scholarly journals An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3251-3251 ◽  
Author(s):  
Rami S Komrokji ◽  
Guillermo Garcia-Manero ◽  
Lionel Ades ◽  
Abderrahmane Laadem ◽  
Bond Vo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Dose Finding ◽  
Open Label ◽  
Advisory Committees ◽  
Treatment Start ◽  
Finding Study ◽  
Dose Finding Study ◽  
Dose Levels

Abstract Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells < 13,000/µL). Secondary objectives include rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible pts had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs (serum erythropoietin [EPO] > 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received < 4 units in the 8 weeks prior to treatment start (low transfusion burden; LTB). Nineteen pts (35%) had IPSS Low and 34 pts (63%) had IPSS Int-1-risk MDS; IPSS risk data were missing for 1 pt. Fifty-one pts (94%) had prior treatment with ESAs, 30 (56%) with hypomethylating agents, 26 (48%) with lenalidomide, and 26 (48%) with other MDS treatments; 15 pts (28%) had serum EPO > 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji: Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.

scholarly journals Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4426-4426
Author(s):  
Mahesh Swaminathan ◽  
Amanda Przespolewski ◽  
Elizabeth A. Griffiths ◽  
James E. Thompson ◽  
Amro Elshoury ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Dose Finding ◽  
High Dose ◽  
Advisory Committees ◽  
High Dose Cytarabine ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3

Abstract Background: Thrombocytopenia is prevalent at presentation and following induction chemotherapy (chemo) regimens in patients (pts) with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML). Eltrombopag (EPAG), oral, nonpeptide thrombopoietin (TPO)-receptor agonist, is currently approved for treatment of chronic immune thrombocytopenia, hepatitis-associated thrombocytopenia, and aplastic anemia. It has also been evaluated as a strategy to mitigate chemo-induced thrombocytopenia in pts with solid tumors, myelodysplastic syndrome, and following allotransplant. Prior studies have demonstrated that EPAG can directly inhibit the proliferation of human AML cells in vitro. Although EPAG has been studied following induction and consolidation chemo in the frontline AML setting, to date, the tolerability and efficacy of EPAG in pts receiving salvage chemo for R/R AML is not known. Objectives: This study's objectives were to (a) estimate the maximum tolerated dose (MTD) and tolerability of EPAG, (b) examine platelet (plt) response (defined as plt count ≥ 100 x 10 9/L), and (c) anti-leukemic activity of EPAG in pts receiving high dose cytarabine (HiDAC) and mitoxantrone (Mito) for R/R AML. Methods: In this phase I open-label study, adult pts (³ 18 yrs) with R/R AML with adequate organ functions and grade 4 thrombocytopenia following HiDAC (given every 12 hrs (3 g/m 2 for age &lt; 50; 1.5 g/m 2 for age ≥50) for 12 doses) and Mito (dosed at 12 mg/m 2 x 3 doses every other day) were eligible. All pts must have had marrow hypoplasia demonstrated on Day 14 ± 3 days from the initiation of HiDAC. EPAG was started daily on Day 14 ± 3 days with dose determined using a standard '3+3' dose-escalation design. EPAG was discontinued if an adequate plt response was achieved or following 9 weeks of therapy. The dose-limiting toxicity (DLT) window was defined as the first 15 days of EPAG dosing. Results: Nine pts with R/R AML were enrolled (Table 1). Median age was 64 yrs (range, 33-80), and 5 pts were men. All pts had intermediate (6/9, 67%), adverse (2/9, 22%), or unknown (1/9, 11%) cytogenetic risk disease. One (1/9) pt had NPM1+FLT3-ITD+ disease. Five pts (56%) had relapsed disease (2pts had prior allotransplant). All pts received HiDAC+Mito chemo and started on EPAG on Day 14 ± 3 days. Three received EPAG 150 mg, and 6 pts received 200 mg daily. The median duration on EPAG was 26 days (range, 11-82). One pt experienced a DLT of grade 3 myocardial ischemia while receiving EPAG 200 mg/day and was taken off study. No other DLTs were reported, and no MTD was determined. The most frequent grade ³3 adverse events (AEs, Table 2): were bacteremia (56%), neutropenic fever (44%), and hyperbilirubinemia (33%). Similarly, common grade 1-2 AEs consisted of hyperbilirubinemia, tachycardia, and confusion (33% each, respectively). At a median follow-up of 30.3 months (mo), all 9 pts had discontinued EPAG. Six pts (67%) achieved plt response (3 each in 150 mg and 200 mg/day dose level). The median time to achieve plt response and the duration of plt response was 27 days (range, 14-41) and 40.5 mo (range, 2-49.6), respectively. Three other pts discontinued EPAG therapy: 1 each due to cardiac ischemia, donor lymphocyte infusion, and patient choice, respectively (Table 3). Of note, 7/9 pts (78%) had clinical response: CR in 5 (56%), CRc (CR+CRp) in 6 (67%), MLFS in 1 (11%, Table 4). Two (2/7 responders) went on to subsequent allotransplant, and 6 died; 2-progressive disease, one each from pneumonia, failure to thrive, encephalopathy, and unknown cause, respectively. Among the 6 pts who achieved plt recovery on EPAG, 5 achieved CR and 1-MLFS following HiDAC+Mito. Conclusion: This phase 1 dose-finding study demonstrated that EPAG 150-200 mg daily following HiDAC+Mito chemo for R/R AML was well tolerated with one DLT of cardiac ischemia (200 mg dose). Two-thirds (67%) of pts achieved plt recovery on EPAG after a median of 27 days (range, 14-41). In these small number of pts (n=9), addition of EPAG therapy did not seem to adversely affect clinical outcomes (CRc 67%) and may have contributed to long-term platelet recovery. Further studies are required to determine the optimal schedule and potential benefit of EPAG added to chemo regimens for R/R AML. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Boston Biomedical: Consultancy; Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Elshoury: Bristol Meyers Squibb: Other: advisory board. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Expand: a Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in Patients with Myelofibrosis and Baseline Platelet Counts Between 50 × 109/L and 99 × 109/L

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 177-177 ◽  
Author(s):  
Claire N Harrison ◽  
Heinz Gisslinger ◽  
Carole B. Miller ◽  
Jean-Jacques Kiladjian ◽  
Edric Atienza ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Dose Finding ◽  
Open Label ◽  
Advisory Committees ◽  
Starting Dose ◽  
Finding Study ◽  
Label Dose ◽  
Phase 1B

Abstract Abstract 177 Background: Ruxolitinib (rux) is a potent oral JAK1 and JAK2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of myelofibrosis (MF). In the two phase 3 COMFORT studies, rux demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. Although there has been considerable experience in patients (pts) who developed thrombocytopenia in the COMFORT studies, there has been limited experience in pts with baseline thrombocytopenia as those with platelet counts (PLTs) < 100 × 109/L were excluded. The aims of EXPAND are to evaluate the safety of rux and to establish the maximum safe starting dose (MSSD) in thrombocytopenic MF pts. Methods: Phase 1b, open-label, dose-finding study (NCT01317875) in pts with PMF, PPV-MF, or PET-MF and baseline PLTs 50–99 × 109/L. A Bayesian logistic regression model will be used to guide dose-escalation decisions; intra-pt dose modification is allowed during the study. The study consists of 2 phases: dose escalation and safety expansion. Starting dose of rux is 5 mg bid with a maximum of 15 mg bid. In the dose-escalation phase, cohorts will be: 5 mg bid, 5 mg AM/10 mg PM, 10 mg bid, 10 mg AM/15 mg PM, and 15 mg bid. Pts are assigned to 1 of 2 strata based on their baseline PLTs: stratum 1, 75–99 × 109/L; stratum 2, 50–74 × 109/L. Each dose level in the second stratum will be open only if both that dose and the following one are deemed safe in the first stratum. In the safety-expansion phase, 20 additional pts (10 in each stratum) will be treated at the respective MSSD for their stratum. Results: 14 pts (PMF, n = 10; PPV-MF, n = 3; PET-MF, n = 1) have been enrolled in 4 cohorts: 4 pts in stratum 1/cohort 1 (5 mg bid), 3 in stratum 1/cohort 2 (5 mg AM/10 mg PM), 4 in stratum 1/cohort 3 (10 mg bid), and 3 in stratum 2/cohort 1 (5 mg bid). At baseline, all pts had an ECOG performance status of 0–2, and spleen length ranged from 5–30 cm below the costal margin. 12 pts have completed > 28 days of treatment and are evaluable. 2 pts were nonevaluable: 1 pt discontinued at day 6 due to granulocytic sarcoma, and 1 pt took an incorrect dosage from day 1 to 7 but treatment is ongoing. Reported adverse events (AEs) were similar to those previously seen with rux. 7 pts experienced grade 3/4 AEs (only 2 anemia events were study-drug related), and 4 pts experienced serious AEs (Table). The majority of hemoglobin and absolute neutrophil count (ANC) abnormalities were grade 1 or 2. No pt had a grade 4 decrease in PLTs or ANC; 2 pts experienced a grade 4 decrease in hemoglobin. No pt discontinued due to anemia, neutropenia, or thrombocytopenia. No hemorrhagic events were observed. The lowest PLTs across all pts ranged from 29–96 × 109/L. No dose-limiting toxicities (DLTs) were observed. Reductions in spleen length were reported for all 12 evaluable pts and 1 ongoing nonevaluable pt. Splenomegaly completely resolved in 3 pts. Spleen length reductions were rapid and occurred within the first few weeks of therapy. Conclusions: In this study, no DLT has occurred with the first 3 dose levels in pts with PLTs 75–99 × 109/L or with the first dose level in pts with PLTs 50–74 × 109/L. Rux was generally well tolerated, similar to results reported in previous studies, and no pt has discontinued because of thrombocytopenia. The study is ongoing, and additional pts are being recruited for both strata. Pts are receiving dose levels approaching those approved for nonthrombocytopenic MF pts. Disclosures: Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Gisslinger:Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharmaceuticals AG: Consultancy, Speakers Bureau. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Atienza:Novartis Pharmaceuticals Corporation: Employment. Stalbovskaya:Novartis Pharma AG: Employment, Equity Ownership. Sirulnik:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Al-Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. McMullin:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Shire: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees.

Results from a Phase 1/2, Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2677-2677
Author(s):  
Madeleine Duvic ◽  
Steven M Horwitz ◽  
Youn H Kim ◽  
Pier Luigi Zinzani ◽  
Gajanan Bhat ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Dose Finding ◽  
Advisory Committees ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3 ◽  
Ecog Ps

Abstract Background: Cutaneous T-cell Lymphomas (CTCL) include several variants of extra-nodal non-Hodgkin's lymphomas characterized by their skin lesions and T-cell surface markers. The most common, mycosis fungoides (MF), often has an indolent course but can transform and rapidly disseminate. While skin-directed therapies are effective for early-stage MF, patients with refractory, transformed or late-stage disease require systemic therapy. Methods: Adult patients with CTCL including MF, transformed MF (T-MF), Sézary syndrome (SS), primary cutaneous anaplastic large cell lymphoma (ALCL), ≥ 1 prior systemic therapy, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were eligible and signed consent. FOL was administered weekly via intravenous push for 3 of 4 weeks; BEX was self-administered orally with food. The standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD), with cohort expansion for dose-limiting toxicities (DLTs). The MTD was the highest dose with < 33% DLT incidence in any cohort. DLTs included the following in Cycle 1: ≥ Grade 3 neutropenia (or G-CSF administered), thrombocytopenia, treatment-related non-hematologic toxicity, hyperlipidemia, or hypothyroidism, and treatment-related adverse events (AEs) causing BEX dose omission for ≥10/28 days or FOL dose omission/reduction. Results: In Cohort 1 (15 mg/m2 FOL + 150 mg/m2 BEX), 0/3 patients had DLTs. In Cohort 2a (15 mg/m2 FOL + 300 mg/m2 BEX), 2/3 patients had DLTs: Grade 3 neutropenia and Grade 2 hypotension (n = 1) and Grade 4 neutropenia and thrombocytopenia (n = 1). Therefore, the combination MTD was identified as 15 mg/m2 + 150 mg/m2. An additional 28 patients were enrolled at the MTD for a total of 34 patients (53% male, 47% female) in the study; all have discontinued treatment. The median age was 66 (range 39-85) years, and the median number of prior therapies was 4 (range 2-14). Histology included MF (53%), T-MF (32%), SS (12%), and ALCL (3%). ECOG PS was 0 (68%), 1 (18%), or 2 (15%). Patients received a median of 6 (range 1-33) cycles of therapy. All patients reported ≥ 1 AE. The most common (>20%) FOL-related AEs were mucositis or mucosal inflammation (68%), fatigue (41%), neutropenia and nausea (32% each), and anemia (24%). The most common (>20%) BEX-related AEs were hypertriglyceridemia (56%), fatigue (44%), neutropenia (32%), nausea (26%), and uncorrected hypothyroidism (24%). Grade 3 and 4 AEs were reported for 79% and 9% of patients, respectively: neutropenia (29% and 6%), hypertriglyceridemia (29% and 0%), and stomatitis (21% and 0%) and one Grade 5 AE of respiratory failure. Serious adverse events (SAEs) were reported for 35% of all patients; SAEs in > 1 patient were neutropenia and hypotension (6% each). Dose omissions and reductions for AEs were required for 74% and 21% of patients, respectively. AEs led to discontinuation for 32% of all patients, most commonly stomatitis (9%) and anemia, fatigue, and neutropenia (6% each). The overall Objective Response Rate was 61% (20/33 evaluable patients); 18/30 [60%] in Cohort 1 and 2/3 [67%] in Cohort 2. Four [12%] patients had a complete response, 16 [48%] partial response, 11 [33%] stable disease, and 2 [6%] progressive disease. Duration of Response ranged from 0-29+ months; median Response Duration was not reached, as 14 patients (3 CRs, 11 PRs) remained in response. Median PFS at the MTD was 12.8 (range 0.5-29.9+) months. Table 1. Response by CTCL Subtype Objective Response Rates CTCL Subtype Overall CR PR All Evaluable, n=33 20 (61%) 4 16 ALCL, n = 1 1 (100%) 1 0 MF, n = 19 12 (63%) 2 10 T-MF, n = 10 5 (50%) 1 4 SS, n = 3 2 (67%) 0 2 Conclusions: The combination of FOL + BEX was well tolerated and efficacious in patients with various CTCL subtypes, as measured by response rates (61% including patients with durable CRs) in this dose-finding study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Therakos: Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Consultancy; Allos (spectrum): Research Funding; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Oncoceutics: Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy. Bhat:Spectrum Pharmaceuticals, Inc: Employment.

scholarly journals Safety and Efficacy of Subcutaneous (SC) Blinatumomab for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2303-2303
Author(s):  
Pilar Martínez Sánchez ◽  
Paul Gordon ◽  
Stefan Schwartz ◽  
Giuseppe Rossi ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Steady State ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Finding ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Pharmacodynamic Profile ◽  
Finding Study ◽  
Phase 1B ◽  
Dose Finding Study

Abstract Background Blinatumomab is a BiTE ® (bispecific T cell engager) molecule that engages patients' T cells to the CD19 antigen on lymphoid tumor cells. Blinatumomab administered as a 28-day continuous intravenous infusion (cIV) is approved in multiple regions for the treatment of R/R B-ALL in adults and children. Subcutaneous delivery may improve the convenience and satisfaction of patients with R/R B-ALL who are candidates for blinatumomab therapy. Here we report the results from the first cohort of adults with R/R B-ALL receiving SC blinatumomab. Methods In this ongoing multicenter, single arm, open-label, phase 1b dose-finding study (NCT04521231), patients received multiple cycles of SC blinatumomab. Each cycle included a treatment period and a treatment-free interval. In cohort 1, cycle 1, patients received a lower first dose of SC blinatumomab for several days followed by a higher dose multiple times weekly; in subsequent cycles, patients received the higher dose several times weekly during the treatment period. Bone marrow (BM) evaluation was performed on day 27 of each cycle. Results Six patients from cohort 1 were included in this June 22, 2021 data cutoff. Median age was 64 (range 38-83) years. The number of prior therapies ranged from 2-4. Two patients had disease refractory to primary therapy or salvage therapy, 2 patients relapsed after chemotherapy, and 2 patients relapsed after prior allogeneic hematopoietic stem cell transplant. Median BM blast count at study start was 85% (range 28%-95%). Only 1 patient had &lt;50% BM blasts (BM blasts=28%). At enrollment, all patients had an ECOG score of 0-1. The median number of SC blinatumomab cycles initiated was 1 (range 1-3). Preliminary pharmacokinetic results support the SC dosing intervals used in this study and potentially longer intervals. Exposures for SC doses were similar to the efficacious exposures of the approved cIV regimen: mean average concentrations at steady state of 215 and 853 pg/mL for the lower and higher SC dosing regimens of cohort 1, respectively, vs mean steady state concentrations of 228 and 616 pg/mL for 9 and 28 µg/day cIV dosing, respectively. The pharmacodynamic profile following SC blinatumomab of peripheral immune cell redistribution (circulating CD3+ and CD8+ CD69+ T cells), transient cytokine elevation (IL-6, IL-10, IFN-γ) and CD19+ B cell counts declining below the detection limit was consistent with the historical pharmacodynamic profile following cIV blinatumomab. No grade ≥3 cytokine release syndrome events were reported (Table). One patient developed herpes encephalitis and experienced a grade 5 neurological event unrelated to blinatumomab; no other neurological events were reported. Two patients discontinued treatment because of adverse events (injection site reaction in patient with no response, hyperleukocytosis due to disease progression). Three patients had complete hematological response (CR) with no measurable residual disease (MRD) (&lt;10 -4) within 2 cycles and 1 patient had a morphological partial response (95% BM blasts at start of cycle 1 to 22% blasts on day 15). This patient discontinued on day 15 of cycle 1 after progression of extramedullary disease. At the time of the data cutoff, 2 patients remained on study. These patients had CR with no MRD. Conclusions In this phase 1b dose-finding study, SC blinatumomab has demonstrated encouraging anti-leukemia activity in heavily pretreated patients with R/R B-ALL. Pharmacokinetic and pharmacodynamic results support the use of SC dosing in this population. The safety profile was manageable and consistent with that reported for cIV blinatumomab. Figure 1 Figure 1. Disclosures Gordon: Amgen: Current Employment, Current equity holder in publicly-traded company. Schwartz: Morphosys: Research Funding; Pfizer: Honoraria, Speakers Bureau; Gilead: Other: Travel grants, Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Rossi: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wong: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment. Markovic: Amgen: Current Employment, Current equity holder in publicly-traded company. Katlinskaya: Amgen: Current Employment, Current equity holder in publicly-traded company. Panwar: Amgen: Current Employment, Current equity holder in publicly-traded company. Zugmaier: Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company.

scholarly journals Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3376-3376
Author(s):  
Olga Salamero ◽  
Tim C.P Somervaille ◽  
Antonieta Molero ◽  
Evelyn Acuña-Cruz ◽  
Jose Pérez-Simón ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Therapeutic Options ◽  
Dose Finding ◽  
Open Label ◽  
Advisory Committees ◽  
Platelet Recovery

Abstract Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

scholarly journals A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3675-3675
Author(s):  
David M Ross ◽  
Alejandro Arbelaez ◽  
Lynette C.Y. Chee ◽  
Chun Yew Fong ◽  
Devendra Hiwase ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Phase 2 ◽  
Publicly Traded ◽  
Open Label ◽  
Advisory Committees ◽  
Maximum Increase ◽  
Phase 2 Study ◽  
Dose Levels

Abstract Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB &lt;10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data. Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of Mitapivat (AG-348), an Oral Activator of Pyruvate Kinase R, in Subjects with Sickle Cell Disease: A Phase 2, Open-Label Study (ESTIMATE)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2047-2047
Author(s):  
Myrthe J. van Dijk ◽  
Minke A.E. Rab ◽  
Anita W. Rijneveld ◽  
Erfan Nur ◽  
Marije Bartels ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Health Research ◽  
Research Funding ◽  
Oxygen Affinity ◽  
Dose Finding ◽  
Phase 2 ◽  
Open Label ◽  
Advisory Committees ◽  
2,3 Dpg

Abstract Background Sickle cell disease (SCD) is one of the most common and devastating inherited blood disorders characterized by a single nucleotide mutation in the beta-globin chain leading to the production of mutant hemoglobin S (HbS). HbS polymerizes upon deoxygenation causing red blood cells (RBC) to sickle which results in extremely painful episodes of vaso-occlusive crisis (VOC), severe hemolytic anemia, chronic multiorgan failure and a reduced life span. An important metabolic feature directly associated with RBC sickling is increased intracellular levels of the glycolytic intermediate 2,3-diphosphyglycerate (2,3-DPG) which promotes deoxygenation by lowering the oxygen affinity of hemoglobin (Hb). Pyruvate kinase R (PKR) is a key enzyme in RBC metabolism, generating adenosine triphosphate (ATP) to maintain energy homeostasis, membrane integrity and deformability, and modulates 2,3-DPG levels. Mitapivat (AG-348) is an oral, small molecule allosteric activator of PKR and shows promise as an anti-sickling agent in addition to its effect in PK deficiency and thalassemia. The safety and efficacy of mitapivat in subjects with SCD was evaluated in the dose finding period of this ongoing phase 2 study. Methods The ESTIMATE study is a phase 2, open-label study in which subjects ≥16 years with SCD (HbSS, HbS/β0, HbS/β+) with a baseline hemoglobin &gt;6.1 g/dL and ≤11.1 g/dL, no chronic transfusion and adequate organ function were eligible. In the 8-week Dose Finding Period, initial dosing of mitapivat was 20 mg twice daily (BID). Subjects received a maximum of two sequential dose escalations of mitapivat (i.e. from 20 mg BID to 50 mg BID and 100 mg BID) depending on safety. The primary endpoints were safety, evaluated by frequency and severity of adverse events (AEs), and efficacy of mitapivat on RBC sickling. RBC sickling was evaluated by change in Point of Sickling (PoS), the pO2 at which sickling occurs as measured by oxygen gradient ektacytrometry on the Lorrca (RR Mechatronics). Secondary endpoints included changes in hematological parameters, levels of 2,3-DPG and ATP, Hb-oxygen affinity (p50) and surrogate markers of organ damage and mortality. Subjects who safely tolerated mitapivat and showed evidence of clinical improvement, were eligible to continue a 52-week follow-up period (Fixed Dose Extension Period). Results Six subjects have been enrolled as of September 2020 and completed the Dose Finding Period. All had homozygous HbSS except one patient who had HbS/β0-thalassemia. Baseline characteristics were: median age of 36 years (range 20-59 years), 4 (66.7%) were female and 5 (83.3%) were on stable-dose hydroxyurea. All subjects received dose escalation to a maximum dose of 100 mg BID. No serious adverse events (SAEs) occurred. Adverse events (AEs) were mild and often transient, with the most common treatment emergent AEs: transaminase increase (n=3 [50.0%], Grade 1), gastrointestinal disorders including dyspepsia, diarrhea and abdominal discomfort (n=3 [50.0%], Grade 1) and headache (n=2 [33.3%], Grade 1). One VOC occurred without hospital admission and did not require dose reduction or discontinuation. Table 1 summarizes the anti-sickling effect as well as the hematological and biochemical response to mitapivat treatment. Sickling occurred at lower pO2 levels in all 6 patients during the Dose Finding Period reflected by a significant decrease in treatment week 8 mean PoS compared to baseline. 5/6 subjects (83.3%) achieved a Hb increase of ≥1 g/dL during this period, which was accompanied by a decrease in hemolytic markers. Consistent with activation of PKR, 2,3-DPG levels decreased and ATP levels increased. Additional results including biomarker data will be presented. Conclusion Mitapivat demonstrated an adequate safety profile during the 8-week Dose Finding Period in patients with SCD. The data show promising efficacy in terms of a decrease in the pO2 at which RBCs start to sickle, as well as increase in Hb from baseline and a concomitant decrease in markers reflecting hemolysis. The observed changes in 2,3-DPG and ATP levels are consistent with the proposed mechanism of the drug. The study is ongoing and further data including follow-up data, patient-reported outcomes, PKR activity and thermostability will be reported at a later stage. Figure 1 Figure 1. Disclosures van Dijk: Agios Pharmaceuticals: Research Funding; Axcella Health: Research Funding. Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Rijneveld: Servier: Research Funding; Amgen: Research Funding. Nur: Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Roche: Speakers Bureau. Schutgens: CSL Behring: Research Funding; Novo Nordisk: Research Funding; OctaPharma: Research Funding; Pfizer: Research Funding; Shire/Takeda: Research Funding; Bayer: Research Funding. Wijk: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Beers: Pfizer: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding.

scholarly journals PTG-300 Eliminates the Need for Therapeutic Phlebotomy in Both Low and High-Risk Polycythemia Vera Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-35 ◽  
Author(s):  
Marina Kremyanskaya ◽  
Yelena Ginzburg ◽  
Andrew T. Kuykendall ◽  
Abdulraheem Yacoub ◽  
Jay Yang ◽  
...  
Keyword(s):  
High Risk ◽  
Iron Deficiency ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Finding ◽  
Phase 2 ◽  
Publicly Traded ◽  
Open Label ◽  
Advisory Committees ◽  
Phase 2 Trial

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels &lt;45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Since, they are seen periodically, PV patients likely spend significant time with hematocrit levels &gt;45%, thereby potentially increasing their risk of thrombosis. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis [Ginzburg Leukemia 2018] and worsens after repeated and/or frequent TP, and often symptomatic from their iron deficiency. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies. In a phase 2 trial in β-thalassemia, PTG-300 leads to a sustained (3-7 days) decrease in serum iron and transferrin saturation (TSAT) but did not demonstrate off-target effects. The current study aims to compare the iron status and phlebotomy requirements in high TP-requiring PV patients before and during treatment with PTG-300 (Figure 1). Methods. PTG-300-04 is a 3-part Phase 2 trial consisting of (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3) a 52-week open label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to enrollment. PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly were adjusted to maintain hematocrit &lt;45%. Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. After instruction, each of the patients self-administered the drug at home. Eight subjects have been treated for ≥3 months with PTG-300 (Figure 2a). Three subjects have been randomized. During the open label dose finding portion of the study, all subjects were phlebotomy-free with the exception of one subject. Three subjects completed part 1 (28 weeks) with no TP as compared to 3-5 TP required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two subjects' (Figure 2b). Two subjects had hematocrits transiently &gt;45% but remained below 45% after phlebotomy in one and dose increase in both. Furthermore, erythrocyte numbers decreased (Figure 2c) and MCV increased in all but two subjects. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron-related parameters were consistent with systemic iron deficiency while serum ferritin increased progressively toward normal range. Most frequent adverse events were injection site reaction (ISR) reported by three patients. Most of the reactions were grade 1-2 and were transient in nature and no patient discontinued the drug. Conclusions. The current results indicate that PTG-300 is an effective agent for the treatment of PV, reversing iron deficiency and eliminating the need for TP in PV patients. Elimination of TP requirements for 7 months in TP-dependent PV patients is significant and unexpected. The effect of PTG-300 on PV-related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. PTG-300 looks very promising in eliminating the therapeutic phlebotomies in both low and high-risk patients. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Dynavax: Current equity holder in publicly-traded company. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding; Protagonist: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding. Hoffman:Forbius: Consultancy; Dompe: Research Funding; Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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