Long-Term Efficacy and Safety of the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non-Transfusion-Dependent Alpha- or Beta-Thalassemia

Abstract Background: The thalassemias are a group of red blood cell (RBC) disorders in which ineffective erythropoiesis and hemolysis occur due to imbalanced production and precipitation of globin chains. Thalassemic RBCs have insufficient levels of ATP to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses. Mitapivat (AG-348) is a first-in-class, small-molecule, oral activator of RBC pyruvate kinase (PKR), a key enzyme regulating ATP production via glycolysis. In a phase 2, open-label trial of mitapivat in adults with α- or β-non-transfusion-dependent (NTD) thalassemia (NCT03692052), 80.0% (16/20) of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (increase ≥ 1.0 g/dL from baseline at 1 or more assessments between Wks 4-12, inclusive). Improvements in markers of hemolysis and erythropoiesis were also observed in pts and mitapivat was generally well tolerated. Methods: Pts aged ≥ 18 (yrs) with a known medical history of α- or β-thalassemia, Hb concentration of ≤ 10.0 g/dL, and ≤ 5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible for the study. All pts started mitapivat at 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. After completion of the 24-wk core period, pts were continued on mitapivat treatment in the extension period if they had achieved a Hb response, or a delayed Hb response (Hb increase of ≥ 1.0 g/dL at ≥ 1 assessment after Wk 12), with no ongoing grade ≥ 3 treatment-emergent adverse events (AE) related to study drug. Eligible pts continued mitapivat at the dose received at their Wk 24 visit. Study visits are conducted every 12 wks and will continue for up to 10 yrs. The extension period of the study is ongoing, here we report data up to Wk 72 visit (data cutoff March 27, 2021). Results: Of the 19 pts who completed the core period, 17 entered the extension period. During the extension period, 16 pts received 100 mg BID mitapivat and 1 received 50 mg BID. As of the cutoff date, 1 pt had discontinued (patient decision). Median (range, in wks) duration of mitapivat treatment for pts who entered the extension period was 70.9; (54.7, 105.6), with 8 of 17 pts receiving 72 wks or more of treatment as of the cutoff date for this analysis. The Median age of pts who entered the extension period was 44 yrs (range 29, 67). Mean baseline (standard deviation [SD]) Hb, total bilirubin and lactate dehydrogenase (LDH) was 8.1 (1.2) g/dL, 40.1 (26.2) μmol/L and 272.4 (121.7) U/L, respectively. Median baseline erythropoietin (EPO) was 70.5 (range 15, 11191) IU/L. Improvements in Hb concentration achieved in the core period were sustained in the extension study (n = 8 at Wk 72; Figure 1). Mean Hb (SD) increase from baseline to Wk 60 (which includes 4 pts with α- and 9 with β-thalassemia) and Wk 72 (which includes 8 pts with β-thalassemia) were 1.5 (0.4) g/dL and 1.7 (0.5) g/dL, respectively. Improvements in markers of hemolysis and ineffective erythropoiesis observed in the core period were maintained in the extension period up to Wk 72 (mean [SD] bilirubin and LDH, -15.8 [16.6] μmol/L and -63.6 [216.0] U/L, respectively; median [range] EPO, -33.0 [-72.0, -16.0] IU/L). The safety profile was consistent with that observed during the core period. AEs occurring in ≥ 15% of pts during the extension period were headache (5/17) and back pain (3/17), none of which were grade ≥ 3. No notable trends for changes in bone mineral density were observed (Figure 2). There were no treatment-related serious AEs during the extension period. Conclusions: In pts with either α- or β-thalassemia, a favorable efficacy-safety profile was observed with long-term treatment with mitapivat. Results show sustained improvements in Hb, hemolysis and ineffective erythropoiesis - despite the globin genotypic heterogeneity of the cohort - and no new safety findings. Mitapivat, through its unique mechanism of action, may represent a novel therapeutic approach for this condition. Two phase 3 trials of mitapivat in α- and β-thalassemia, one in pts who are NTD and one in pts who are transfusion-dependent, will be initiated in 2021. Figure 1 Figure 1. Disclosures Kuo: Bluebird Bio: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy. Layton: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cerus: Membership on an entity's Board of Directors or advisory committees. Lal: Chiesi: Consultancy; Agios Pharmaceuticals: Consultancy; bluebird bio, Inc.: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Terumo Corporations: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Insight Magnetics: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Al-Samkari: Dova/Sobi: Consultancy, Research Funding; Moderna: Consultancy; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Agios: Consultancy, Research Funding. Bhatia: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tong: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lynch: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Uhlig: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Vichinsky: Agios Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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Risk and Severity of Cytokine Release Syndrome in Patients with Relapsed/Refractory (R/R) AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Blood ◽

10.1182/blood-2021-149366 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3416-3416

Author(s):

Tara L. Lin ◽

Justin M Watts ◽

Alice S. Mims ◽

Prapti Patel ◽

Paul J Shami ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Bispecific Antibody ◽

Study Drug ◽

Survival Outcome ◽

Cytokine Release ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract APVO436 is a recombinant T-cell engaging humanized bispecific antibody designed to redirect host T-cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies. We evaluated the risk, severity, and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose escalation phase of a Phase 1B study (ClinicalTrials.gov identifier: NCT03647800). A total of 46 R/R AML/MDS patients received single agent APVO436 as weekly intravenous infusions at 10 different dose levels, ranging from 0.3 mcg to 60 mcg. CRS was the 7th th most common AE after pyrexia, diarrhea, infusion related reaction, peripheral edema, fatigue, and anemia affecting 10 (21.7%) of the 46 patients. Grade 3-4 CRS was the 6 th most common Grade ≥3 AE following febrile neutropenia, anemia, hyperglycemia, decreased platelet count, and sepsis occurring in 4 of the 46 patients (8.7%) treated with APVO436 in Study 5001 regardless of any relationship with the study drug APVO436. CRS was reported as an SAE in 7 (70%) of the 10 patients who developed CRS. CRS lead to dose interruptions in 4 patients, dose reduction in 1 patient, and permanent discontinuation of the study drug in 1 patient. Only 2 of the 46 patients experienced DLT and it was related to CRS in both patients. One patient treated in Cohort 4 who developed grade 2 CRS died due to complications from acute renal failure. Notwithstanding the fact that it is a potentially life-threatening complication, CRS did not significantly affect the overall survival outcome of the safety population (Figure 1). The average survival times were 169.1±42.1 days for patients who developed CRS and 173.9±27.2 days for the remainder of patients (P=0.9) (Table 1). The median survival was 188 days for patients with CRS and 151 days for those without CRS (Log-rank C 2 = 0.042, P=0.7) (Figure 1). Premedication with steroids (Dexamethasone) did not eliminate the risk of CRS. Of 4 patients who developed Grade ≥3 CRS, 2 had received steroid prophylaxis. Notably, CRS did not show an apparent dose-relationship. The average dose levels were 0.28±0.21 (Median: 0.19) µg/kg for those patients who developed CRS and 0.28±0.27 (Median: 0.20) µg/kg for those who did not develop CRS (P=0.97). There was a borderline significant age difference between patients who did versus patients who did not develop CRS (72.9±1.6 years [Median 73.5 years] vs. 63.3±2.3 years [Median: 65.0 years] (P=0.04). Diagnosis, dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS (Table 1). There was a statistically insignificant (P=0.1) trend toward higher absolute lymphocyte count (ALC) for patients who experienced CRS. Patients with a higher leukemia burden, as determined by higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood did not have a higher incidence of CRS. Cytokine profiling in select patients who developed Grade 2-4 CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response is IL-6: Within 1-2 days following the first dose of APVO436, the mean serum IL-6 concentration was elevated 145-fold over baseline (755 vs 5.2) and at the end of one week it was still elevated 83-fold over baseline. APVO436-associated CRS was generally manageable with standard of care and in most cases it resolved rapidly with the administration of tocilizumab at standard doses combined with dexamethasone. APVO436-related CRS was not required for clinically meaningful responses in R/R AML patients, and it did not affect their survival outcome. Notably patients who developed CRS after APVO436 therapy were not more or less likely to have a favorable response. Among 8 patients with favorable responses, 4 experienced a CRS and 4 did not. APVO436-related CRS was not required for clinically meaningful responses in R/R AML patients, and it did not affect the survival outcome. Prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS as well as patients who did not experience CRS after APVO436 infusions. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Watts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Mims: Kura Oncology: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi-Saynko: Consultancy; Glycomemetics: Research Funding; Leukemia and Lymphoma Society: Consultancy; Aptevo: Research Funding; Xencor: Research Funding. Patel: Peerview: Honoraria; BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding. Shami: Chimerix: Research Funding; BMS: Consultancy; Gilead: Consultancy; Takeda: Consultancy; Chimerix: Research Funding; Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Aptevo: Research Funding. Cull: Aptevo: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Lee: oncotelic therapeutics: Current equity holder in publicly-traded company; Aptevo therapeutics: Consultancy. Uckun: oncotelic therapeutics: Current equity holder in publicly-traded company; Aptevo therapeutics: Consultancy; Reven Pharmaceuticals (Reven LLC): Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽

10.1182/blood-2019-123406 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3512-3512

Author(s):

Rachael F. Grace ◽

D. Mark Layton ◽

Frédéric Galactéros ◽

Wilma Barcellini ◽

Eduard J. van Beers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

The Core ◽

Equity Ownership ◽

Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses >25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽

10.1182/blood.v114.22.3286.3286 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3286-3286 ◽

Cited By ~ 5

Author(s):

Philipp D. le Coutre ◽

Anna Turkina ◽

Dong-Wook Kim ◽

Bernadeta Ceglarek ◽

Giuliana Alimena ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Study Drug ◽

Cytogenetic Response ◽

Efficacy And Safety ◽

Advisory Committees ◽

Imatinib Resistant ◽

Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

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Updated Interim Results of the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Patients with Relapsed or Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) (CC-5013-CLL-009 Study)

Blood ◽

10.1182/blood.v120.21.3925.3925 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3925-3925 ◽

Cited By ~ 2

Author(s):

Clemens Wendtner ◽

Michael Hallek ◽

Graeme Fraser ◽

Anne-Sophie Michallet ◽

Peter Hillmen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Median Number ◽

Advisory Committees ◽

Starting Dose ◽

Purine Analog ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.

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A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2021-150049 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3411-3411

Author(s):

Maro Ohanian ◽

Martha L. Arellano ◽

Moshe Y. Levy ◽

Kristen O'Dwyer ◽

Hani Babiker ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

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Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-140641 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25 ◽

Cited By ~ 1

Author(s):

Sham Mailankody ◽

Jeffrey V. Matous ◽

Michaela Liedtke ◽

Surbhi Sidana ◽

Shahbaz Malik ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Assessment ◽

Publicly Traded ◽

Advisory Committees ◽

Oncology Research ◽

Car T ◽

Grade 3 ◽

Dose Levels

Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges, availability and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR Ttm cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted with Talen® technology to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion (LD). Methods This is an open-label, Phase 1 trial (NCT04093596) in adults with R/R multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Patients receive LD followed by ALLO-715 at 1 of 4 dose levels (DL) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated. These include: FCA (fludarabine (F) 90 mg/m2, cyclophosphamide (C) 900 mg/m2, and ALLO-647 (A) 39 mg divided over 3 days), FCA+ (same F and C but ALLO-647 (A+) dose of 90 mg divided over 3 days); as well as CA (same C and A divided over 3 days, but no F given). Results As of 08 July 2020, 19 pts had enrolled and 15 had received ALLO-715 at 3 DLs: 3 pts at DL1 (3 FCA and 0 CA); 7 pts at DL2 (4 FCA and 3 CA); 5 pts at DL3 (3 FCA and 2 CA). As of the data cutoff, no pts had received FCA+ or ALLO-715 DL4. Patients were heavily pre-treated and in advanced stage of disease with a median of 5 (range 3-11) prior lines of therapy and 31.6% ISS Stage III at screening. All but 1 had a prior autologous stem cell transplant. 52.6% (10/19) of patients had high risk cytogenetics, and 26.3% (5/19) had extramedullary disease. The most common Grade ≥3 adverse events were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). Four episodes of Grade ≥3 infections occurred in 4 pts. Three of these were Grade 3 and included parvovirus B19, staphylococcal bacteremia, and pneumonia, which resolved with treatment. The fourth was a Grade 5 episode that occurred on day 8 post-ALLO-715 infusion in a rapidly progressing, refractory myeloma pt who, on day 1, developed a non-neutropenic fever and multifocal pneumonia with negative blood and sputum cultures. The patient progressed to respiratory failure and only comfort care was pursued. This death was considered related to conditioning (CA). No DLTs to ALLO-715 had been reported as of the data cutoff. In addition, no neurotoxicity (ICANS) or GvHD had been reported as of the data cutoff. Cytokine release syndrome was reported in 4 pts (24%). Three episodes were Grade 1 and 1 was Grade 2 (Lee Grading); all resolved without tocilizumab or corticosteroids. Fifteen pts were efficacy evaluable (defined as receiving ALLO-715, and undergoing at least one response assessment or discontinuing prior to the first response assessment), with a median follow-up of 2 months (range 0, 10 months). A higher dose of ALLO-715 (DL3) was associated with greater anti-cancer activity with 3/5 pts responding per IMWG (60%, 95% CI 14.7, 94.7). In pts who received DL3 FCA, 2/3 responded (1 sCR and 1 VGPR, Table 1). All DL3 pts who responded experienced at least a VGPR and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14. Four (80%) out of the 5 responders were still in response at the time of the data cutoff. ALLO-715 cell expansion by qPCR was observed at all dose levels. Conclusions These early data suggest that ALLO-715 and ALLO-647 have a manageable safety profile. ALLO-715 shows evidence of clinical activity in the allogeneic setting in pts with R/R multiple myeloma and suggests that higher cell doses are associated with greater anti-cancer activity. Enrollment is ongoing in cohorts with higher ALLO-715 (480M CAR+ T-cells) and ALLO-647 (90mg). Updated safety, efficacy, PK/PD data will be presented. Clinical trial information: NCT04093596. Disclosures Mailankody: Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sidana:Janssen: Consultancy. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Karski:Crisper Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lovelace:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhou:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Balakumaran:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Ended employment in the past 24 months. Hari:BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; GSK: Consultancy; Incyte Corporation: Consultancy.

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Updated Results from an Open-Label, Multicenter, Expanded Treatment Protocol (ETP) Phase (Ph) 3b Study of Ruxolitinib (RUX) in Patients (Pts) with Polycythemia Vera (PV) Who Were Hydroxyurea (HU) Resistant or Intolerant and for Whom No Alternative Treatment (Tx) Was Available

Blood ◽

10.1182/blood-2018-99-111479 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1774-1774 ◽

Cited By ~ 2

Author(s):

Lynda Foltz ◽

Gian-Matteo Pica ◽

Hacene Zerazhi ◽

Jan Van Droogenbroeck ◽

Sorin Visanica ◽

...

Keyword(s):

Cell Carcinoma ◽

Board Of Directors ◽

Research Funding ◽

Blood Count ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Medical Need ◽

Equity Ownership ◽

Grade 3

Abstract BACKGROUND Few Tx options are available for pts with inadequately controlled PV. European LeukemiaNet defined resistance/intolerance was seen in ≈25% pts treated with HU (Alvarez-Larran et al, 2012). In the HU-resistant/intolerant PV pts evaluated in the pivotal RESPONSE study (week [wk] 208), RUX was well tolerated and superior to standard therapy in achieving durable hematocrit (HCT) control, hematologic response, and spleen size and symptom reductions. This Ph 3b ETP study was planned to provide RUX Tx to HU-resistant/intolerant PV pts, who have no alternative standard Tx, and are not eligible for any ongoing clinical studies. Results from wk 24 data cutoff of this study (Devos et al) were presented at ASH 2017. Here, we report consolidated findings from the ETP study at wk 96 data cutoff (Dec 29, 2017 [final database lock]) to further support the use of RUX in this pt population with an unmet medical need. METHODS RUX Tx was initiated at a starting dose of 10 mg bid (could be titrated to a maximum of 25 mg bid). Visits were scheduled every 4 wks until wk 24 and every 12 wks thereafter; final analysis was done when all pts had been followed for 30 days after discontinuation of Tx or completion of Tx per protocol (transitioned to commercial RUX or until Dec 31, 2017, whichever date occurred first). The primary endpoint was to assess the safety of RUX. Secondary endpoints included change in HCT level, change in spleen length, and pt-reported outcomes (change in MPN-SAF TSS score). HCT control at wk 24 was defined by absence of phlebotomy (PBT) eligibility starting at wk 8 and continuing through wk 24, with no more than 1 PBT eligibility occurring after first dose date and prior to wk 8. PBT eligibility was defined by confirmed HCT >45% (at least 3 percentage points higher than HCT at baseline [BL]), or confirmed HCT >48%. Blood count remission at wk 24 was defined by HCT control, and white blood cell count <10 × 109/L, and platelet count ≤400 × 109/L. RESULTS At data cutoff, 161 pts with PV were enrolled (BL characteristics similar to that presented at ASH 2017). End of Tx was reported for all 161 pts: Tx duration completed per protocol (141 pts), adverse event (AE [12 pts]), consent withdrawal (3 pts), pt decision (2 pts), disease progression (2 pts), and death (due to accident [1 pt]). The median exposure was 25.1 wks (range, 0.4-104.7), and median dose intensity of RUX was 20.0 mg/day (range, 6.7-47.7). AEs (regardless of study drug relationship) led to dose adjustment/interruption in 37.9% pts and study drug discontinuation in 8.7% pts. The most common hematologic AEs (rate=number of events per 100 pt-year exposure [pt-year exposure=110.2]; all grades]) included anemia (31.8) and thrombocytosis (10.0), while headache (24.5), diarrhea (14.5), constipation (12.7), and fatigue (12.7) were the most frequent non-hematologic AEs. For all reported grade 3/4 AEs, exposure-adjusted rate was less than 3. Thromboembolic events (all grade; Standardized MedDRA Query) were reported in 3 pts. Disease progression was reported in 4 pts (myelofibrosis=3 pts; acute myeloid leukemia=1 pt). The incidence of other neoplasms (regardless of study drug relationship) was low (leiomyoma, malignant melanoma, marginal zone lymphoma, renal cancer [1 pt each]; squamous cell carcinoma [2 pts]; basal cell carcinoma [3 pts]). Infections (all grades) were reported in 57 pts (grade 3/4 in 5 pts). At wk 24, 73 pts (45.3% [95% CI, 37.5%-53.4%]) achieved HCT control; hematologic remission was seen in 29 pts (18% [95% CI 12.4%-24.8%]). Changes in blood count parameters over time are shown in Fig. 1. In evaluable pts (N=105), use of PBT decreased from BL (39 PBTs between screening and BL) to end of Tx (5 PBTs in 12 wks prior). Best spleen response from BL for each pt by wk 96 is shown in Fig. 2. At least 50% spleen length reduction was seen in 86.7% (78/90) of pts from BL at any time in the study. Overall, 33.8% (46/136) of pts had ≥50% reduction in MPN-SAF TSS from BL at the end of Tx. CONCLUSION The observed safety profile of RUX in the ETP study was consistent with that of the RESPONSE studies. Efficacy results were close to the observed values in the RESPONSE studies. RUX Tx resulted in HCT control, hematologic remission, spleen response, and symptom reduction in this HU-resistant/intolerant pt population in need of a viable Tx option. Safety and efficacy findings from this ETP study support the use of RUX for pts with inadequately controlled PV, an unmet medical need. Disclosures Foltz: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. de Almeida:Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ranta:Novartis: Consultancy. Cartes:Novartis: Honoraria. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chrit:Novartis: Employment, Equity Ownership. Yin:Novartis: Employment. Morando:Novartis: Employment, Equity Ownership. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

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Blinatumomab in Children with Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R-ALL): Final Results of 110 Patients Treated in an Expanded Access Study (RIALTO)

Blood ◽

10.1182/blood-2020-141336 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Noemi Mergen ◽

Peter Bader ◽

Sima Jeha ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Final Analysis ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Grade 3

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and <18 years of age with R/R CD19+ BCP-ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [alloHSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks on and 2 weeks off) for up to 5 cycles and safety follow-up visit 30 days post-treatment. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow-cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and alloHSCT rate after blinatumomab treatment. Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3) remain unchanged compared with the primary analysis (Table 1). For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 92% (n=11) achieved CR and MRD response; 75% (n=9) proceeded to HSCT (Table 2). Of the 5 patients who had received prior blinatumomab , 4 achieved CR. Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

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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 ◽

10.1182/blood-2021-147335 ◽

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 <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.

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A Lysa Phase II Study of Oral JAK1/2 Inhibitor Ruxolitinib in Advanced Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

Blood ◽

10.1182/blood.v128.22.4160.4160 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4160-4160 ◽

Cited By ~ 2

Author(s):

Eric W Van Den Neste ◽

Marc Andre ◽

Thomas Gastinne ◽

Aspasia Stamatoullas ◽

Corinne Haioun ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Study Drug ◽

Median Number ◽

Primary Objective ◽

Additional Treatment ◽

Advisory Committees ◽

Grade 3

Abstract Background: JAK2 constitutive activation/overexpression is frequent in classical HL tumor cells and many autocrine/paracrine cytokines stimulate HL cells by recognizing JAK1- or JAK2-bound receptors. Thus, JAKs blockade may be of therapeutic value in HL. Methods: A phase II study (HIJAK study)was conducted to evaluate safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in R/R HL, given at 20 mg bid for 6 cycles of 28 days. Dosage at 15 mg bid was planned for patients with platelets comprised between 75 and 200 x 109/L at inclusion. Patients with platelets < 75 x 109/L, neutrophils < 1000 x 109/L were excluded. Maintenance beyond 6 cycles was permitted if disease control. The primary objective was overall response rate (ORR, Cheson 2007) at 6 cycles. Secondary objectives were safety, B symptoms relief, best ORR, response duration, PFS and OS. To be evaluable for response and survivals, patients had to receive at least one cycle of the study drug. The safety set included all patients who received at least one dose of ruxolitinib. Median follow-up was 27.1 months (95% CI: 14.4-27.1). Results: 33 patients were included between Jul 2013 and Dec 2014 in 10 LYSA centers in France and Belgium: M/F, 21/12; median age 37 (range 19-80) years; stage III/IV, 75.8%; B symptoms, 51.5%; median number of prior lines, 5 (range 1-16); prior transplantation, 60.6%; prior radiotherapy, 54,5%; prior brentuximab vedotin (BV), 82%; refractory to last therapy, 81.8%. Overall, median number of ruxolitinib cycles was 4. Nine (27.3%) patients received at least 6 cycles and 6 (18.2%) maintenance. ORR at the end of induction was 3/32 (9.4%) patients, all PRs. Best ORR at any time during study was 18.8% (6/32) with five PRs and 1 patient who converted into CR beyond 6 cycles. Transient stable disease was noted in 11 patients. Rapid and durable alleviation of B-symptoms (pruritus, fever, sweating) was frequently noted, especially pruritus which was present in 35.5% of patients before treatment and 6.6% of them after one cycle of ruxolitinib. Median duration of response was 7.7 months (95% CI: 1.8-NA). Two patients remain on therapy. Median PFS was 3.5 months (95%CI: 1.9-4.6) and median OS was 27.1 months (95%CI: 14.4-27.1). Using bead-based immunoassays, plasma levels of 27 cytokines related to the immune system were measured at baseline and after cycle 1. Before ruxolitinib, there was no difference in cytokine levels between responders and non-responders. In responders, the only cytokine that significantly decreased was CX-CL10 (P.01). In patients presenting with pruritus (n=11), PDGF-BB, IL-5, IL-10, IL-12, IL-13, IL-17, eotaxin, FGF basic, MIP1b, rantes, and VEGF were significantly increased. In the latter patients, ruxolitinib treatment significanlty decreased PDGF-BB, IL-10, IL-12, IL-13, IL-17, FGF basic and VEGF. Among patients who were analyzable for JAK2 amplification in RS cells (n=12), polysomy was detected in all of them and specific JAK2 amplification in one. Further analysis of Jak2 targets by IHC will be performed. 40 adverse events (AEs) were reported in 14/33 patients (42.4%), of which 18 were related to ruxolitinib and 18 were grade ≥ 3. One AE led to permanent treatment discontinuation. No AE leading to death was reported. 87.5% of AEs recovered without sequelae. Eight SAEs (infection, 3; anemia, 1; diarrhea, 1; subdural hematoma, 1; bone pain, 1; pulmonary embolism, 1) were reported in 4 patients (12.1%), of which 2 were related to ruxolitinib. No grade 4 neutropenia and 1 grade 3/4 thrombocytopenia was observed. Five patients had grade 3 anemia. Twelve patients died due to lymphoma (83.3%) or toxicity of additional treatment (8.3%) or other reason (8.3%). Among 30 patients who progressed (initial site in 97% and/or new site in 60%), 25 (83.3%) were retreated: with chemotherapy in 19 (comprising bendamustine in 10) and/or immunotherapy in 9 (rituximab, n=4; BV, n=3; nivolumab, n=2). Transplantation was eventually performed in 5/25 (4 allogenic, 1 autologous). In the 25 patients who were retreated, CR/PR rates were 10/15%, respectively. Conclusions: Ruxolitinib shows hints of activity beyond simple anti-inflammatory action in highly advanced, mostly refractory, HL patients, although most responses are short-lived. Toxicity was limited suggesting potential to be combined with other modalities. Further treatment, beyond ruxolitinib, was possible in most patients, even with chemotherapy. Disclosures Haioun: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Ghesquieres:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Roche France: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria.

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