employment. Overend:AstraZeneca: Employment, Equity Ownership. Adelman:AstraZeneca: Employment, Equity Ownership. Fabbri:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Cosaert:AstraZeneca: Employment. OffLabel Disclosure: AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of Aurora Kinase B (AurKB), is an investigational agent in clinical trials for human cancers including AML/MDS.

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Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry

Blood ◽

10.1182/blood.v116.21.2241.2241 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2241-2241

Author(s):

Hubert Schrezenmeier ◽

Robert A Brodsky ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Employment Equity ◽

Advisory Committees ◽

Clone Size ◽

History Of ◽

Equity Ownership ◽

To Receive

Abstract Abstract 2241 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, pulmonary hypertension, pain, anemia, and severe fatigue. PNH clones occur in a number of patients with concomitant aplastic anemia (AA) and other bone marrow disorders (BMD). Some patients with PNH and/or BMD may require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow hypoplasia. Aims: To characterize the use of RBC transfusions among PNH patients with and without underlying AA. Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry regardless of the proportion of cells with deficiency of glycosylphosphatidyl-inositol anchored proteins (GPI-AP), bone marrow pathology, symptoms, or treatments. Sites collect clinical history at enrollment and additional data every 6 months. Demographic data, use of transfusions and other treatments, lab results, and symptoms are summarized for PNH patients with and without AA. Results: As of June 30, 2010 there were 655 enrolled patients in the Registry (53% female, median age 43). At enrollment, 28% of patients had history of AA and 45% had no history of BMD. Patients with underlying AA had lower median GPI-AP deficient granulocytes than those without BMD (median = 53% vs. 86%, respectively, p<.01) and patients in both groups had similar evidence of hemolytic activity when stratified by clone size (median LDH fold above normal upper limit was 0.90 vs. 0.94, p=.39 for patients with and without AA and clone size <10%; median = 3.41 vs. 4.84, p=.08 for AA vs. no BMD and clone size ≥50%). Not all PNH patients required transfusions: 56% of all patients required transfusions in the year prior to enrollment. Although patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall, some differences emerged when stratified by clone size. For patients with clone size <50%, AA patients were almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08). However, regardless of underlying AA, the proportion of patients receiving transfusions, in the prior year increased as clone size increased (29%, 31%, and 69% for clone sizes <10%, 10–49%, and ≥50%, respectively, p<.01). When patients were stratified by percent reticulocytes at enrollment (below vs. above the median value of 4.16%), 45% vs. 75% received transfusion in the prior year (p<.01). Among patients receiving a transfusion in the year prior to enrollment, the mean number of RBC units transfused was 9.6 for patients with underlying AA and 7.9 for patients with no BMD (p=.10). However, approximately twice as many patients with AA received 20+ RBC units in that year compared to patients without BMD (20% vs. 11%, p=.09). Number of transfused units in that year was similar by clone size (mean 9.5 vs. 8.6 for clone size <50% vs. ≥50%, p=.57). Concomitant treatment with anticoagulants or immunosuppressants was similar among patients who had received a transfusion in the past year compared to patients with no transfusions (39% vs. 33%, p=.13 and 26% vs. 22%, p=.25 respectively). Patients with AA had more bruising and bleeding while patients without BMD had more hemoglobinuria, dysphagia, and abdominal pain. Transfused patients with AA had more fatigue than non-transfused patients with AA (68% vs. 48%, p=.02). Conclusions: A substantial proportion (56%) of patients with PNH, but not all, required at least one transfusion in the year prior to enrolling in the registry, independent of underlying AA. The proportion of patients who had at least one transfusion increased with clone size. Among patients who had at least one transfusion, there was a trend for patients with underlying AA to receive more RBC units than patients without BMD. PNH patients with AA have fewer GPI-AP deficient granulocytes but demonstrate elevated hemolysis similar to patients without history of BMD when patients with similar clone sizes were compared. This Global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Schrezenmeier: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Maciejewski: Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Kanakura: Alexion: Membership on an entity's Board of Directors or advisory committees. Hoechsmann: Alexion: Speakers Bureau. Rosse: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell: Alexion Pharma International: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Clinical Benefit of Ruxolitinib Treatment after Crossover from Best Available Therapy in Patients with Polycythemia Vera: Analysis of the RESPONSE Trial

Blood ◽

10.1182/blood.v124.21.3181.3181 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3181-3181 ◽

Cited By ~ 1

Author(s):

Jean-Jacques Kiladjian ◽

Alessandro M. Vannucchi ◽

Martin Griesshammer ◽

Tamas Masszi ◽

Simon Durrant ◽

...

Keyword(s):

High Risk ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

To Receive ◽

Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis, and in many cases leukocytosis and thrombocytosis. PV is driven by activating mutations in the JAK/STAT pathway, primarily JAK2V617F. For high-risk patients, a commonly used first-line therapy is hydroxyurea (HU); however, a subgroup of patients become intolerant of or resistant to HU. The phase 3 RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU (modified European LeukemiaNet criteria). Patients randomized in the BAT arm were permitted to cross over to receive RUX from Week 32 of the study. The results of the primary analysis comparing RUX to BAT prior to crossover have been reported, in which RUX was superior to BAT in achieving hematocrit control, reductions in spleen volume, and improvements in PV-related symptoms. This current analysis was conducted to evaluate the efficacy of RUX treatment in patients who crossed over from BAT relative to their original BAT treatment and relative to those originally randomized to RUX. Methods : Enrollment criteria included PV diagnosis, age ≥18 years, resistance to or intolerance of HU, splenomegaly, and phlebotomy requirement to control hematocrit. Patients were randomized 1:1 to receive open-label RUX 10 mg BID or BAT administered based on investigator judgment. BAT may have included HU, interferon/pegylated interferon, pipobroman, anagrelide, immunomodulators (eg, lenalidomide or thalidomide), or no medication. The protocol allowed for dose modifications (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Patients in the BAT group could cross over to RUX from Week 32 if they had not met the primary endpoint, or after Week 32 due to protocol-defined disease progression. The primary study endpoint was a composite of hematocrit control and a ≥35% reduction in spleen size at Week 32. Hematocrit was assessed at screening, every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32, and 2, 4, 6, 8, 16, 24, and 32 weeks following crossover. Spleen volume was assessed by magnetic resonance imaging at screening and study Weeks 16, 32, 48, 64, 80 and every 32 weeks thereafter. The number of phlebotomy procedures was evaluated over time in each group. Results : A total of 110 patients were randomized to RUX and 112 to BAT; study discontinuation by Week 32 (before crossover was permitted) was 11% in both groups. However, most patients in the BAT arm crossed over to receive RUX treatment immediately after the Week 32 visit (84% between Weeks 32 and 48); only 3% of patients remained in the BAT arm compared with 85% in the RUX arm at the time of the data analysis (median 81-week follow-up). With up to 32 weeks on BAT therapy, 25% of patients in this group did not require a phlebotomy; in contrast, with up to 32 weeks on RUX, 79% of patients after crossover and 74% of patients initially randomized to RUX did not require phlebotomy. The number of phlebotomy procedures adjusted for 100 patient-years during BAT therapy was 196.8 vs 38.5 after crossover to RUX and 34.1 on randomized RUX treatment. Reduction in spleen volume from baseline at any visit occurred in 49% of patients receiving BAT, vs 73% of patients after crossover to RUX and 88% of patients initially randomized to RUX. The proportion of patients achieving at least a 35% reduction in spleen volume (best percentage change) was 1.8% during BAT treatment vs 38.5% after crossover to RUX and 60.0% during randomized RUX treatment. Conclusion : Treatment with RUX after crossover from BAT resulted in improved clinical outcomes compared with original BAT treatment. These findings support the primary RESPONSE results and further validate the efficacy of RUX in this patient population. Disclosures Kiladjian: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals : Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Verstovsek:Incyte Corporation: Research Funding.

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C5 Polymorphism in a Dutch Patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) and No Asian Ancestry, Resistant to Eculizumab, but in Vitro Sensitive to Coversin

Blood ◽

10.1182/blood.v126.23.1209.1209 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1209-1209 ◽

Cited By ~ 2

Author(s):

Saskia Langemeijer ◽

Jun-Ichi Nishimura ◽

Wynne Weston-Davies ◽

Miles A Nunn ◽

Yuzuru Kanakura ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Poor Response ◽

Healthy Controls ◽

Employment Equity ◽

Advisory Committees ◽

Asian Ancestry ◽

Equity Ownership ◽

Terminal Complement

Abstract Eculizumab (Soliris®) is a humanized monoclonal antibody that targets complement factor C5and inhibits the production of C5a and formation of the terminal complement membrane attack complex. It is registered for the treatment of PNH and aHUS. Eculizumab results in significant reduction of hemolysis in PNH, improves symptoms and reduces the incidence of PNH related thrombosis . A poor response, defined as sustained high levels of LDH during treatment with eculizumab irrespective of improvement of clinical symptoms, has been reported in a subgroup of PNH patients (Nishimura et al, NEJM 2014;370:632-639). These patients had a genetic variant of C5 which occurs in approximately 3.5% of the Japanese and 1% of the Chinese Han populations and interferes with binding of eculizumab to C5. We describe the first patient with no known Asian ancestry with a poor response to eculizumab, who subsequently had a good in vitro response to protein rEV576 (syntheticOrnithodoros moubata complement C5 binding) or coversin. Coversin is a recombinant small protein derived from a tick salivary molecule which binds to C5 and, through steric hindrance, interferes with the access of C5 convertase to the active site and thus prevents cleavage to C5a and C5b in a similar fashion to eculizumab. Our 30-year old male patient commenced treatment with Eculizumab because of PNH (granulocyte clone size: 90%), severe haemolysis (LDH 3-6x ULN, and peak value of 17xULN), transient renal failure, extreme fatigue and erectile dysfunction. He had no history of thrombosis and no underlying bone marrow disease. During eculizumab treatment (dosed 600 mg iv every 7 days, weeks 1-4 and 900 mg biweekly starting in week 5) he felt better, seemed less fatigued and experienced less erectile dysfunction. However, laboratory examination showed sustained elevated markers of hemolysis. Other causes of hemolysis were excluded. Underdosing of eculizumab was ruled out by demonstrating sustained high LDH levels at different time points in between subsequent eculizumab infusions and by measuring trough levels of eculizumab (>100ug/ml). In vitro terminal complement complex blockage by eculizumab through antibody-coated chicken red blood cell lysis was indicative of ongoing active hemolysis in our patient's serum. The presence of Human Anti-Drug Antibodies was excluded using an illuminescent MSD®assay. Treatment was discontinued when the patient experienced increased hemolysis (LDH 9x ULN) and macroscopic hemoglobinuria one day after receiving a dose of 900 mg eculizumab. As expected, discontinuation did not result in further increase of hemolysis parameters or clinical change. To investigate whether a mutation of complement C5 might explain the eculizumab resistance in our patient, DNA analysis of the coding region of C5 was performed. This showed a single C5 heterozygous missense mutation, c.2653C>A, which predicts p.Arg885Ser. This new mutation was very similar to variants previously found in Japanese patients (c.2654G>A, which predicts p.Arg885His) and an Argentinian patient with Asian ancestry (c.2653C>T, which predicts p.Arg885Cys), indicating the importance of this amino acid in C5 recognition by eculizumab. The same mutation was demonstrated in the DNA of our patient's healthy father. Since coversin binds to an epitope on C5 remote from the eculizumab binding site, we hypothesised that it might block C5 cleavage in our patient. Serum samples from our patient and 6 healthy controls were spiked with ascending doses of either eculizumab or coversin and complement activity was measured using a commercially available CH50 Equivalent ELISA (Quidel Corporation ®). In agreement with our in vivo observation eculizumab was incapable of inhibiting CH50 activity in the patient's serum beyond approximately 75%, even at concentrations of 100ug/ml. In contrast coversin, even in concentrations of 10 ug/ml inhibited complement activity completely, both in serum of our patient and serum of healthy controls. We conclude that coversin may prove a useful alternative to eculizumab for patients with resistance due to C5 polymorphisms. Figure 1. Change in serum complement C5 activity in response to ascending doses of coversin (Cov) and eculizumab (Ecu). R2 = patient sample, NC3 = normal control Figure 1. Change in serum complement C5 activity in response to ascending doses of coversin (Cov) and eculizumab (Ecu). R2 = patient sample, NC3 = normal control Disclosures Nishimura: Alexion Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Weston-Davies:Volution Immuno Pharmaceuticals: Employment, Equity Ownership. Nunn:Volution Immuno Pharmaceuticals: Employment, Equity Ownership. Kanakura:Alexion Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mackie:Volution Immuno Pharmaceuticals (Uk) Ltd: Research Funding. Muus:Alexion Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Open-Label, Multicenter, Phase 2/3 Study of Recombinant Crisantaspase Produced in Pseudomonas Fluorescens (RC-P) in Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) Following Hypersensitivity to Escherichia coli-Derived Asparaginases

Blood ◽

10.1182/blood-2019-123710 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2586-2586

Author(s):

Luke Maese ◽

Rachel E. Rau ◽

Elizabeth A. Raetz ◽

Tong Lin ◽

Jin Zhu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Plan ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

E Coli ◽

Equity Ownership ◽

To Receive

Background: L-asparaginase, an important component of ALL therapy, hydrolyzes the nonessential amino acid asparagine, depleting plasma levels and selectively killing leukemic lymphoblasts that are asparagine autotrophs. L-asparaginases are immunogenic and can induce hypersensitivity reactions; high neutralizing antibody titers may limit their therapeutic effect. The inability to receive asparaginase secondary to hypersensitivity has prognostic implications for patients with ALL and has been associated with significantly worse outcomes (Silverman LB, et al. Blood 2001;97:1211-1218; Gupta S, et al. J Clin Oncol. 2019;37[suppl]: Abstract 10005). Alternative preparations are needed to ensure that all patients unable to receive E. coli-derived asparaginase due to hypersensitivity are able to receive adequate treatment. RC-P is a recombinant crisantaspase. Due to the use of a novel Pseudomonas fluorescens technology expression platform, RC-P has no immunologic cross-reactivity to E. coli-derived asparaginases. In a study of RC-P administration in healthy adults (JZP458-101), the enzyme was well tolerated and maintained adequate (≥0.1 IU/mL) serum asparaginase activity (SAA), a surrogate marker for asparagine depletion, for up to 72 hours. Study Design and Methods: This is an open-label, multicenter, dose confirmation and pharmacokinetic (PK) study (JZP458-201) of RC-P in patients with ALL or LBL who develop allergic reactions to an E. coli-derived asparaginase and have ≥1 dose of E. coli-derived asparaginase remaining in their treatment plan (Table). For these patients, 6 doses of RC-P will be substituted for each dose of long-acting E. coli-derived asparaginase. Individual patient treatment duration will vary depending on the number of E. coli-derived asparaginase doses that remain in the patient's original treatment plan. The study will consist of 2 sequential parts: Part A will determine the dose of RC-P for intramuscular (IM) administration and confirm safety and efficacy; Part B will define the optimal dose and schedule of intravenous (IV) RC-P. Blood samples will be collected at prespecified time points to determine SAA levels, and patients will be monitored for adverse events. Immunogenicity of RC-P treatment will also be assessed. The primary objectives are to (1) determine the efficacy of IM RC-P administration measured by the last 72-hour nadir SAA (NSAA) level being ≥0.1 IU/mL during the first course of treatment, and (2) assess the safety and tolerability of IM RC-P in patients with ALL/LBL who are hypersensitive to E. coli-derived asparaginases. Secondary objectives include determination of the efficacy of IM RC-P measured by the last 48-hour and last 72-hour NSAA levels being ≥0.4 IU/mL during the first course, characterization of PK of IM RC-P using a population PK approach, and assessment of immunogenicity following repeat administration of RC-P. Exploratory objectives include determination of the efficacy, safety, PK, and immunogenicity of IV RC-P. Disclosures Raetz: Pfizer: Research Funding. Lin:Jazz Pharmaceuticals: Employment, Equity Ownership. Zhu:Jazz Pharmaceuticals: Employment, Equity Ownership. Kim:Jazz Pharmaceuticals: Employment, Equity Ownership. Chandula:Jazz Pharmaceuticals: Employment, Equity Ownership. McClung:Jazz Pharmaceuticals: Employment, Equity Ownership. Gray:Jazz Pharmaceuticals: Employment, Equity Ownership. Choi:Jazz Pharmaceuticals: Employment, Equity Ownership. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Adamson:Pfizer: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amneal Pharmaceuticals: Equity Ownership; Allergan: Equity Ownership; Gilad Sciences: Equity Ownership; Medtronic: Equity Ownership; Merck: Equity Ownership, Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Eisa: Research Funding; Celator: Research Funding; Seattle Genetics: Research Funding; United Therapeutics: Research Funding; Sanofi/Aventis: Research Funding; Jubilant Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; Cancer Prevention Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Lilly: Research Funding; Springworks: Research Funding; Millennium: Research Funding. OffLabel Disclosure: The abstract presents data from an investigational agent.

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

Blood ◽

10.1182/blood-2019-127523 ◽

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.

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

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

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

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Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽

10.1182/blood-2019-122775 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4739-4739

Author(s):

Pieter Sonneveld ◽

Maria-Victoria Mateos ◽

Adrián Alegre ◽

Thierry Facon ◽

Cyrille Hulin ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Research Funding ◽

Indirect Comparison ◽

Employment Equity ◽

Advisory Committees ◽

Post Transplant ◽

Post Induction ◽

Adjusted Indirect Comparison ◽

Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽

10.1182/blood.v128.22.390.390 ◽

2016 ◽

Vol 128 (22) ◽

pp. 390-390 ◽

Cited By ~ 8

Author(s):

Mark A. Schroeder ◽

H. Jean Khoury ◽

Madan Jagasia ◽

Haris Ali ◽

Gary J. Schiller ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Janus Kinase ◽

Cell Transplant ◽

Employment Equity ◽

Advisory Committees ◽

Daily Dose ◽

Equity Ownership ◽

Grade 3 ◽

Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

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