Primary Analysis Results from an Open-Label Phase II Study of INCB039110, a Selective JAK1 Inhibitor, in Patients with Myelofibrosis

Abstract Background: Janus kinases (JAKs), including JAK1 and JAK2, mediate the signaling of cytokines and growth factors implicated in the pathogenesis of myelofibrosis (MF). Suppression of JAK2 leads to cytopenias due to its involvement in the signaling pathways of thrombopoietin and erythropoietin. Purpose: The objective of this ongoing study is to evaluate the efficacy and safety of INCB039110, a selective JAK1 inhibitor, in patients with MF with the goal of improving MF-related symptoms with less myelosuppression than seen with JAK1/JAK2 inhibition. Here, we report the 12- and 24-week efficacy and safety of INCB039110 in a phase II trial. Methods: Adults with intermediate-1 or higher (per Dynamic International Prognostic Scoring System [DIPSS]) primary MF (PMF), post–polycythemia vera MF (PPV-MF), or post–essential thrombocythemia MF (PET-MF) were eligible regardless of JAK2V617F mutation status. A platelet count of ≥ 50 × 109/L, hemoglobin ≥ 8.0 g/dL (transfusions permitted), and a palpable spleen or prior splenectomy were required. Patients assessed the severity of 19 disease-related symptoms daily using the modified Myelofibrosis Symptom Assessment Form v3.0 electronic diary. Spleen volume (SV) was evaluated by magnetic resonance imaging or computed tomography at baseline, week 12, and week 24. The primary endpoint was the proportion of patients with a ≥ 50% reduction from baseline in total symptom score (TSS, consisting of the sum of 6 individual symptom scores: night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, and bone/muscle pain) at week 12. Other endpoints included the proportion of patients with a ≥ 50% reduction from baseline in TSS at week 24, percentage change from baseline in TSS at week 12 and 24, percentage change from baseline in SV at week 12 and 24, and safety. The study used a Simon 2-stage design to assess 3 separate dose cohorts (100 mg twice daily [BID], 200 mg BID, and 600 mg once daily [QD]). A dose cohort could be expanded if ≥ 3 of the first 10 patients met the primary endpoint (intent-to-treat method). Results: Enrollment is complete and 87 patients have been treated with INCB039110: 10 in the 100 mg BID, 45 in the 200 mg BID, and 32 in the 600 mg QD groups; 10, 42, and 31 patients, respectively, were evaluable for the primary endpoint. The 200 mg BID and 600 mg QD cohorts met criteria for expansion. Enrolled patients (mean age, 64 years) had PMF (55%), PPV-MF (26%), or PET-MF (18%), and most had intermediate-1 (37%) or intermediate-2 (47%) risk by DIPSS. Mean SV at baseline was 2442.7 cm3, mean hemoglobin was 10.2 g/dL, and mean platelet count was 246.7 × 109/L. Reductions in TSS were similar between the 200 mg BID and 600 mg QD groups, and largely maintained through week 24 (Table). Modest reductions in spleen volume were attained in the 200 mg BID and 600 mg QD groups. TableINCB039110 Dose100 mg BID200 mg BID600 mg QD Patients with ≥ 50% improvement in TSS,* n/N (%)Week 122/10 (20)15/42 (36)10/31 (32)Week 242/10 (20)12/42 (29)11/31 (35) Median change from baseline in TSS,† %Week 12−28.5−45.8−37.2Week 24−57.2−48.6−46.7Median change in SV,† %Week 12−0.5−14.1−14.5Week 24−31.1−17.4−17.1 * Patients who discontinued prior to the week 12 or 24 visit were considered nonresponders at that time point. † Only patients with baseline and week 12 or 24 data were included. Negative change = improvement. Mean platelet count is shown in Figure 1. Mean hemoglobin levels in patients who entered the study without transfusion requirements and did not receive post-baseline blood transfusions are shown in Figure 2. In these patients, the mean percent change from baseline in hemoglobin at week 24 increased by 5.6% in the 200 mg BID group and 8.6% in the 600 mg QD group. The most common nonhematologic adverse events (occurring in > 15% of enrolled patients overall regardless of causality) were fatigue (29%), nausea (21%), upper respiratory tract infection (18%), constipation (17%), diarrhea (17%), and cough (16%); most of these events were grade 1 or 2 and did not appear to be dose dependent. New or worsening grade 3 or 4 anemia occurred in 33% and 0% of patients, respectively, and thrombocytopenia in 24% and 5% of patients, respectively. Conclusions: Patients with MF treated with the JAK1 inhibitor INCB039110 (200 mg BID or 600 mg QD) continued to show meaningful improvements in MF-related symptoms and modest decreases in spleen size, while preserving mean hemoglobin levels over time through week 24. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Mascarenhas: Incyte Corporation: Consultancy. Talpaz:ARIAD, BMS, Sanofi. Incyte, Pfizer: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Savona:Karyopharm: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead : Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene : Membership on an entity's Board of Directors or advisory committees. Paquette:Incyte Corporation: Speakers Bureau. Coughlin:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eastern Health: Employment. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hunter:Incyte Corporation: Employment. Assad:Incyte Corporation: Employment. Clark:Incyte Corporation: Employment. O'Neill:Incyte Corporation: Employment. Hoffman:All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte Corporation: Research Funding.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Randomized Phase II Study Evaluating the Efficacy and Safety of Deferasirox in Non-Transfusion-Dependent Thalassemia Patients with Iron Overload.

Blood ◽

10.1182/blood.v114.22.5111.5111 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5111-5111 ◽

Cited By ~ 1

Author(s):

Ali Taher ◽

John B. Porter ◽

Antonis Kattamis ◽

Vip Viprakasit ◽

Tomasz Lawniczek ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Iron Concentration ◽

Transferrin Saturation ◽

Safety Data ◽

Efficacy And Safety ◽

Thalassemia Intermedia ◽

Advisory Committees

Abstract Abstract 5111 Background Clinically mild forms of thalassemia exist that, unlike β-thalassemia major, require no or only infrequent transfusions (eg. β-thalassemia intermedia, HbH disease). However, due to increased gastrointestinal iron absorption secondary to ineffective erythropoiesis these patients may still develop iron overload. For example, thalassemia intermedia patients (n=74) within a cross-sectional study had a mean serum ferritin (SF) of 1023 ng/mL (range 15–4140) and a mean liver iron concentration (LIC) of 9 mg Fe/g dw (range 0.5–32.1) at baseline despite most being transfusion-naïve (n=20) or rarely transfused (n=45), and only nine receiving regular transfusions (2–4 times/yr) (Taher et al. ITIFPaP: 13th International TIF Conference for Thalassaemia Patients & Parents, October 8–11 2008, Singapore, poster number MON04). Non-transfusional iron overload leads to the same serious clinical sequelae as transfusional iron overload, including liver, cardiac and endocrine dysfunctions. As patients with non-transfusional iron overload are not candidates for phlebotomy due to their underlying anemia, chelation therapy is the only available option for decreasing their iron burden. However, there is currently limited data available on the use of chelation in this population. The once-daily oral iron chelator deferasirox (Exjade®) is currently approved for the treatment of iron overload in patients with transfusion-dependent anemia. This prospective, randomized, double-blind, placebo-controlled Phase II ‘THALASSA’ study will evaluate the efficacy and safety of deferasirox in patients with non-transfusion-dependent thalassemia. Methods Non-transfusion-dependent thalassemia patients aged ≥10 yrs will be randomized 2:1:2:1 to starting doses of deferasirox/placebo 5 mg/kg/day/ deferasirox/placebo 10 mg/kg/day over a planned 12-month treatment period. Doses can be doubled after 6 months should patients require a higher dose, which will be determined after 6 months of treatment. All patients are required to have a baseline LIC of ≥5 mg Fe/g dw, as measured by R2 magnetic resonance imaging, and SF levels of >300 ng/mL. Patients will be excluded if they have: anticipated regular transfusions during the study (sporadic transfusions, such as in cases of infection, are allowed); any transfusion within 6 months prior to study start, chelation within 1 month prior to study start; HbS variants of thalassemia; impaired renal and liver function. Primary efficacy endpoint is absolute change from baseline in LIC at 12 months; secondary efficacy endpoints include change from baseline in LIC after 6 months and in SF after 6 and 12 months, as well as change in hematological and iron metabolism parameters (eg hemoglobin, transferrin saturation). Safety assessments include adverse event and laboratory parameter monitoring. 156 patients are planned for inclusion. Results As of 3 August 2009, 18 sites had been activated. Sites currently activated are in Thailand (n=5), Turkey (n=4), Italy (n=3), Malaysia (n=2), UK (n=2) Lebanon (n=1). Fifty-seven patients have been randomized to either deferasirox or placebo and their demographic data are shown in Table 1. Conclusions Similar to transfusion-dependent thalassemia patients, non- transfusion-dependent thalassemia patients also develop iron overload. This ongoing study will generate prospective efficacy and safety data for the use of deferasirox in non-transfusion-dependent thalassemia patients with iron overload. To prevent long term complications due to iron overload, it is important to assess iron chelation in this patient population as they are not candidates for phlebotomy due to the underlying anemia. Disclosures Taher: Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Pereno:Novartis Pharma AG: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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Long Term Follow up of a Phase 2 Study of Ruxolitinib in Patients with Splanchnic Vein Thrombosis Associated with Myeloproliferative Neoplasm

Blood ◽

10.1182/blood.v126.23.2803.2803 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2803-2803 ◽

Cited By ~ 2

Author(s):

Lisa Pieri ◽

Chiara Paoli ◽

Umberto Arena ◽

Fabio Marra ◽

Fabio Mori ◽

...

Keyword(s):

Platelet Count ◽

Weight Gain ◽

Board Of Directors ◽

Phase Ii ◽

Esophageal Varices ◽

Research Funding ◽

Advisory Committees ◽

Splanchnic Vein Thrombosis ◽

Vein Thrombosis

Abstract Background: Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis, both Primary (PMF) and secondary to PV or ET (PPV-MF and PET-MF). A MPN is frequently the underlying cause of splanchnic vein thrombosis (SVT). Ruxolitinib, a JAK1/2 inhibitor, efficiently reduced spleen volume and improved symptoms in patients (pts) with MF and PV in the COMFORT-I/II and RESPONSE phase III trials, and in ET pts in a phase II study. We reported (Blood 2014 124:3192) that ruxolitinib was safe in pts with MPN associated to SVT and effective in reducing spleen size at the planned primary endpoint analysis at 24 weeks (w) in a phase II clinical trial. Herein we present follow up data with cut off at 1 year after core period (a total of 72 w of treatment). Methods: Main enrolment criteria included diagnosis of PV, ET, PMF or PPV-/PET-MF associated with SVT, splenomegaly >5 cm below costal margin (bcm), active anticoagulant or antiaggregant thrombosis prophylaxis, platelet count (plt) >100 x109/L, neutrophils count >1x109/L, normal hepatic and renal function, absence of esophageal varices >grade 2. Pts who completed the 24 w of study treatment and tolerated well the drug and had evidence of clinically-significant improvement were allowed to enter an extension phase aimed at collecting and reviewing safety and efficacy data. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis. Results: Diagnosis of MPN were: PMF 8 (38.1%), PV 5 (23.8%), ET 4 (19.1%), PPV-MF 3 (14.3%), PET-MF 1 (4.8%). Nineteen pts had spleno-porto-mesenteric thrombosis and 3 Budd-Chiari syndrome (BCS); one pt had both sites involved. Initial dose of ruxolitinib was 10 mg BID for PV, 25 mg BID for ET, 15 mg BID for MF pts with baseline (bl) platelet count of 100 to 200x109/L and 20 mg BID for platelet count >200x109/L. Currently 17/21 pts are on active treatment, 14 completed w72; final data for all 17 pts will be available at meeting. One pt with MF discontinued from the study being shifted to commercial ruxolitinib at w60, one ET and one MF pt discontinued for inefficacy at w24 and one MF pt for an unrelated adverse event after w72. Efficacy: 13/21 (61.9%) pts obtained a ≥50% spleen length (sl) reduction by palpation at w24, that was maintained at w72 in 8/14 pts (57.1%). Median sl reduction at w72 was 63% (range 0-100). No significant differences in resistive or pulsatility index of splanchnic artery were noted, nor in esophageal varices status evaluated at w72. 10/11 evaluated pts with echocardiography at w72 showed a median reduction of the cardiac output of 20.1% (range 2.3-42.2) mainly due to a reduction of heart rate and of cardiac index (-21.9%, range 8.8-44.3) due to increase in body surface area. The first effect could be attributed to decrease of proinflammatory cytokines, the second to weight gain associated with ruxolitinib. Symptomatology was evaluated by MPN-SAF up to w24, showing a median total symptom score reduction from 65 to 42. Safety: regardless of drug relationship, the most common adverse events (AE) (% any grade, % grade ≥3) were thrombocythopenia (57.1%; 14.3%) and anemia (33.3%, 19%) that were the main reasons for dose adjustments. Other AE included AST or ALT increase (42.9%, 0%), diarrhea (28.6%, 0%), abdominal pain (23.8%, 0%), ascites (19%, 0%), fever (23.8%, 0%), neutropenia, (9.5%, 9.5%), upper airways infection (19%, 0%), weight gain (14.3%, 4.8%), muscle cramps (14.3%, 0%). Three serious AE occurred: one case of hepatocarcinoma in a pts with BCS, one grade 2 pneumonia and one grade 2 haematemesis not related to esophageal varices. Median ruxolitinib total daily dose at w72, after dose adjustments, was 19.1 mg for MF, 16 mg for PV and 28.3 mg for ET. Median hemoglobin reduced from 12.9 gr/dL (range 9.4-16.7) at bl to 10.7 (8.4-14.4) at w16 and recovered at w72 (12.1, range 10.8-14.7). No pts received transfusions. Median platelet count was 212 x109/L (100-389) at bl, reached to the lowest level at w4 (139, range 48-252) and improved to 160 (69-285) at w72. Median leukocyte count decreased from 7.3 x109/L (1.8-16.4) at bl to 4.08 (1.2-21.7) at w 24, and remained substantially stable through w 72 (4.96; range 2.45-17.3). Median reduction of JAK2 allele burden at w72 was 9% (range 0-38). Conclusions: At w 72 follow up, ruxolitinib continues to be safe in pts with MPN associated to SVT and maintains efficacy against splenomegaly in 57% of the pts. Disclosures De Stefano: Roche: Research Funding; GlaxoSmithKline: Speakers Bureau; Bruno Farmaceutici: Research Funding; Novartis: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding; Celgene: Speakers Bureau; Shire: Speakers Bureau; Amgen: Speakers Bureau. Barbui:Novartis: Speakers Bureau. Vannucchi:Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

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Successful Treatment of MYC rearrangement Positive Large B Cell Lymphoma Patients with R-CHOP21 Plus Lenalidomide: Results of a Multicenter Phase II HOVON Trial

Blood ◽

10.1182/blood-2018-99-110240 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 786-786 ◽

Cited By ~ 7

Author(s):

Martine E.D. Chamuleau ◽

Marcel Nijland ◽

Josée M Zijlstra ◽

Rogier Mous ◽

P.J. Lugtenburg ◽

...

Keyword(s):

Ct Scan ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Pet Ct ◽

Grade 3 ◽

Pet Ct Scan

Abstract Background: Patients with MYC rearrangement positive large B cell lymphoma other than Burkitt lymphoma (MYC+ LBCL), have a dismal prognosis following standard first line therapy with R-CHOP. Retrospective studies report complete remission rates < 50% and 2-year overall survival (OS) of approximately 35%. Lenalidomide is an immunomodulatory drug and is able to down-regulate MYC and its target genes and proteins in B cells that harbor a MYC rearrangement. We report data of a prospective phase II study evaluating the efficacy of lenalidomide in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients. Methods: A national screening program for MYC rearrangement by fluorescence in situ hybridization (FISH) was performed in newly diagnosed LBCL patients. Patients with a proven MYC rearrangement, ≥ 18 year, Ann Arbor stage II-IV, were offered participation in a single arm phase II study. Treatment consisted of 6 cycles R-CHOP21 plus lenalidomide 15 mg on day 1-14, followed by two additional rituximab administrations. Use of G-CSF was mandatory. All patients received intrathecal methotrexate prophylaxis. 18F-FDG PET-CT (PET-CT) scans were performed at baseline, midterm (after 3 cycles) and end-of-treatment (EOT). Diagnostic lymphoma samples were centrally reviewed including immunohistochemical (IHC) work-up and complementary BCL2 and BCL6 FISH analysis. Cell of origin classification was determined by IHC (Hans) and by gene expression profiling (Lymph2Cx). The primary endpoint was complete metabolic response rate (CMR) on EOT PET-CT scan, according to the Deauville criteria and assessed by 2 independent nuclear medicine physicians performing central review. In case of discordance, a third adjudicator reviewed. Confirmation of bone marrow (BM) negativity at EOT for patients with positive BM at diagnosis was not required for CMR. Secondary endpoints included disease free survival (DFS), progression free survival (PFS), OS and predictive value of midterm PET-CT for EOT PET-CT scan. Data cut-off was July 4th 2018. Results: From April 2015 to February 2018, 85 patients were included at 20 hospitals. Planned interim analysis (after 26 consecutive patients completed treatment) revealed no safety concerns. At data cut-off, central data management, pathology and imaging review processes were completed for the first 60 patients. The remaining patients (60 to 85) are still on treatment or have recently finished treatment. Among the first 60 patients, 2 were declared ineligible, leaving 58 patients for this analysis (demographics and disease characteristics in table 1). Central pathology review confirmed diagnosis of MYC+ LBCL in all patients. Additional FISH analysis revealed that 41/58 patients (71%) had MYC and BCL2 and/or BCL6 rearrangements (double hit or triple hit), 11/58 (19%) had a single MYC rearrangement, 6/58 (10%) had a MYC rearrangement but no information on BCL2 and BCL6. At EOT PET-CT scan (primary endpoint), 36/58 patients (62%) were in CMR (95% confidence interval (CI) 50%-71%). 2/58 patients (3%) reached a partial metabolic response (PMR), and 20/58 patients (34%) had progressive disease (PD). At midterm PET-CT, 39/58 patients (67%) were in CMR; of these 29 were still in CMR and 10 showed PD at EOT PET-CT. 18/58 patients (31%) were in PMR at midterm; 7 of them converted to CMR, 2 remained in PMR, 9 showed PD at EOT. One patient went off protocol after two cycles due to progression. With a median follow-up of 17.2 months, 1-year estimates for OS were 79% (CI 66%-88%), for DFS 74% (CI 59%-85%), and for PFS 60% (CI 47%-72%). Grade 3 and 4 adverse events (AE) were seen in 26 (43%) respectively 9 patients (15%). Most common grade 3-4 AEs were gastrointestinal disorders, infections, and neutropenia. 55 serious AEs were reported in 27 patients (all hospitalization). 1 patient went off protocol due to grade 3 diarrhea. Univariate regression analyses revealed no significant prognostic factors for achieving CMR or prolonged survival yet. Conclusion: These data represent the first prospective trial worldwide for newly diagnosed MYC rearrangement positive LBCL patients. Treatment with R2CHOP demonstrates acceptable toxicity and promising efficacy with 62% CMR on centrally reviewed PET-CT scan and a 1-year OS rate of 79%. In December 2018, all 85 registered patients will have finished treatment and complete analysis of the primary endpoint and additional biological studies will be available. Disclosures Chamuleau: Gilead: Research Funding; celgene: Research Funding; Genmab: Research Funding; BMS: Research Funding. Mous:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; sandoz: Membership on an entity's Board of Directors or advisory committees. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Kersten:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 2a Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Myelofibrosis

Blood ◽

10.1182/blood-2019-123244 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 556-556 ◽

Cited By ~ 11

Author(s):

Kristen Pettit ◽

Aaron T. Gerds ◽

Abdulraheem Yacoub ◽

Justin M. Watts ◽

Maciej Tartaczuch ◽

...

Keyword(s):

Platelet Count ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Once Daily ◽

Equity Ownership

Ruxolitinib (Jakafi®) is the one approved therapy for myelofibrosis (MF) based on reduction of splenomegaly and symptoms but JAK inhibition has not proven to significantly modify disease progression. There remains the need for novel therapies with distinct modes of action that can improve the patient experience of MF and impact progression. Lysine-specific demethylase, LSD1, is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors. LSD1 bound to GFI1b permits maturation of progenitors to megakaryocytes and enables their normal function. IMG-7289 (bomedemstat) is an orally available LSD1 inhibitor. In mouse models of myeloproliferative neoplasms (MPN), IMG-7289 reduced elevated peripheral cell counts, spleen size, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting its clinical development. IMG-7289-CTP-102 is an ongoing, multi-center, open-label study that recently transitioned from a Phase 1/2a dose-range finding study to a Phase 2b study of IMG-7289 administered orally once-daily in adult patients with intermediate-2 or high-risk MF resistant to or intolerant of ruxolitinib. The key objectives are safety, PD, changes in spleen volume (MRI/CT) and total symptoms scores (TSS) using the MPN-SAF instrument. Inclusion criteria included a platelet count ≥100K/μL. Bone marrow (BM) biopsies and imaging studies (both centrally-read) were conducted at baseline and during washout (post-Day 84). The MPN-SAF was self-administered weekly. Phase 1/2a patients were treated for 84 days followed by a washout of up to 28 days. Patients demonstrating clinical benefit could resume treatment for additional 12 week cycles. Dosing was individually tailored using platelet count as a biomarker of effective thrombopoiesis. Patients were started at a presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL. This preliminary analysis includes 20 patients; 18 enrolled in the Phase 1/2a study, 2 in the Phase 2b portion. 50% had PMF, 35% Post-ET-MF, 15% Post-PV-MF. The median age was 65 (48-89) with 70% males. The median baseline platelet count was 197 k/μL (102-1309k/μL). 12 patients (56%) were transfusion-dependent at baseline. Sixty percent were IPSS-classified as high risk, the remainder, intermediate risk-2. 71% had more than 1 mutation of the 261 AML/MPN genes sequenced of which 63% were high molecular risk (ASXL1, U2AF1, SRSF2) mutations; 31% had abnormal karyotypes. Sixteen patients completed the first 12 weeks; 4 patients withdrew, one due to fatigue (Day 33), one for progressive disease (Day 39), one due to physician decision (Day 76), one for an unrelated SAE of cellulitis (Day 83). All patients were up-titrated from the starting dose 0.25 mg/kg to an average daily dose of 0.89 mg/kg ± 0.20 mg/kg, the dose needed to achieve the target platelet count range; 17 achieved the target platelet range in a mean time of 45 days. Of patients evaluable for response after cycle 1 in Phase1/2a (N=14), 50% had a reduction in spleen volume from baseline (median SVR: -14%; -2% to -30%). Further, 79% (N=11) recorded a reduction in TSS (mean change -28%; -13% to -69%); for 21% of patients (N=3), the change was >-50%. Improved BM fibrosis scores at Day 84 were observed in 2/13 patients. Two patients had improvement in transfusion requirements. Plasma IL-8 levels were significantly elevated in 6/14 patients at baseline and dropped in a dose-dependent manner over 21 days in 5/6 patients. The mean duration of treatment is 166 days (14-539) at the census point in this ongoing study. Nineteen patients (95%) reported 358 AEs of which 22 were SAEs. Of the SAEs, 2 were deemed by investigators as possibly related: painful splenomegaly and heart failure. There have been no safety signals, DLTs, progression to AML, or deaths. This is the first clinical study of an LSD1 inhibitor in patients with MPNs. Once-daily IMG-7289 was well-tolerated in a heterogeneous population of patients with advanced MF and limited therapeutic options. Despite under-dosing and slow dose escalation, IMG-7289 improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients. The Phase 2b 24-week expansion study with more aggressive dosing aimed at preserving safety and enhancing efficacy is open for enrollment in the US, UK and EU. Figure Disclosures Pettit: Samus Therapeutics: Research Funding. Gerds:Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy. Yacoub:Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Natsoulis:Imago BioSciences: Consultancy, Equity Ownership. Jones:Imago BioSciences: Employment, Equity Ownership. Talpaz:Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding. Peppe:Imago BioSciences: Employment, Equity Ownership. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rienhoff:Imago Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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Efficacy and Safety Of Fedratinib (SAR302503/TG101348) In Patients With Intermediate- Or High-Risk Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, Or Post-Essential Thrombocythemia (ET) MF Previously Treated With Ruxolitinib: Interim Results From a Phase II Study (JAKARTA-2)

Blood ◽

10.1182/blood.v122.21.661.661 ◽

2013 ◽

Vol 122 (21) ◽

pp. 661-661 ◽

Cited By ~ 11

Author(s):

Claire N Harrison ◽

Nicolaas PM Schaap ◽

Sonja Zweegman ◽

Eric Jourdan ◽

Jean-Jacques Kiladjian ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Symptom Burden ◽

Efficacy And Safety ◽

Advisory Committees ◽

Once Daily ◽

Previously Treated ◽

Grade 3

Abstract Background The JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. Methods JAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. Results At the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. Conclusions Interim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: Harrison: Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity’s Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.

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Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100 × 109/L): A Comparison to Patients with Normal or High Starting Platelet Counts

Blood ◽

10.1182/blood.v120.21.176.176 ◽

2012 ◽

Vol 120 (21) ◽

pp. 176-176 ◽

Cited By ~ 4

Author(s):

Moshe Talpaz ◽

Ronald Paquette ◽

Lawrence Afrin ◽

Solomon Hamburg ◽

Katarzyna Jamieson ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Equity Ownership ◽

Eortc Qlq

Abstract Abstract 176 Background: Ruxolitinib (RUX) has demonstrated clinical benefit for patients with myelofibrosis (MF) with or without the JAK2V617F mutation at starting doses of 15 or 20 mg PO BID by alleviating symptoms, improving quality of life measures, reducing spleen volume and exhibiting an apparent increase in overall survival in the phase III placebo (PBO)-controlled COMFORT-I study. Reversible declines in platelet count and hemoglobin (Hgb) can occur with ruxolitinib but are rarely treatment-limiting. Patients with MF who have low platelet counts represent an important subset of MF patients; given the potential risk of bleeding complications, a dosing strategy for such patients is needed. We assessed an alternative strategy using lower starting doses of ruxolitinib with subsequent dose escalation in patients with MF who have platelet counts of 50–100 × 109/L (Study INCB018424-258; NCT01348490). Methods: RUX dosing started at 5 mg BID. With adequate platelet count, doses could increase by 5 mg once daily every 4 weeks to 10 mg BID. Further increases required evidence of suboptimal efficacy. Assessments include measurement of MF symptoms (MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]); Patient Global Impression of Change (PGIC); EORTC QLQ-C30, measurement of spleen volume by MRI, and safety/tolerability. Results: A total of 50 patients have enrolled, with data available for 41 patients. Nineteen have completed 24 weeks of treatment; >70% of these patients attained a final dose of ≥10 mg BID of RUX. Treatment was generally well tolerated in this study population with no withdrawals for thrombocytopenia or bleeding events. Based on analysis of adverse events, no new safety signals were observed in this population of MF patients with low platelet counts. Data for efficacy parameters, including spleen volume reduction, TSS reduction, and improvement in EORTC-QLQ-C30 subscales and PGIC were consistent with RUX treatment in the COMFORT-I study, and demonstrated clinically meaningful efficacy compared with the COMFORT-I PBO arm (Table). Of 19 patients with platelet count data through Week 24, 5 showed increased platelet count over the duration of the study (range of increase: 20 to 95 x109/L); all 5 patients had optimized dosing to ≥10 mg BID. Compared with the 14 patients showing smaller increases or modest decreases in platelet count, these 5 patients were younger (mean age: 63 years vs. 71 years), had been diagnosed with MF more recently (2.2 years vs. 5.2 years) and had lower DIPSS scores (60% Intermediate-1; 20% Intermediate-2; 20% High vs. 0% Intermediate-1; 79% Intermediate-2; 21% High). Four patients (9.8%) reported adverse events of bleeding (excluding events related to bruising) of any grade (all events were Grade 1 except one Grade 2 hematochezia), consistent with previously reported hemorrhage frequency in the COMFORT-I study (16.8%, RUX; 12.6%, PBO). Conclusions: These preliminary findings suggest that a dosing strategy of a low starting dose of RUX with escalation to 10 mg BID may be appropriate in MF patients who have low platelet counts. Most patients were able to titrate to a dose of ≥10 mg BID of RUX, a dose showing efficacy for both spleen volume and patient-reported outcomes generally consistent with previously reported data from Phase III trials. An increase in platelet counts was observed in approximately one-fourth of patients who completed 24 weeks of RUX treatment. Escalation to, and subsequent maintenance of, a 10 mg BID dose of RUX also preserves both Hgb and platelet count which may be beneficial for MF patients with anemia or thrombocytopenia. Disclosures: Talpaz: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paquette:Incyte: Consultancy. Jamieson:Sunesis: Membership on an entity's Board of Directors or advisory committees; Blue Distinction Centers for Transplants BlueCross BlueShield Association: Consultancy. Lyons:Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Research Funding. Tiu:Incyte: Honoraria, Speakers Bureau. Winton:Incyte Corporation: Consultancy, Honoraria. Odenike:Incyte: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis:Membership on an entity's Board of Directors or advisory committees. Peng:Incyte: Employment, Equity Ownership. Sandor:Incyte: Employment, Equity Ownership. O'Neill:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Leopold:Incyte: Employment, Equity Ownership. Levy:Incyte: Employment, Equity Ownership. Kantarjian:Incyte Corporation: grant support Other. Verstovsek:Incyte Corporation: Research Funding.

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The Efficacy and Safety of Caplacizumab in Japanese Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): An Open-Label, Phase 2/3 Study

Blood ◽

10.1182/blood-2021-148427 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1009-1009

Author(s):

Yoshitaka Miyakawa ◽

Kazunori Imada ◽

Satoshi Ichikawa ◽

Hitoji Uchiyama ◽

Yasunori Ueda ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Japanese Patients ◽

Efficacy And Safety ◽

Open Label ◽

Advisory Committees ◽

Immune Mediated

Abstract Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP), or acquired TTP (aTTP), is a life-threatening thrombotic microangiopathy that requires prompt treatment to improve patient outcomes. Caplacizumab is a von Willebrand factor (VWF)-directed antibody fragment that rapidly inhibits VWF-platelet interaction and prevents microthrombi formation in iTTP. Based on efficacy and safety demonstrated in the Phase 3 HERCULES trial, caplacizumab, in conjunction with therapeutic plasma exchange (TPE) and immunosuppression, is approved in the USA and EU for aTTP. The aim of this Phase 2/3 study (NCT04074187), conducted in Japan, was to evaluate the efficacy and safety of caplacizumab in Japanese patients with iTTP. Methods Japanese patients aged ≥18 years with a clinical diagnosis of iTTP who had received ≤1 TPE were enrolled in this single-arm, open-label study. Patients received caplacizumab in conjunction with TPE and immunosuppression, during daily TPE, and for ≥30 days after discontinuation of TPE. Treatment extension was allowed for ≤8 weeks in case of persistent ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency defined by the investigator and patients were followed for 4 weeks after end of caplacizumab treatment. Primary endpoint was the proportion of patients with a recurrence of iTTP during the overall study period, assessed in the per-protocol (PP) population; recurrence rate ≤20% was the success criterion. Key secondary endpoints were assessed in the PP and modified intention-to-treat (mITT) populations. Treatment-emergent adverse events (TEAEs) were assessed in the safety population. PP population included patients who completed treatment and follow-up per protocol or had a recurrence of iTTP; mITT and safety populations included patients with ≥1 dose of caplacizumab. All analyses were descriptive. The study was conducted in accordance with the Declaration of Helsinki. Results A total of 21 patients were enrolled and treated with caplacizumab; 6 patients discontinued (adverse event: n=2, physician decision: n=4), and 15 patients were included in the PP population. In the mITT population, median age (range) was 59 (22-86) years; 16 (76%) patients presented with an initial episode; median (range) platelet count at baseline was 21.5 (8-78) ×10 9/L;10 (48%) patients received rituximab; median duration (range) of caplacizumab exposure during the overall treatment period was 35 (7-69) days. All patients in the PP population had ADAMTS13 activity <10%. During the overall study period, 1 (7%) patient experienced iTTP recurrence. Median (95% confidence interval [CI]) time to platelet count response was 2.79 (1.76-3.59) days. Additional efficacy endpoints are shown in Table 1. The most common TEAEs were constipation and insomnia, reported in 43% and 29% of patients, respectively (Table 2); 2 treatment-emergent TE events were reported, cerebral infarction and deep vein thrombosis, in 1 patient each. One patient had a treatment-related serious bleeding event of pulmonary alveolar hemorrhage. No deaths occurred during the overall study period (treatment and follow-up). Conclusions In Japanese patients with iTTP, caplacizumab in conjunction with TPE and immunosuppression was associated with a low rate of recurrence of iTTP and fast normalization of platelet count and organ damage markers. These findings are comparable to those in the HERCULES study, in which caplacizumab was associated with 12% recurrence rate and median (95% CI) time to platelet count normalization of 2.69 (1.89-2.83) days (Scully M, et al. N Engl J Med. 2019;380 [4]:335-346). Caplacizumab was well tolerated, and no new safety signals were identified in the Japanese population. Funding This research was funded by Sanofi. Figure 1 Figure 1. Disclosures Miyakawa: Sanofi: Research Funding; Zenyaku Kogyo: Consultancy; Sanofi: Consultancy; argenx: Consultancy, Research Funding. Imada: Celgene Co., Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.,: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria. Ichikawa: Sanofi: Honoraria; AstraZeneca: Honoraria; Chugai: Honoraria. Handa: Daiichi Sankyo: Research Funding; Janssen: Honoraria; BMS: Honoraria; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding. Matsushita: Shire/Takeda: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational and investigational support; CSL Behring: Honoraria; JB: Honoraria; KMB: Honoraria; Nichiyaku: Honoraria; Octapharm: Honoraria; Sysmex: Honoraria; Baltaxa/Shire/Takeda: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Educational and investigational support; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kirin: Honoraria. Hashimoto: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Ohshima: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Tahara: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Tanaka: Sanofi KK: Current Employment, Other: May hold shares and/or stock options. Matsumoto: Sanofi: Consultancy; Takeda: Consultancy; Alexion Pharma: Consultancy; Asahi Kasei Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Alfesa Pharma: Patents & Royalties: ELISA for measuring ADAMTS13 activity.

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Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Blood ◽

10.1182/blood-2019-124330 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 179-179

Author(s):

Jessica K. Altman ◽

Tsila Zuckerman ◽

Olga Frankfurt ◽

Selina M. Luger ◽

Dale L. Bixby ◽

...

Keyword(s):

Board Of Directors ◽

Standard Therapy ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Prior Exposure ◽

Efficacy And Safety ◽

First Line ◽

Advisory Committees ◽

Ongoing Phase

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

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